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3.A.1.1:  The Carbohydrate Uptake Transporter-1 (CUT1) Family

Maltooligosaccharide porter. The 3-D structure has been reported by Oldham et al. (2007). An altering access mechanism has been suggested for the maltose transporter resulting from rigid-body rotations (Khare et al., 2009). The maltose-binding protein is open in the catalytic transition state for ATP hydrolysis during maltose transport (Austermuhle et al. 2004). Bordignon et al. (2010) and Schneider et al. (2012) reviewed the extensive knowledge available on MalEFGK2, its mode of action and its regulatory interactions.  The transporter sequesters the MalT transcriptional activator at the cytoplasmic surface of the membrane in the absence of the transport substrate (Richet et al. 2012).  The crystal structures of the transporter complex MBP-MalFGK2 bound with large malto-oligosaccharide in two different conformational states have also been determined. In the pretranslocation structure, Oldham et al. 2013 found that the transmembrane subunit MalG forms two hydrogen bonds with malto-oligosaccharide at the reducing end. In the outward-facing conformation, the transmrembrane subunit MalF binds three glucosyl units from the nonreducing end. These structural features explain why large modified malto-oligosaccharides are not transported by MalFGK2 despite their high binding affinity to MBP. In the transport cycle, substrate is channeled from MBP into the transmembrane pathway with a polarity such that both MBP and MalFGK2 contribute to the overall substrate selectivity of the system (Oldham et al. 2013).  Stabilization of the semi-open MalK2 conformation by maltose-bound MBP is key to the coupling of maltose transport to ATP hydrolysis in vivo, because it facilitates the progression of the MalK dimer from the open to the semi-open conformation, from which it can proceed to hydrolyze ATP (Alvarez et al. 2015). Both the binding of MalE to the periplasmic side of the transmembrane complex and binding of ATP to MalK2 are necessary to facilitate the conformational change from the inward-facing state to the occluded state, in which MalK2 is completely dimerized (Hsu et al. 2017). An integrated transport mechanism of the maltose ABC importer has been proposed (Mächtel et al. 2019).

MalEFGK of E. coli
MalE (receptor [R])
MalF (membrane [M])
MalG (membrane [M])
MalK (cytoplasmic [C])

The galactooligosaccharide (transports the di, tri and tetrasaccharides) uptake porter GanOPQ (GanSPQ; MalEFG) functioning with the energizing ATPase MsmX (see 3.A.1.1.26).  These oligosaccharides are derived from galactans and arabinogalactans, compenents of pectins in plant cell walls (Watzlawick et al. 2016).

GanOPG of Bacillus subtilis
YufK, GanO or GanS (R) (O07009)
YufL or GanP (M) (O32261)
YufM or GanQ (M) (O07011) MsmX (C) (see 3.A.1.1.26)

Glycerol-phosphate porter. Transports both glycerol-3-P and glycerol-3-P diesters including glycerophosphocholine but not glycerol-2-P (Yang et al. 2009; Wuttge et al. 2012).  UgpB (the receptor) binds glycerol 3-P with high affinity, but not glycerol 2-P (Wuttge et al. 2012).  UgpB (the receptor) binds glycerol 3-P with high affinity, but not glycerol 2-P (Wuttge et al. 2012).

UgpABCE of E. coli
UgpB (R)
UgpA (M)
UgpE (M)
UgpC (C)

Lactose porter
LacEFGK of Agrobacterium radiobacter
LacE (R)
LacF (M)
LacG (M)
LacK (C)

Hexitol (glucitol; mannitol) porter
SmoEFGK of Rhodobacter sphaeroides
SmoE (R)
SmoF (M)
SmoG (M)
SmoK (C)

Cyclodextrin porter
CymDEFG of Klebsiella oxytoca
CymE (R)
CymF (M)
CymG (M)
CymD (C)

Maltose/trehalose porter
MalEFGK of Thermococcus litoralis
MalE (R)
MalF (M)
MalG (M)
MalK (C) (not sequenced)

Sucrose/maltose/trehalose porter (sucrose-inducible)
AglEFGK of Sinorhizobium meliloti
AglE (R)
AglF (M)
AglG (M)
AglK (C)

The oligosaccharide (glucuronate-linked to a xylo-oligosaccharide) ABC uptake porter, GuoEFGK in AguEFGK. GuoE binds with high affinity a four sugar aldotetrouronic
acid [2-O-α-(4-O-methyl-α-D-glucuronosyl)-xylotriose] (Shulami et al., 1999; S.Shulami, personal communication)

GuoEFGK of Geobacillus stearothermophilus
AguE or GuoE (R) (C9RT46)
AguF or GuoF (M) (Q09LY7)
AguG or GuoG (M) (Q09LY6)
AguK or GuoK (C) (not identified)

Alginate (MW 27,000 Da) (and Alginate oligosaccharides) uptake porter. ABC transport system, AlgQ1AlgM1AlgM2(AlgS)2: AlgS, 363 aas, BAB03314; AlgQ1, 502 aas, 3VLW_A;  AlgM1, 324 aas, BAB03315.1; AlgM2, 293 aas, BAB03316.1. Sphingomonas species A1 is a 'pit-forming' bacterium that directly incorporates alginate into its cytoplasm through a pit-dependent transport system, termed a 'superchannel' (Murata et al., 2008). The pit is a novel organ acquired through the fluidity and reconstitution of cell surface molecules, and through cooperation with the transport machinery in the cells. It confers upon bacterial cells a more efficient way to secure and assimilate macromolecules (Murata et al., 2008).  The substrate-transport characteristics and quaternary structure of AlgM1M2SS with AlgQ1 have been determined (Maruyama et al. 2015). The addition of poly- or oligoalginate enhanced the ATPase activity of reconstituted AlgM1M2SS coupled with one of the periplasmic solute-binding proteins, AlgQ1 or AlgQ2. External fluorescence-labeled oligoalginates were specifically imported into AlgM1M2SS-containing proteoliposomes in the presence of AlgQ2, ATP, and Mg2+. The crystal structure of AlgQ2-bound AlgM1M2SS adopts an inward-facing conformation. The interaction between AlgQ2 and AlgM1M2SS induces the formation of an alginate-binding tunnel-like structure accessible to solvent. The translocation route inside the transmembrane domains contains charged residues suitable for the import of acidic saccharides (Maruyama et al. 2015). 

This bacterium  is a Gram-negative rod, containing glycosphingolipids in the cell envelope, and is named Sphingomonas sp. strain A1 (Murata et al. 2022). The pit was dynamic, with repetitive opening and closing during growth on alginate, and directly included alginate concentrated around the pit, particularly by flagellins, alginate-binding proteins, localized on the cell surface. Alginate incorporated into the periplasm was subsequently transferred to the cytoplasm by cooperative interactions of periplasmic solute-binding proteins and an ATP-binding cassette transporter in the cytoplasmic membrane. The mechanisms of assembly, functions, and interactions between the above-mentioned molecules were clarified using structural biology. The pit was transplanted into other strains of sphingomonads, and the pitted recombinant cells were effectively applied to the production of bioethanol, bioremediation for dioxin removal (Murata et al. 2022). The outer membranes of Sphingomonas strains contain GSL and is different from that of other Gram-negative bacteria, which contain LPSs in their cell envelope. Because of this property, the cell surface of Sphingomonas strains is more hydrophobic than that of other Gram-negative bacteria and shows high affinity toward hydrophobic chemicals such as dioxin and polypropylene glycol.

Strain A1 cells use polyuronates (alginate and pectin) and their depolymerization products as carbon sources for growth. Glucose and pyruvate can be utilized as carbon sources, but far less efficiently than polyuronates. Strain A1 cells grew well on alginate and oligoalginates with different M/G ratios at pH 6–7, 30 ℃ in aerobic conditions, with a doubling time of approximately 25 min. However, unlike almost all of the alginate-degrading bacteria analyzed to date, the cells of strain A1 contained most of their alginate lyases in the cytoplasm. This means that alginate in the medium has to enter the cells in order to make contact with alginate lyases (Murata et al. 2022).

The morphological characteristics of the cell surface were examined with cells of strain A1 grown in the presence or absence of alginate. The following morphological observations were made (Murata et al. 2022): (i) cells grown on alginate were of two types that always coexisted in the medium: cells with or without a pit, and this feature was not observed in the absence of alginate. (ii) The surface of cells grown in the absence of alginate showed a pleat-like structure without a pit. (iii) Cells grown in the presence of alginate produced pits on their cell surface, and The pits contained even globular particles, some of which were insoluble forms (granules) of alginate. (iv) When the alginate-grown cells were treated with ruthenium red, an agent used to stain mucopolysaccharides, the pit periphery was strongly and specifically stained, suggesting that alginate was concentrated in the pit. (v) The thin section of cells grown on alginate showed a specific region where the cell surface sunk into the cells but no such structures were observed in cells grown in the absence of alginate. (vi) The average pit size was 0.02–0.1 µm in diameter (Murata et al. 2022). Thus, (a) the pit is formed only in the presence of alginate, (b) the pit functions as a concentrator of alginate, and (c) strain A1 cells have a pit-dependent alginate assimilation system, which differs from the alginate import and degradation pathway of other alginate-degrading microbes.

There are six protein constituents in the ABC transporter: AlgQ1, Q2, M1 M2 and S (AlgS is present with two copies where Q1 and 2 are periplasmic binding proteins, M1 and M2 comprise the integral membrane transport channel, and S is the dimeric ATPase. Alginate accumulated in the pit is delivered into the periplasm and then transported to the cytoplasm by this ABC transporter. Alginate is finally degraded into constituent monosaccharides by alginate lyases present in the cytoplasm. The gene cluster encoding these proteins are AlgO (regulatory protein)-AlgS-AlgM1-AlgM2-AlgQ1-AlgQ2. There are 8 cell surface proteins, p1 - p8.  P1 - p4 are TonB-dependent outer membrane transporters; p5 and p6 are flagellin-like proteins with alterred central domains of ~150 aas and high affinity for alginate (Kd = 10-9), and p7 and p8 are periplasmic alginate binding proteins (Murata et al. 2022).

AlgSM1M2Q1 of Sphingomonas sp.A1
AlgS (C)
AlgM1 (M)
AlgM2 (M)
AlgQ1 (R)
AlgQ2 (R)

Saturated and unsaturated oligogalacturonide transporter, TogMNAB (transports di- to tetrasaccharide pectin degradation products which consist of D-galacuronate, sometimes with 4-deoxy-L-threo-5-hexosulose uronate at the reducing end of the oligosaccharide) (Hugouvieux-Cotte-Pattat et al. 2001). Regulated by pectin utilization regulator KdgR (Rodionov et al. 2004)

Oligogalacturonide transporter TogMNAB of Erwinia chrysanthemi
TogM (M)
TogN (M)
TogA (C)
TogB (R)

Palatinose (isomaltulose; 6-O-α-D-glucopyranosyl-D-fructose) uptake porter
PalEFGK of Erwinia rhapontici
PalE (R)
PalF (M)
PalG (M)
PalK (C)

Glucose, mannose, galactose porter
GlcSTUV of Sulfolobus solfataricus
GlcS (R)
GlcT (M)
GlcU (M)
GlcV (C)

Arabinose, fructose, xylose porter
AraSTUV of Sulfolobus solfataricus
AraS (R)
AraT (M)
AraU (M)
AraV (C)

Trehalose porter
TreSTUV of Sulfolobus solfataricus
TreS (R)
TreT (M)
TreU (M)
TreV (C)

Maltooligosaccharide porter (Maltose is not a substrate, but maltotriose is.)
PF1933, 1936, 1937, 1938 of Pyrococcus furiosus
PF1938 (R)
PF1937 (M)
PF1936 (M)
PF1933 (C)

Trehalose/maltose/sucrose porter (trehalose inducible)
ThuEFGK of Sinorhizobium meliloti
ThuE (R)
ThuF (M)
ThuG (M)
ThuK (C)

N-Acetylglucosamine/N,N'-diacetyl chitobiose porter (NgcK (C) not identified)
NgcEFG of Streptomyces olivaceoviridis
NgcE (R)
NgcF (M)
NgcG (M)

Platinose (isomaltulose) (6-O-α-D-glucopyranosyl-D-fructofuranose) porter
PalEFGK of Agrobacterium tumefaciens
PalE (R)
PalF (M)
PalG (M)
PalK (C)

The fructooligosaccharide porter, MsmEFGK (Barrangou et al., 2003)
MsmEFGK of Lactobacillus acidophilus
MsmE (R) AAO21856
MsmF (M) AAO21857
MsmG (M) AAO21858
MsmK (C) AAO21860

The xylobiose porter; BxlEFG(K) (Tsujibo et al., 2004)
BxlEFGK of Streptomyces thermoviolaceus
BxlE (R) CAB88161
BxlF (M) CAB88162
BxlG (M) CAB88163
BxlK (C) Unknown

The maltose, maltotriose, mannotetraose (MalE1)/maltose, maltotriose, trehalose (MalE2) porter (Nanavati et al., 2005). For MalG1 (823aas) and MalG2 (833aas), the C-terminal transmembrane domain with 6 putative TMSs is preceded by a single N-terminal TMS and a large (600 residue) hydrophilic region showing sequence similarity to MLP1 and 2 (9.A.14; e-12 & e-7) as well as other proteins.

MalE1E2FGK of Thermotoga maritima
MalE1 (R) (binds maltose, maltotriose and mannotetraose) (AAD36279)
MalE2 (R) (binds maltose, maltotriose and trehalose) (AAD36901)
MalF1 (M) (AAD36278)
MalG1 (M) (AAD36277)
[MalG2 (M) (AAD36899]
MalK (C) (AAD36351)

The cellobiose/cellotriose (and possibly higher cellooligosaccharides), CebEFGMsiK [MsiK functions to energize several ABC transporters including those for maltose/maltotriose and trehalose] (Schlösser et al., 1997, Schlösser et al., 1999)

CebEFGMsiK of Streptomyces reticuli
CebE (R) (CAB46342)
CebF (M) (CAB46343)
CebG (M) (CAB46344)
MsiK (CAA70125)

The glucose/mannose porter TTC0326-8 plus MalK1 (ABC protein, shared with 3.A.1.1.25) (Chevance et al., 2006).
TTC0326-8 MalK1 of Thermus thermophilus
TTC0326 (M) - Q72KX4
TTC0327 (M) - Q72KX3
TTC0328 (R) - Q72KX2
MalK1 or TTC0211 (C) - Q72L52

The trehalose/maltose/sucrose/palatinose porter (TTC1627-9) plus MalK1 (ABC protein, shared with 3.A.1.1.24) (Silva et al. 2005; Chevance et al., 2006). The receptor (TTC1627) binds disaccharide alpha-glycosides, namely trehalose (alpha-1,1), sucrose (alpha-1,2), maltose (alpha-1,4), palatinose (alpha-1,6) and glucose.  The structures have been solved to a resolution range of 1.6-2.0 Å (Chandravanshi et al. 2019).

TTC1627-9 + MalK1 of Thermus thermophilus
TTC1627 (R) (Q72H68)
TTC1628 (M) (Q72H67)
TTC1629 (M) (Q72H66)
MalK1 (TTC0211) (C) (Q72L52)

The maltose porter, MdxEFG and MsmX (Ferreira and Sá-Nogueira, 2010). The MsmX ATPase can function with other receptor-dependent ABC transporters (TC# 3.A.1.1.2 and 3.A.1.1.34). The crystal structure of MsmX provides a framework to understand the molecular basis of the broader specificity of interaction with the transmembrane subunits of these systems (Leisico et al. 2020).

The maltose porter of Bacillus subtilis, MalEFG/MsmX.
MalE (R) - O06989
MalF (M) - O06990
MalG (M) - O06991
MsmX (C) - P94360

Maltose/Maltotriose/maltodextrin (up to 7 glucose units) transporters MalXFGK (MsmK (3.A.1.1.28) can probably substitute for MalK; Webb et al., 2008).

MalXFGK of Streptococcus mutans:
MalX (R) (Q8DT28)
MalF (M) (Q8DT27)
MalG (M) (Q8DT26)
MalK (C) (Q8DT25)

The raffinose/stachyose transporter, MsmEFGK (MalK (3.A.1.1.27) can probably substitute for MsmK; Webb et al., 2008). This system may also transport melibiose, isomaltotriose and sucrose as well as isomaltosaccharides (Russell et al. 1992).

MsmEFGK of Streptococcus mutans:
MsmE (R) (Q00749)
MsmF (M) (Q00750)
MsmG (M) (Q00751)
MsmK (C) (Q00752)

Aldouronate transporter, LplA,B,C (Chow et al., 2007)
LplABC of Paenibacillus sp. JDR-2:
LplA (R)(A9QDR6)
LplB (M)(A9QDR7)
YtcP (M)(A9QDR8)
LplC - not identified

Glucose porter, GtsABCD (del Castillo et al., 2008).  The orthologue of GtsA (receptor) in P. aeruginosa (64% identical to the P. putida GtsA has been biochemically characterized (Stinson et al. 1977) and corresponds to the sequence with UniProt acc# Q9HZ48 (Friedhelm Pfeiffer, personal communication).

The glucose porter of Pseudomonas putida, GtsABCD:
GtsA (R) (Q88P38)
GtsB (M) (Q88P37)
GtsC (M) (Q88P36)
GtsD (C) (Q88P35)

The trehalose-recycling ABC transporter, LpqY-SugA-SugB-SugC (essential for virulence) (Kalscheuer et al., 2010). It is probably involved in the recycling of extracellular or cell wall trehalose released from trehalose-containing molecules (De la Torre et al. 2021).

LpqY-SugA-SugB-SugC of Mycobacterium tuberculosis
LpqY (R) (Q7D8J9)
SugA (M) (O50452)
SugB (M) (O50453)
SugC (C) (O50454)  

The glucosylglycerol uptake transporter (functions in osmoprotection and also transports sucrose and trehalose (Mikkat and Hagemann, 2000) (most similar to 3.A.1.1.8).
GgtABCD of Synechocystis sp. strain PCC6803
GgtA (C) (Q55035)
GgtB (R) (Q55471)
GtC (M) (Q55472)
GgTD (M) (Q55473)

The N,N'-diacetylchitobiose uptake transporter, DasABC/MsiK (MsiK energizes several ABC transporters (see 3.A.1.1.23)) (Saito et al., 2008).

DasABC MsiK of Streptomyces coelicolor
DasA (R) (Q8KN19)
DasB (M) (Q8KN18)
DasC (M) (Q8KN17)
MsiK (C) (Q9L0Q1)

The arabinosaccharide transporter AraNPQMsmX. Transports α-1,5-arabinooligosaccharides, at least up to four L-arabinosyl units; the key transporter for α-1,5-arabinotriose and α-1,5-arabinotetraose, but not for α-1,5-arabinobiose which is transported by AraE. MsmX is also used by the MdxEFG-MsmX system (3.A.1.1.36) (Ferreira and Sá-Nogueira, 2010). Involved in the uptake of pectin oligosaccharides with either MsmX or YurJ as the ATPase (Ferreira et al. 2017).

AraNPQ-MsmX of Bacillus subtilis 
AraN (R) (P94528) 
AraP (M) (P94529)
AraQ (M) (P94530)
MsmX (C) (P94360) 

Glycerol uptake porter, GlpSTPQV (Ding et al., 2012).

GlpSTPQV of Rhizobium leguminosarum 
GlpS (C) (G3LHY8)
GlpT (C) (G3LHY9)
GlpP (M) (G3LHZ0)
GlpQ (M) (G3LHZ1)
GlpV (R) (G3LHZ3) 

Putative transport system


Q93J94 (R)
Q93J93 (M)
Q93J92 (M)
Q9L0Q1 (C?)

Predicted arabinoside porter. Regulated by arabinose-responsive regulator AraR (Rodionova et al. 2012).

AraEFG of Thermotoga maritima
AraE (R) (TM0277) -
AraF (M) (TM0278) Q9WYB4
AraG (M) (TM0279) Q9WYB5

Inositol phosphate porter (Rodionova et al. 2013). Binds inositol phosphate with low Kd and inositol with a lower affinity.

InoEFGK of Thermotoga maritima
InoE (R) TM0418 (Q9WYP9)
InoF (M) TM0419 (Q9WYQ0)
InoG (M) TM0420 (Q9WYQ1)
InoK (C) TM0421 (Q9WYQ2)

Alpha-1,4-digalacturonate porter (Nanavati et al., 2006). Regulated by pectin utilization regulon UxaR (Rodionova et al. 2012).

AguEFG of Thermotoga maritima
AguE (R) (TM0432) (Q9WYR3)
AguF (M) (TM0431) (Q9WYR2)
AguG (M) (TM0430) (Q9WYR1)

Predicted chitobiose porter. Regulated by chitobiose-responsive regulator ChiR (Kazanov et al., 2012).

ChiEFG of Thermotoga maritima
ChiE (R) (TM0810) (Q9WZR7)
ChiF (M) (TM0811) (Q9WZR8)
ChiG (C) (TM0812) (Q9WZR9)

Trehalose porter. Also binds sucrose (Boucher and Noll, 2011). Induced by glucose and trehalose. Directly regulated by trehalose-responsive regulator TreR (Kazanov et al., 2012).

TreG (M) (ThemaDRAFT_1378) G4FGN6 TreF (M) (ThemaDRAFT_1379) G4FGN7 TreE (R) (ThemaDRAFT_1380) G4FGN8

α-glucoside uptake permease, Agl3E/Agl3F/Agl3G. Plays a role in normal morphogenesis and antibiotic production. Strongly induced by trehalose and melibiose, and weakly induced by lactose and glycerol but not glucose (Hillerich and Westpheling 2006).The operon is controlled by a GntR homologue, Agl3R, and downstream of the gntR gene is a gene encoding an extracellular carbohydrase.

Agl2E/3F/3G of Streptomyces coelicolor
Agl3E (R); 425aas (Q9FBS5)
Agl3F (M) 6TMSs; 310aas (Q9FBS6)
Agl3G (M) 7TMSs; 303aas (Q9FBS7)
(ABC protein (C) not identified) 

Agl3E, Agl3F and Agl3G ABC porter. Induced by trehalose and melibiose using a GntR-like transcription factor (Hillerich and Westpheling 2006).  The ATPase subunit, Agl3K, may be the MsiK (Sco4240; see 3.A.1.1.33) protein (Saito et al. 2008).

Agl3EFG (Sco7167-5) of Streptomyces coelicolor.
Agl3E (R)
Agl3F (M)
Agl3G (M)
Agl3K (unknown)  

MalEFG (K unknown), involved in maltose and maltodextrin uptake (van Wezel et al. 1997).  The MalK protein may be the MsiK (Sco4240; Q9L0Q1; see 3.A.1.1.33) protein.

MalEFG (Sco2231-29) of Streptomyces coelicolor.
MalE (R)
MalF (M)
MalG (M)

Maltose transporter, MusEFGKI.  All five genes have been reported to be essential for uptake activity (Henrich et al. 2013).  The MusI gene product is of 215 aas with 5 TMSs and comprises the founding member of a distinct family of poorly characterized protein in TC family 9.B.28. 

MusEFGKI of Corynebacterium glutamicum

Probable glucoside uptake porter, YcjNOPV.  Encoded in an operon or gene cluster with a glucosyl hydrolase and two oxidoreductases (Moussatova et al. 2008).

YcjNOPV of E. coli
YcjN (R) (430 aas)
YcjO (M) (293 aas)
YcjP (M) (280 aas)
YcjV (C) (360 aas)

ABC-type fucose uptake porter FucABCD.  The ATPase subunit, FucD, has not been identified (Manzoor I., Shafeeq S., Afzal M. and Kuipers OP, JMMB, in press, 2015).

FucABCD of Streptococcus pneumoniae
FucA, (R)
FucB, (M)
FucC, (M)

The lacto-N-biose I (LNB; Gal β-1,3-GlcNAc)/galacto-N-biose (GNB; Gal β-1,3-GalNAc) transporter.  The solute-binding protein crystallizes only in the presence of LNB or GNB, and it was therefore named GNB/LNB-binding protein (GL-BP) (Wada et al. 2007; Suzuki et al. 2008; Asakuma et al. 2011). Isothermal titration calorimetry measurements revealed that GL-BP specifically binds LNB and GNB with K(d) values of 0.087 and 0.010 μM, respectively, and the binding process is enthalpy-driven. The crystal structures of GL-BP complexed with LNB, GNB, and lacto-N-tetraose (Galbeta1-3GlcNAcbeta1-3GaSuzuki et al. 2008; Asakuma et al. 2011). Isothermal titration calorimetry measurements revealed that GL-BP specifically binds LNB and GNB with K(d) values of 0.087 and 0.010 μM, respectively, and the binding process is enthalpy-driven. The crystal structures of GL-BP complexed with LNB, GNB, and lacto-N-tetraose (Galbeta1-3GlcNAcbeta1-3Galbeta1-4Glc) were determined.  The MalF and MalG membrahe proteins arAsakuma et al. 2011). Isothermal titration calorimetry measurements revealed that GL-BP specifically binds LNB and GNB with K(d) values of 0.087 and 0.010 μM, respectively, and the binding process is enthalpy-driven. The crystal structures of GL-BP complexed with LNB, GNB, and lacto-N-tetraose (Galbeta1-3GlcNAcbeta1-3Galbeta1-4Glc) were determined.  The MalF and MalG membrahe proteins are encoded adjacent to the gene for GL-BP, but the ATPase was not identified.

The LNB/GNB uptake transporter of Bifidobacterium longum
MalE homologue
MalF homologue
MalG homologue
MalK homologue, not identified.

The polyol (mannitol, glucitol (sorbitol), arabitol (arabinitol; lyxitol)) uptake porter, MtlEFGK (Brünker et al. 1998).

MtlEFGK of Pseudomonas fluorescens
MtlE, R, 436 aas
MtlF, M, 296 aas
MtlG, M, 276 aas
MtlK, C, 367 aas

Probable glycerophosphocholine (GPC) uptake porter (Chandravanshi et al. 2016). The system may include a receptor and three membrane proteins (of 378 aas and 6 TMSs, 299 aas and 7 TMSs, and 113 aas and 3 TMSs (?). The ATPase has not been identified.

GPC uptake porter of Thermus thermophilus

Maltose - maltoheptaose transporter, MalEFGK.  MalEF is a R-M fusion protein with the MalE domain N-terminal and the MalF domain C-terminal. The protein, of 733 aas, has 8 TMSs, one N-terminal to MalE (a signal sequence for export of the MalE domain to the periplasm), an extra TMS at the N-terminus to bring the N-terminus to the periplasmic side of the inner membrane, and then the usual 6 TMSs observed for many ABC membrane proteins.  MalG (M, 272 aas, 6 TMSs) and MalK (C, 374 aas) are of normal size and composition. While MalE of E. coli was able to additionally increase ATPase activity of MalFGK2 in vitro, the isolated MalE domain of B. bacteriovorus failed to stimulate the E. coli system (Licht et al. 2018). The adjacent genes are an α-amylase (Q6MNM3) and a glucokinase (Q6MNM4).

MalEF/MalG/MalK of Bdellovibrio bacteriovorus
MalEF, R-M, 733 aas, 8 TMSs (Q6MNM0)
MalG, M, 272 aas, 6 TMSs (Q6MNM1)
MalK, C, 374 aas, (Q6MNM2)


Sugar (sucrose, maltose, glucose, fructose, esculin (coumarin β-glucoside)) uptake system possibly consisting of 5 or 6 proteins (see below) (Nieves-Morión and Flores 2017). These proteins are all implicated in sugar uptake, but they may include components of multiple transporters. The system may also regulate formation of septal nanopores (Flores et al. 2018).

Sugar uptake porter of Nostoc (Anabaena) strain PCC7120
GlsR, MalE-like, All1916, 418 aas and 1 N-terminal TMS (R) (Q8YVQ8)
GlsQ, MalF-like, Alr2532, 301 aas and 6 TMSs (M) (Q8YU29)
GlsP, MalG-like, All0261, 276 aas and 6 TMSs (M) (Q8Z042)
GlsC, MalK-like, Alr4781, 432 aas and 0 TMSs (C) (Q8YMZ3)
GlsD, MalK-like, All1823, 366 aas and 0 TMSs (C) (Q8YVZ3)

Oligosaccharide transporter RafEFGK. RafE, the binding protein, has be extensively characterized.  It binds α-(1,6)-linked glucosides and galactosides of varying size, linkage, and monosaccharide composition with preference for the trisaccharides raffinose and panose. This preference is reflected in the α-(1,6)-galactoside uptake profile of the bacterium. Structures of RafE (BlG16BP) in complex with raffinose and panose revealed the basis for the ligand binding plasticity, which recognizes the non-reducing α-(1,6)-diglycosidic linkages in its ligands (Ejby et al. 2016). RafK has not be identified experimentally, but it may be NCIB protein acc# WP_022543180.1, ATP binding protein, annotated as UgpC, and this protein has been enterred into TCDB as RafK. Sugar binding substrates of RafE include: raffinose (highest affinity), panose, melibiose, stachyose, verbascose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, isomaltohexaose, and isomaltoheptaose (Ejby et al. 2016).

RafEFGK of Bifidobacterium animalis
RafE, (R) D3R799; 439 aas and 1 N-terminal TMS
RafF, (M) D3R798;  330 aas and 6 TMSs
RafG, (M) D3R797; 301 aas and 6 TM
RafK (C) WP_022543180.1, 377 aas and 0 TMSs.

Putative ABC sugar uptake porter with 4 constituents which unlike other members of this subfamily, has two large membrane proteins of 16 - 18 TMSs.

Candidatus Heimdallarchaeota
ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
OLS24721 R, 427 aas
OLS20027, M, 641 aas and 16 putative TMSs
OLS20028, M, 779 aas and 18 putative TMSs
OLS20029, C, 379 aa

Four comoponent ABC uptake porter, possibly transporting mannosyl glycerate.  The four components of this system and a potential mannosyl glycerate hydrolase are encoded within a single operon.

Putative mannosy glycerate transporter
R, 428 aas and 1 N-terminla TMS, D7BAR7
M, 281 aas and 6 TMSs, D7BAR6
M, 266 aas and 6 TMSs, D7BAR5
C, ATPase, cytoplasmic, D7BAR4

Uptake transport system for L-arabinose and D-xylose, XacGHIJK (Johnsen et al. 2019). The system has a receptor, two 6 TMS membrane proteins and two ATPases.  xacGHIJK is upregulated by growth in the presence of either D-xylose or L-arabinose, mediated by the transcriptional regulator, XacR, the general regulator of xac catabolic genes (Johnsen et al. 2019).

XacGHIJK of Halofax volcanii

ABC uptake porter consisting of AbnE (R), AbnF (M) and AbnJ (M).  The ATPase (C) has not been identified and does not appear to be encoded within the same gene cluster. This gene cluster also encodes an extracellular arabinanase, an intracellular arabinofuranosidase, and many other enzymes of arabinose/pentose metabolism as well as a sensor kinase/response regulator and another ABC transporter, probably specific for arabinose (TC# 3.A.1.2.32).

AbnEF(G?)J of Geobacillus stearothermophilus (Bacillus stearothermophilus)
AbnE, R, B3EYM9
AbnF, M, B3EYN0
AbnG, C, ?
AbnJ, M, B3EYN1

Four component putative ABC transporter specific for N-acetylglucosamine.

Putative N-acetylglucosamine transporter of Rhizobium meliloti (strain 1021) (Ensifer meliloti) (Sinorhizobium meliloti)
ATPase (C) of 352 aas
Membrane protein (M) of 279 aas and 6 TMSs
Membrane protein (M) of 313 aas and 6 TMSs
Binding receptor of 419 aas and 1 N-terminal TMS

Probable ABC transport system for the uptake of oligosaccharides (including a tetrasaccharide) of glucose, galactose and N-acetylglucosamine. The two membrane proteins are of 320 and 317 aas, both with 6 TMSs, and an extracytoplasmic binding receptor; the ATPase has not been identified.

ABC transporter of Bifidobacterium longum subsp. infantis

UspABC putative sugar uptake transporter, that probably imports peptidoglycan precursors (Karlikowska et al. 2021).

UspABC of Mycolicibacterium smegmatis (Mycobacterium smegmatis)
UspA, M, I7GC87, 290 aas and 6 TMSs
UspB, C, I7G593, 275 aas
UapC or MdxE, R, I7FQ33, 430 aas and 1 TMS

ABC sugar uptake porter with four protein components, 1 C, 2 M, and 1 R. This system has been found only in pathogenic Mycobacterium species (De la Torre et al. 2021).

Rv2038c - 0Rv2041c of Mycobacterium tuberculosis
Rv2038c, O53482, C, 357 aas
Rv2039c, O53483, M, 280 aas and 6 TMSs
Rv2080c, O53484, M, 300 aas and 6 TMSs
Rv2081c, O53485, R, 439 aas and 1 TMS

MdxEFG/MsmX maltose/cyclodextrin uptake system of the ABC-type. This system transports (takes up) maltose and malto-cyclodextrins.  The binding specificity of MdxE and its role in the cyclodextrin import in Thermoanaerobacterales has been determined (Aranda-Caraballo et al. 2023).

MdxEFG/MsmX of Thermoanaerobacterium xylanolyticum
MdxE, 420 aas and 1 N-terminal TMS
MdxF, 306 aas and 6 TMSs (F6BI03)
MdxG, 293 aas and 6 TMSs (F6BI04)
MsmX, 371 aas and 0 TMSs (F6BHH9)
3.A.1.2:  The Carbohydrate Uptake Transporter-2 (CUT2) Family

Ribose porter.  RbsA has two ATPase domains fused together; RbsB is the substrate receptor; RbsC has 10 TMSs with N- and C-termini in the cytoplasm and forms a dimer (Stewart and Hermodson, 2003).  ABC importers can be divided into two classes. Type I importers follow an alternating access mechanism driven by the presence of the substrate. Type II importers accept substrates in a nucleotide-free state, with hydrolysis driving an inward-facing conformation.  RbsABC2 seems to share functional traits with both type I and type II importers, as well as possessing unique features, and employs a distinct mechanism relative to other ABC transporters (Clifton et al. 2014).

RbsABC of E. coli
RbsA (C)
RbsB (R)
RbsC (M)

Arabinose porter (Horazdovsky and Hogg 1989).

AraFGH of E. coli
AraF (R)
AraG (C)
AraH (M)

Galactose/glucose (methyl galactoside) porter
MglABC of E. coli
MglA (C)
MglB (R)
MglC (M)

Xylose porter
XylFGH of E. coli
XylF (R)
XylG (C)
XylH (M)

Multiple sugar (arabinose, xylose, galactose, glucose, fucose) putative porter
ChvE, GguAB of Agrobacterium tumefaciens
ChvE (R)
GguA (C)
GguB (M)

D-allose porter.  The structure of AlsB has been solved at 1.8 Å resolution (Chaudhuri et al. 1999). Ten residues from both the domains form 14 hydrogen bonds with the sugar. 6-Deoxy-allose, 3-deoxy-glucose and ribose bind with reduced affinity so AlbP can function as a low affinity transporter for D-ribose (Chaudhuri et al. 1999).

AlsABC of E. coli
AlsB (R)
AlsA (C)
AlsC (M)

Fructose/mannose/ribose porter
FrcABC of Sinorhizobium meliloti
FrcA (C)
FrcB (R)
FrcC (M)

Autoinducer-2 (AI-2, a furanosyl borate diester: (3aS,6S,6aR)-2,2,6,6a-tetrahydroxy-3a-methyltetrahydrofuro[3,2-d][1,3,2]dioxaborolan-2-uide) uptake porter (Taga et al., 2001, 2003)

LsrACDB of E. coli
LsrB (R) AAC74589
LsrA (C) AAC74586
LsrC (M) AAC74587
LsrD (M) AAC74588

Rhamnose porter (Richardson et al., 2004) (Transport activity is dependent on rhamnokinase (RhaK; AAQ92412) activity (Richardson and Oresnik, 2007) This could be an example of group translocation!)
RhaSTP of Rhizobium leguminosarum bv. trifolii
RhaS (R) AAQ92407
RhaT (C) AAQ92408
RhaP (M) AAQ92409

The purine nucleoside permease (probably transports guanosine, adenosine, 2'-deoxyguanosine, inosine and xanthosine with decreasing affinity in this order) (Deka et al., 2006)
PnrA-E of Treponema pallidum
PnrA (R) (TmpC; Tp0319) (P29724)
PnrB (?51 aas; 1 TMS; Tp0320) (O83340)
PnrC (C) (533 aas; duplicated; Tp0321) (NP_218761)
PnrD (M) (400 aas; 10 TMSs; Tp0322) (NP_218762)
PnrE (M) (316 aas; 10 TMSs; Tp0323) (NP_218763)

The erythritol permease, EryEFG (Geddes et al., 2010) (probably orthologous to 3.A.1.2.16)

EryEFG of Sinorhizobium meliloti
EryE (C) (CAC48737)
EryF (M) (CAC48738)
EryG (R) (CAC48735)

The (deoxy)ribonucleoside permease; probably takes up all deoxy- and ribonucleosides (cytidine, uridine, adenosine and toxic analogues, fluorocytidine and fluorouridine tested), but not ribose or nucleobases (Webb and Hosie, 2006)
RnsABCD of Streptococcus mutans
RnsA (R) (AAN58814)
RnsB (C) (AAN58813)
RnsC (M) (AAN58812)
RnsD (M) (AAN58811)

The probable autoinducer-2 (AI-2;, a furanosyl borate diester: 3aS,6S,6aR)-2,2,6,6a-tetrahydroxy-3a-methyltetrahydrofuro[3,2-d][1,3,2]dioxaborolan-2-uide) uptake porter (Shao et al., 2007) (50-70% identical to RbsABC of E. coli; TC# 3.A.1.2.1)

RbsABC of Aggregatibacter actinomycetemcomitans (Actinobacillus succinogens)
RbsA (C) (A6VKS8)
RbsB (R) (A6VKT0)
RbsC (M) (A6VKS9)

Putative L-arabinose porter (Rodionov et al. 2010).

AraUVWZ of Shewanella oneidensis
AraU (R) (Q0HIQ8)
AraV (C-C) (Q0HIQ7)
AraW (M; 10 TMSs) (Q0HIQ6)
AraZ (M; 9 TMSs) (Q0HIQ5)

The putative xylitol uptake porter, XltABC (Rodionov et al., 2010)

XltABC of Shewanella pealeana
XltA (C) (A8H4W7)
XltB (M; 9 TMSs) (A8H4W6)
XltC (R) (A8H4W5)

The erythritol uptake permease, EryEFG (Yost et al., 2006) (probably orthologous to 3.A.1.2.11)

EryEFG of Rhizobium leguminosarum
EryE (C) (Q1M4Q7)
EryF (M) (Q1M4Q8)
EryG (R) (Q1M4Q9)

General nucleoside uptake porter, NupABC/BmpA (transports all common nucleosides as well as 5-fluorocytidine, inosine, deoxyuridine and xanthosine) (Martinussen et al., 2010) (Most similar to 3.A.1.2.12). NupA is 506aas with two ABC (C) domains. NupB has 8 predicted TMSs, NupC has 9 or 10 predicted TMSs in a 4 + 1 (or 2) + 4 arrangement.

NupABC/BmpA of Lactococcus lactis
BmpA (R) (D2BKA1)
NupA (C) (A2RKA7)
NupB (M) (A2RKA6)
NupC (M) (A2RKA5)

Xylose porter (Nanavati et al. 2006). Regulated by xylose-responsive regulator XylR (Kazanov et al., 2012).

XylFEK of Thermotoga maritima
XylF (M) (TM0112) (Q9WXW7)
XylE (R) (TM0114) (Q9WXW9)
XylK (C) (TM0115) (Q9WXX0)

D-ribose porter (Nanavati et al., 2006). Induced by ribose (Conners et al., 2005).

RbsABC of Thermotoga maritima
RbsA (C) (TM0956) (Q9X051)
RbsB (R) (TM0958) (Q9X053)
RbsC (M) (TM0955) (Q9X050)  

Glucose porter. Also bind xylose (Boucher and Noll 2011). Induced by glucose (Frock et al. 2012). Directly regulated by glucose-responsive regulator GluR (Kazanov et al., 2012).

GluEFK of Thermotoga maritima
GluE (     GluE (R) (ThemaDRAFT_1377) (G4FGN5)
GluF (M) (ThemaDRAFT_1376) (G4FGN4); 9 TMSs
GluK (C) (ThemaDRAFT_1375) (G4FGN3)  

The myoinositol (high affinity)/ D-ribose (low affinity) transporter IatP/IatA/IbpA. The structure of IbpA with myoinositol bound has been solved (Herrou and Crosson 2013).

IatP/IatA/IbpA of Caulobacter crescentus
IatP (M) (B8H230)
IatA (C) (B8H229)
IbpA (R) (B8H228)

ABC sugar transporter that plays a role in the probiotic benefits through acetate production (Fukuda et al. 2012).

Sugar transporter of Bifidobacterium longum
BL1694, 385 aas (R) (Q8G3R1)
BL1695, 517 aas (C) (Q8G3R0)
BL1696, 405 aas (M) (Q8G3Q9)

ABC sugar transporter, FruEFGK, important for the probiotic effect of Bifidobacterium longum and involved in producing acetate (Fukuda et al. 2012).  The system is specific for fructose (highest affinity) ribose and xylose.  All three sugars induce the system (Wei et al. 2012). 

Sugar transporter of Bifidobacterium longum
BL0033 of 327 aas (R) (Q8G848)
BL0034 of 513 aas (C) (Q8G847)
BL0035 of 356 aas (M) (Q8G846)
BL0036 of 340 aas (M) (Q8G845)

XylFGH downstream of characterized transcriptional regulator, ROK7B7 (Sco6008); XylF (Sco6009); XylG (Sco6010); XylH (Sco6011)) (Świątek et al. 2013).

XylFGH of Streptomyces coelicolor 
XylF (R)
XylG (C)
XylH (M; 12 TMSs) 

Putative sugar uptake porter, YtfQRT/YjfF (Moussatova et al. 2008).

YtfQRT/YjfF of E. coli
YtfQ (R)
YtfR (C)
YtfT (M)
YjfF (M)

Xylose transporter, XylFGH (XylF (R), 359 aas; XylG (C), 525 aas; XylH (M), 389 aas.  Controlled by a 3 component sensor kinase/response regulator system (XylFII, sensor, A6LW07; LytS, SK, A6LW08; YesN, RR, A6LW09) (Sun et al. 2015). The XylFII-LytS complex provides the molecular basis for D-xylose utilization and metabolic modification (Li et al. 2017).

XylFGH of Clostridium beijerinckii
XylF (R)
XylG (C)
XylH (M; 12 TMSs)

Sugar (pentose?) transport system, YphDEF

YphDEF of E. coli
YphD (M) 332 aas, 10 TMSs
YphE (C) 503 aas
YphF (R) 327 aas

Riboflavin uptake ABC transporter, RfuABCD.  The periplasmic binding protein (RfuA) has been crystallized at 1.3 Å resolution with riboflavin bound (Deka et al. 2013). Similar systems are found in other spirochetes such as Treponema denticola, and Borrelia burgdorferi (Deka et al. 2013).

RfuABCD of Treponema pallidum
RfuA, R, 343 aas and 1 N-terminal TMS
RfuB, C, 586 aas and 0 TMSs
RfuC, M, 377 aas and 9 or 10 TMSs
RfuD, M, 313 aas and 9 TMSs (may be N-terminally truncated)

High affinity fructose uptake porter, FrtABC, Km (fructose) = ~100μM; expression of the frtABC operon is regulated by the product of the upstream gene, frtR, FrtR, a LacI/GalR-type repressor that allows activation in the presence of fructose (Ungerer et al. 2008). When FruR is eliminated, the cells become hypersensitive to fructose, and the level of fruABC expression is much higher than in the presence of wild type cells grown on fructose (Ungerer et al. 2008).

FrtABC of Anabaena (Nostoc) variabilis
FrtA, Ava2171, Q3MB45, 341 aas with 1 N-terminal TMS (R)
FrtB, Ava2172, Q3MB44, 517 aas and 0 TMSs (C)
FrtC, Ava2173, Q3MB43, 332 aas and 8 TMSs (M)

3-component ABC-type putative general nucleoside uptake porter consisting of a receptor, a putative lipoprotein with two N- and C-terminal TMSs (R; 405 aas), an integral membrane protein of about 20 TMSs in a 1 + 4 (tight) + 4 (loose) +2 +1 + 4 (tight) +4 (loose) TMS arrangement (M; 864 aas), and a cytoplasmic ATPase (C; 563 aas).  It appears that the membrane protein contains a 9 (or 10) TMS repeat unit, and that there are two extra TMSs separating the two repeat units.  These are homologous to the two membrane constituents of TC# 3.A.1.2.17.

Candidatus Heimdallarchaeota
ABC uptake porter of Candidatus Heimdallarchaeota
OLS24537, R
OLS24538, C
OLS24539, M

Putative purine porter with 4 components (Chandravanshi et al. 2019).

Putative purine porter of Thermus thermophilus
R, 379 aas and 1 TMS (Q5SIR3)
M, 277 aas and 9 TMSs
M, 349 aas and 8 - 10 TMSs
C, 489 aas and 0 TMSs

ABC-type putative arabinose transport system, AraEGHP. The genes encoding this system are found within a large gene cluster including many arabinose/pentose metabolic enzymes, a sensor kinase/response regulator pair, and an ABC uptake system specific for araino-oligosaccharides of 2 to 8 sugar units (TC# 3.A.1.1.57) (Lansky et al. 2020).

AraEGHP of Geobacillus stearothermophilus (Bacillus stearothermophilus)
AraE, R, B3EYL8
AraG, C, ATPase, B3EYM1
AraH, M, B3EYM2
AraP, R, B3EYL5

XylFGH of T. ethanolicus (Erbeznik et al. 2004).

XylFGH of Thermoanaerobacter ethanolicus (Clostridium thermohydrosulfuricum), a thermophilic, anaerobic, ethanol-producing eubacterium
XylF (R), 366 aas
XylG (C),507 aas
XylH (M)388 aas and 12 TMSs.
3.A.1.3:  The Polar Amino Acid Uptake Transporter (PAAT) Family

Histidine/arginine/lysine/ornithine porter (Heuveling et al. 2014). In contrast to some homologous homodimeric systems, the heterodimeric histidine transporter of Salmonella enterica Typhimurium  ligands only one substrate molecule in between its two transmembrane subunits, HisM and HisQ (Heuveling et al. 2019).

HisJ (histidine receptor)-ArgT (arg/lys/orn receptor)-HisMPQ of Salmonella typhimurium
HisJ (R)
ArgT (R)
HisM (M)
HisQ (M)
HisP (C)

Three component ABC L-glutamine porter. The basal ATPase activity (ATP hydrolysis in the absence of substrate) is mainly caused by the docking of the closed-unliganded state of GlnH onto the transporter domain of GlnPQ. Unlike glutamine, arginine binds both GlnH domains, but does not trigger their closing. Comparison of the ATPase activity in nanodiscs with glutamine transport in proteoliposomes suggested that the stoichiometry of ATP per substrate is close to two (Lycklama A Nijeholt et al. 2018).

GlnHPQ of E. coli
GlnH (R)
GlnP (M)
GlnQ (C)

Arginine porter
ArtI (arginine receptor #1)/ArtJ (arginine receptor #2)-ArtMQP of E. coli
ArtP (C)
ArtQ (M)
ArtM (M)
ArtJ (R)
ArtI (R)

Glutamate/aspartate porter.  Similar in sequence to 3.A.1.3.19 which is specific for Glu, Asp, Gln and Asn (Singh and Röhm 2008).

GltIJKL of E. coli
GltI (R)
GltJ (M)
GltK (M)
GltL (C)

Octopine porter
OccQMPT of Agrobacterium tumefaciens
OccT (R)
OccQ (M)
OccM (M)
OccP (C)

Nopaline porter
NocQMPT of Agrobacterium tumefaciens
NocT (R)
NocQ (M)
NocM (M)
NocP (C)

Glutamate/glutamine/aspartate/asparagine porter
BztABCD of Rhodobacter capsulatus
BztA (R)
BztB (M)
BztC (M)
BztD (CC)

General L-amino acid porter; transports basic and acidic amino acids preferentially, but also transports aliphatic amino acids (catalyzes both uptake and efflux) (Prell et al. 2009; Hosie et al. 2002Hosie et al. 2002).

AapJQMP of Rhizobium leguminosarum
AapJ (R)
AapQ (M)
AapM (M)
AapP (C)

Glutamate porter
GluABCD of Corynebacterium glutamicum
GluA (C)
GluB (R)
GluC (M)
GluD (M)

Cystine/cysteine/diaminopimelate transporter, CysXYZ; these proteins are also designated FliY/YecS/YecC.  Note, another transporter is designated CysZ in E. coli (TC# 2.A.121.1.1).  CysXYZ also transports the toxic amino acid analogues, L-selenaproline (SCA; L-selenazolidine-4-carboxylic acid) and L-selenocystine (SeCys) (Deutch et al. 2014). FliY binds L-cystine, L-cysteine, and D-cysteine with micromolar affinities, but binding of the L- and D-enantiomers induced different conformational changes in FliY, where the L- enantiomer/SBP complex interacted more efficiently with the YecSC transporter. YecSC has low basal ATPase activity that is moderately stimulated by apo-FliY, more strongly by D-cysteine-bound FliY, and maximally by L-cysteine- or L-cystine-bound FliY (Sabrialabe et al. 2020). FliY may exist in a conformational equilibrium between an open, unliganded form that does not bind to the YecSC transporter and closed, unliganded and closed, liganded forms that bind this transporter with variable affinities but equally stimulate its ATPase activity. These findings differ from previous observations for similar ABC transporters, highlighting the extent of mechanistic diversity in this large protein family (Sabrialabe et al. 2020).

Cys/Dap porter of E. coli
CysX or FliY (R)
CysY or YecS (M)
CysZ or YecC (C)

Arginine/ornithine (but not lysine) porter (Nishijyo et al. 1998).

AotJQMP of Pseudomonas aeruginosa
AotJ (R)
AotQ (M)
AotM (M)
AotP (C)

Arginine/lysine/histidine/glutamine porter
BgtAB of Synechocystis PCC6803
BgtA (C)
BgtB (R-M)

Uptake system for L-cystine (Km=2.5 μM), L-cystathionine, L-djenkolate ( 2-amino-3-[(2-amino-3-hydroxy-3-oxopropyl)sulfanylmethylsulfanyl] propanoic acid), and S-methyl-L-cysteine (Burguière et al., 2004, Burguière et al., 2005)

TcyJKLMN (YtmJKLMN) of Bacillus subtilis
TcyJ (R) (NP_390816)
TcyK (R) (O34852)
TcyL (M) (O34315)
TcyM (M) (O34931)
TcyN (C) (O34900)

Uptake system for L-cystine (Burguière et al., 2004)

TcyABC (YckKJI) of Bacillus subtilis
TcyA (R) (P42199)
TcyB (M) (P42200)
TcyC (C) (P39456)

Putative uptake system for arginine, YqiXYZ (Sekowska et al., 2001)

YqiXYZ of Bacillus subtilis
YqiX (R) (P54535)
YqiY (M) (P54536)
YqiZ (C) (P54537)

Uptake system for glutamate and aspartate (Leon-Kempis et al., 2006). This four component system appears to be important for pathogenicity (Gao et al. 2017).

PEB1 transport system Campylobacter jejuni
PEB1a (R) (Q0P9X8)
PED1b (M) (A1VZQ3)
PEB1c (C) (A3ZI83)
PEP1d (M) (EAQ71872.1)

Basic amino acid uptake transporter, BgtAB (BgtA is shared with NatFGH/BgtA; 3.A.1.3.18; Pernil et al., 2008)
BgtAB of Anabaena sp. PCC7120
BgtA (C) (Q8YPM6)
BgtB (R-M) (Q8YSA2)

Acidic and neutral amino acid uptake transporter NatFGH/BgtA. BgtA is shared with BgtAB (3.A.1.3.17; Pernil et al., 2008)
NatFGH-BgtA of Anabaena sp. PCC7120
BgtA (C) (Q8YPM6)
NatF (R) (Q8YPM9)
NatG (M) (Q8YPM8)
NatH (M) (Q8YPM7)

Acidic amino acid uptake porter, AatJMQP (Singh and Röhm, 2008).  It is the sole system that  transports glutamate and glutamine, but it can also transport aspartate and asparagine (Singh and Röhm 2008).

AatJMQP of Pseudomonas putida
AatJ (R) Q88NY2
AatM (M) Q88NY3
AatQ (M) Q88NY4
AatP (C) Q88NY5

The putative lysine uptake system, LysXY

LysXY of Streptococcus pyogenes
LysX (R-M) (Q9A1H0)
LysY (C) (Q9A1H1)

Hydroxy L-proline uptake porter, HprABC (Johnson et al. 2008).

HprABC of Pseudomonas aeruginosa
HprA (C) (Q9I488)
HprB (M) (Q9I487)
HprC (R) (Q9I484)

Amino acid transporter, AatJMQP. Probably transports L-glutamate, D-glutamate, L-glutamine and N-acetyl L-glutamate (Johnson et al. 2008). Very similar to 3.A.1.3.19 of P. putida

AatJMQP of Pseudomonas aeruginosa
AatJ (R) (Q9I402)
AatM (M) (Q9I403)
AatQ (M) (Q9I404)
AatP (C) (Q9I405)

Amino acid transporter, PA5152-PA5155. Probably transports numerous amino acids including lysine, arginine, histidine, D-alanine and D-valine (Johnson et al. 2008). Regulated by ArgR.

PA5152-PA5144 of Pseudomonas aeruginosa
PA5152 (C) (Q9HU32)
PA5153 (R) (Q9HU31)
PA5154 (M) (Q9HU30)
PA5155 (M) (Q9HU29)

Putative methionine uptake porter, Sco_5260, 5259, 5258. Defects cause impaired sporulation, reduced growth and reduced production of actinorhodin and undecylprodigiosin. Induced by S-adenosylmethionine (Shin et al. 2007).

Sco_5260, 5259, 5258 of Streptomyces coelicolor
Sco5260 (R) 320aas (Q9F3K5)
Sco5259 (M) 316aas (Q9F3K6)
Sco5258 (C) 253aas (Q9F3K7) 

Glutamine transporter, GlnQP. Takes up glutamine, asparagine and glutamate which compete for each other for binding to the substrate/transmembrane protein constituent of the system (Fulyani et al. 2015). Tandem substrate binding domains  differ in substrate specificity and affinity, allowing cells to efficiently accumulate different amino acids via a single ABC transporter. Analysis revealed the roles of individual residues in determining the substrate affinity (Fulyani et al. 2013). Protein-protein interactions and conformational states were studied simultaneously using PIFE-FRET (Ploetz et al. 2021).

GlnPQ of Lactococcus lactis subsp. cremoris (Streptococcus cremoris)

The putative polar amino acid uptake porter, YhdWXYZ.  Probably under NtrBC transcriptional control (Jiang et al. 2006).

YhdWXYZ of E. coli
YhdW (R)
YhdX (M)
YhdY (M)
YhdZ (C)

Basic amino acid uptake porter, ArtIQ2N2. Transports Arginine, lysine and histidine.  Several 3-d structures have been solved (4YMS, 4YMT, 4YMU, etc., Yu et al. 2015).  These revealed one binding site for substrate per ArtQ monomer.  Heuveling et al. 2018 then showed that in the close homologue, ArtMP of Geobacillus stearothermophilus, that just one of these two sites needed to bind substrate to get transport.

ArtIQ2N2 of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)
ArtI (R)
ArtQ (M)
ArtN (C)

Putative amino acid uptake porter, YckIJK; deletion of YckK (substrate binding protein) increases sensitivity to the antimicrobial peptide, cecropin (Chen et al. 2015). 

YckIJK of Haemophilus psarasuis
YckI (C)
YckJ (M)
YckK (R)

Histidine/Arginine/Lysine (basic amino acid) uptake porter, HisJ/ArgT/HisP/HisM/HisQ [R, R, C, M, M, respectively] (Gilson et al. 1982). HisJ binds L-His (preferred), but 1-methyl-L-His and 3-methyl-L-His also bind, while the dipeptide carnosine binds weakly; D-histidine and the histidine degradation products, histamine, urocanic acid and imidazole do not bind. L-Arg, homo-L-Arg, and post-translationally modified methylated Arg-analogs also bind with the exception of symmetric dimethylated-L-Arg. L-Lys and L-Orn show weaker interactions with HisJ and methylated and acetylated Lys variants show poor binding.The carboxylate groups of these amino acids and their variants are essential (Paul et al. 2016).

Basic amino acid transporter of E. coli

Putative ABC amino acid uptake porter with 3 constituents. The membrane protein is different from other members of this subfamily in having 10 TMSs in a 3 + 2 + 3 + 2 TMS arrangement with a probable 5 TMS duplication), and the receptor has two TMSs at the N- and C-termini.

Candidatus Heimdallarchaeota
Putative amino acid uptake porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
OLS25600, R, 372 aas, 2 TMSs, N- and C-terminal
OLS25601, M, 472 aas, 10 TMSs
OLS25602, C, 251 aas, 0 TM
3.A.1.4:  The Hydrophobic Amino Acid Uptake Transporter (HAAT) Family

Leucine; leucine/isoleucine/valine porter (also transports phenylalanine and tyrosine; Koyanagi et al., 2004)
LivK (leucine-specific receptor)-LivJ (Leu/Ile/Val receptor)-LivHMGF of E. coli
LivJ (R)
LivK (R)
LivH (M)
LivM (M)
LivG (C)
LivF (C)

Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE.

NatA-E neutral amino acid porter of Synechocystis sp.PCC6803
NatA (C)
NatB (R)
NatC (M)
NatD (M)
NatE (C)

General L- (and D-)amino acid uptake porter (transports acidic, basic, polar, semipolar and hydrophobic amino acids). The amino and carboxyl groups do not need to be α since γ-aminobutyric acid (GABA) is a substrate. The system may function with additional binding proteins since L-alanine uptake is not dependent on BraC.
BraCDEF of Rhizobium leguminosarum
BraC (R)
BraD (M)
BraE (M)
BraF (C)

The high-affinity (<1 μM) urea porter
UrtA-E urea porter of Anabaena sp. PCC7120
UrtA (R)
UrtB (M)
UrtC (M)
UrtD (C)
UrtE (C)

The high affinity urea/thiourea/hydroxyurea porter (Beckers et al., 2004)
UrtA-E of Corynebacterium glutamicum
UrtA (R) CAF19637
UrtB (M) CAF19636
UrtC (M) CAF19638
UrtD (C) CAF19639
UrtE (C) CAF19640

The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB) (Picossi et al., 2005)
NatA-E of Anabaena sp. strain PCC7120
NatA (C) BAB73003
NatB (R) BAB73533
NatC (M) BAB73004
NatD (M) BAB73241
NatE (C) BAB74611

The protocatechuate (3,4-dihydroxybenzoate) uptake porter, PcaMNVWX (Maclean et al., 2011)

PcaMNVWX of Sinorhizobium (Ensifer) meliloti
PcaM (R) (Q92TN0)
PcaN (M) (Q92TN1)
PcaV (M) (Q92TN2) 
PcaW (C) (Q92TN3) 
PcaX (C) (Q92TN4) 

Branched chain amino acid uptake transporter. Transports alanine (Hoshino and Kose 1990).

BraC-G of Pseudomonas aeruginosa
BraG (C) (P21630)
BraE (C) (P21629)
BraE (M) (P21628)
BraD (M) (P21627)
BraC (R) (P21175)

Uptake transporter, CamABCD of cholate (steroid) metabolites, 1β(2'-propanoate)-3aα-H-4α(3"(R)-hydroxy-3"-propanoate)-7aβ-methylhexahydro-5-indanone and a desaturated analog (Swain et al. 2012).

CamABCD of Rhodococcus jostii
CamA, R, 405 aas (Q0S717)
CamB, M, 285 aas, 8 TMSs (Q0S718)
CamC, M-C, 607 aas, 10 TMSs in a 5 + 5 arrangement followed by the C domain (Q0S719)
CamD, C, 245 aas (Q0S720)

The branched chain hydrophobic amino acid transporter, LivJFGHM (Basavanna et al. 2009).

LivJFGHM of Streptococcus pneumoniae
LivJ (R) 286 aas
LivF (C) 236 aas
LivG (C) 254 aas
LivH (M) 292 aas, 7 TMSs
LivM (M) 318 aas, 9 TMSs

The phenylpropeneoid uptake porter, CouPSTW.  The purple photosynthetic bacterium Rhodopseudomonas palustris is able to grow photoheterotrophically under anaerobic conditions on a range of phenylpropeneoid lignin monomers, including coumarate, ferulate, caffeate, and cinnamate. RPA1789 (CouP) is the periplasmic binding-protein component of the ABC uptake system (CouPSTU).  CouP binds a range of phenylpropeneoid ligands with Kd values in the nanomolar range. The crystal structure of CouP with ferulate as the bound ligand shows H-bond interactions between the 4-OH group of the aromatic ring with His309 and Gln305. H-bonds are also made between the carboxyl group on the ferulate side chain and Arg197, Ser222, and Thr102 (Salmon et al. 2013). Within the same operon are a diguanylate cyclase (Q6N8W3) and a phenylacetate-CoA ligase (Q6N8W5).

CouPSTW of Rhodopseudomonas palustris 
CouP (R) 385 aas
CouS (C) 239 aas
CouT (M-C) 590 aas
CouW (M) 346 aas

ABC-type uptake porter for pyruvate and monocarboxylate 2-oxo acids.  Pyruvate uptake has been measured and is inhibited by monocarboxylate 2-oxo-acids such as 2-oxobutyrate, 2-oxovalerate, 2-oxoisovalerate, 2-oxoisocaproate and 2-oxo 3-methylvalerate which are probably substrates (Pernil et al. 2010). 

ABC porter of Anabaena (Nostoc) strain 7120
Alr2535, Q8YU26, 268 aas, 1 N-terminal TMS (R)
Alr2536, Q8YU25, 316 aas, 9 TMSs, (M)
Alr2538, Q8YU24, 308 aas and 8 TMSs (M)
Alr2539, Q9YU22, 259 aas and 0 TMSs (C)
Alr2541, Q9YU20, 264 aas and 0 TMSs (C)

ABC amino acid transport systems, of unknown specificity, but homologous to the LIV system of hydrophobic amino acid transport, similar to 3.A.1.4.1 and 3.A.1.4.10.

Candidatus Heimdallarchaeota
ABC transporter of 5 constituents, LivFGHIJ of Candidatus Heimdallarchaeota archaeon
LivJ, R, 470 aas and 2 TMSs, N- and C-terminal
LivH, M, 805 aas and 20 aas in an 11 + 8 +1 TMS arrangement.  Other LivHs are homologous to    TMSs 12 - 19
LivI or LivM, M, 255 aas and 6 TMSs in a 5 + 1 arrangement
LivG, M-C, 937 aas and 19 TMSs
LivF, C, 233 aas and 0 TMSs

Branched chain amino acid uptake (BCAA) porter consisting of 5 proteins.

Candidatus Campbellbacteria
BCAA transporter of Candidatus Campbellbacteria bacterium GW2011_OD1_34_28 (groundwater metagenome LivF (C), AKM83893
LivJ  (R), AKM83894
LivG  (C), AKM83896
LivH  (M), AKM83897
LivI  (M), AKM83898

ABC transporter for benzoate and phenyl proponoids with 6 subunits, one receptor (R) for benzoate and one receptor (R) for phenyl proponoids derived from plant lignins. There are also two membrane constituents (M) and two cytoplasmic ATPases (C) (see proteins for this system) (Vagts et al. 2021).

ABC transporter with six subunits:
Periplasmic binding receptor for benzoate (R) with 395 aas and 1 N-terminal TMS (CAI09138; ebA5303)
Membrane protein with 288 aas and 7 TMSs (CAI09139; ebA5304)
Membrane protein with 324 aas and 8 TMSs (CAI09140; ebA5306)
Cytoplasmic ATPase of 253 aas and 0 TMSs (CAI09141; ebA5307)
Cytoplasmic ATPase of 238 aas and 0 TMSs (CAI09142; ebA5309)
Periplasmic binding receptor for phenyl propionoids of 380 aas and one N-terminal TMS (CAI09145; ebA5316)
3.A.1.5:  The Peptide/Opine/Nickel Uptake Transporter (PepT) Family

Oligopeptide porter (also takes up amino glycoside antibiotics such as kanamycin, streptomycin and neomycin as well as cell wall-derived peptides such as murein tripeptide). It transports substrate peptides of 2-5 amino acids with highest affinity for tripeptides. Also transports δ-aminolevulinic acid (ALA). [May be regulated by PTS Enzyme INtr-aspartokinase.] ATP-binding to OppDF may result in donation of peptide to OppBC and simultaneous release of OppA (Doeven et al., 2008).
OppABCDF of Salmonella typhimurium
OppA (R)
OppB (M)
OppC (M)
OppD (C)
OppF (C)
MppA (R) (in E. coli)

Dipeptide porter. Also transports δ-aminolevulinic acid (ALA) and heme (Létoffé et al., 2008).
DppABCDE of Bacillus subtilis
DppA (C)
DppB (M)
DppC (M)
DppD (C)
DppE (R)

Nickel porter. Histidine 416 of NikA is essential for nickel uptake (Cavazza et al., 2011).

NikABCDE of E. coli
NikA (R)
NikB (M)
NikC (M)
NikD (C)
NikE (C)

Agrocinopine (an opine)/Agrocin 84 (an antibiotic) porter (Kim and Farrand, 1997)
AccABCDE of Agrobacterium tumefaciens
AccA (R)
AccB (C)
AccC (C)
AccD (M)
AccE (M)

Probable cationic peptide porter (may also take up peptide antibiotics and protamine; implicated in K+ homeostasis) [SapD can stimulate the K+ uptake activities of TrkH and TrkG (TC #2.A.38.1.1) in the presence of ATP] (Mason et al., 2006)
SapABCDF of Salmonella typhimurium
SapA (R)
SapB (M)
SapC (M)
SapD (C)
SapF (C)

The β-glucoside (cellobiose (β-1,4), cellotriose, cellotetraose, cellopentaose, laminaribiose (β-1,3), laminaritriose, sophorose) uptake porter, CbtABCDF
The β-glucoside uptake porter of Pyrococcus furiosus, CbtABCDF
CbtA (R)
CbtB (M)
CbtC (M)
CbtD (C)
CbtF (C)

The α-galactoside (melibiose, raffinose) uptake porter, AgpABCDF
The α-galactoside uptake porter of Rhizobium meliloti
AgpA (R)
AgpB (M) (not identified)
AgpC (M) (not identified)
AgpD (C) (not identified)
AgpF (C) (not identified)

Maltose and maltooligosaccharide porter

MalEFGK of Sulfolobus solfataricus
MalE (R)
MalF (M)
MalG (M)
MalK (C-C)

Cellobiose and cellooligosaccharide porter
CbtABCDF of Sulfolobus solfataricus
CbtA (R)
CbtB (M)
CbtC (M)
CbtD (C)
CbtF (C)

Oligopeptide porter (transports peptides of 4-35) amino acyl residues; di- and tripeptides are not transported; hydrophobic basic peptides are preferred). OppA determines the specificity of the system (Doeven et al., 2004). A large cavity in OppA binds proline-rich peptides preferentially (Berntsson et al., 2009). Two crystal structures of OppA with different nonapeptides show binding in different registers (Berntsson et al., 2011).

OppABCDF of Lactococcus lactis
OppA (R) (Q9CEK0)
OppB (M) (P0A4N7)
OppC (M) (P0A4N9)
OppD (C) (Q07733)
OppF (C) (P0A2V4)

Glutathione porter, YliABCD or GsiABCD (Suzuki et al., 2005). Changes in the redox balance in the medium and in E. coli cells affect the ability of bacteria to form biofilms. An increase in the level of aeration in the culture of wild-type bacteria led to a 3-fold decrease in the mass of biofilms (Kalashnikova et al. 2023). Mutants lacking components of the glutathione and thioredoxin redox systems, as well as transporters involved in the transmembrane cycling of glutathione, showed increased biofilm formation ability. The effect of exogenous glutathione on biofilm formation depended on the culturing conditions. The addition of 0.1-1 mM Trolox (a water-soluble analog of vitamin E) was accompanied by a 30-40% reduction in biofilm formation (Kalashnikova et al. 2023).

YliABCD of E. coli
YliA (GsiA) (C-C) (P75796)
YliB (GsiB) (R) (P75797)
YliC (GsiC) (M) (P75798)
YliD (GsiD) (M) (P75799)

Probable rhamnose oligosaccharide porter. Induced by rhamnose (Conners et al., 2005).

RtpEFGKL of Thermotoga maritima
RtpE (R) (TM1067) Q9X0F7
RtpF (M) (TM1066) Q9X0F6
RtpG (M) (TM1065) Q9X0F5
RtpK (C) (TM1064) Q9X0F4
RtpL (C) (TM1063) Q9X0F3

Probable xylan oligosaccharide porter (Conners et al., 2005). Induced by xylan and xylose. Regulated by xylose-responsive regulator XylR (Kazanov et al. 2012).

XloEFGKL of Thermotoga maritima
XloE (R) (TM0071) Q9WXS6
XloF (M) (TM0072) Q9WXS7
XloG (M) (TM0073) Q9WXS8
XloK (C) (TM0074) Q9WXS9
XloL (C) (TM0075) Q9WXT5

Probable cellobiose porter. Induced by barley, glucomannan (Conners et al., 2005)

CelEFGKL of Thermotoga maritima
CelE (R) (TM1223) Q9X0V0
CelF (M) (TM1222) Q9X0U9
CelG (M) (TM1221) Q9X0U8
CelK (C) (TM1220) Q9X0U7
CelL (C) (TM1219) Q9X0U6

Probable mannose/mannoside porter. Induced by beta-mannan (Conners et al., 2005). Regulated by mannose-responsive regulator manR (Kazanov et al., 2012).

MtpEFGKL of Thermotoga maritima
MtpE (R) (TM1746) Q9X268
MtpF (M) (TM1747) Q9X269
MtpG (M) (TM1748) Q9X270
MtpK (C) (TM1749) Q9X271
MtpL (C) (TM1750) Q9X272

β-glucoside porter (Conners et al., 2005). Binds cellobiose, laminaribiose (Nanavati et al. 2006). Regulated by cellobiose-responsive repressor BglR (Kazanov et al. 2012).

BglpEFGKL of Thermotoga maritima
BglE (R) (TM0031) Q9WXN8
BglF (M) (TM0030) Q9WXN7
BglG (M) (TM0029) Q9WXN6
BglK (C) (TM0028) Q9WXN5
BglL (C) (TM0027) Q9WXN4

The proline betaine uptake porter (Alloing et al., 2006)

PrbABCD of Sinorhizobium meliloti
PrbA (R) (Q92NF1)
PrbB (M) (Q92NF0)
PrbC (M) (Q92NE9)
PrbD (C-C) (Q92NE8)

The oligopeptide transporter OppA1-5, B1, C1, DF (functions with five binding proteins of differing induction properties and peptide specificities; OppA1-3 are chromosomally encoded; OppA4 and 5 are plasmid encoded.) (Medrano et al., 2007)
OppA1-5,B1,C1,D,F of Borrelia burgdorferi
OppA1 (R): O51307
OppA2 (R): O54584
OppA3 (R): O51308
OppA4 (R): O31315
OppA5 (R): O50927
OppB1 (M): O31307
OppC1 (M): O51310
OppD (C): O31309
OppF (C): O31310

The major oligopeptide uptake porter, Opp-3 (of four paralogues, this is the only one that mediates nitrogen nutrition (Hiron et al., 2007).
Opp-3 of Staphylococcus aureus
OppB (M) = (Q2FZR7)
OppC (M) = (Q2FZR6)
OppD (C) = (Q2FZR5)
OppF (C) = (Q2FZR4)
OppA (R) = (Q2FZR3)

5-6 amino acyl oligopeptide transporter AppA-F (Koide and Hoch, 1994).
AppABCDF of Bacillus subtilis
AppA(R) (P42061)
AppB(M) (P42062)
AppC(M) (P42063)
AppD(C) (P42064)
AppF(C) (P42065)

The Microcin C/peptide uptake porter, YejABEF (Novikova et al., 2007).  The 'Trojan horse' antibiotic, microcin C, consists of a nonhydrolyzable aspartyl-adenylate that is efficiently imported into bacterial cells owing to a covalently attached peptide. Once inside the cell, the peptide "carrier" is removed by proteolytic processing to release a potent aspartyl tRNA synthetase inhibitor (Severinov and Nair 2012).

YejABEF of E. coli:
YejA (R) (P33913)
YejB (M) (P0AFU1)
YejE (M) (P33915)
YejF (C-C) (P33916)

The peptide transporter OppA,B,C,D,F (influences biofilm formation; Lee et al., 2004). Similar to 3.A.1.5.1, OppA is similar to the Vibrio furnissii OppA that provides several functions: hemolysis, antibiotic resistance, and virulence (Wu et al., 2007).
OppABCDF of Vibrio fluvialis:
OppA (R) (Q5V9S2)
OppB (M) (Q5V9S1)
OppC (M) (Q5V9S0)
OppD (C) (Q5V9R9)
OppF (C) (Q5V9R8)

The Ethylene diamine tetraacetate (EDTA) uptake porter, EppABCD (Zhang et al., 2007).

EppABCD of EDTA-degrading bacterium BNC1:
EppA (R) (Q9F9T7)
EppB (M) (Q9F9T6)
EppC (M) (Q9F9T5)
EppD (C-C) (Q9F9T4)

The antimicrobial peptide (protamine, melittin, polymyxin B, human defensin (HBD)-1 and HBD-2 exporter, YejABEF (Eswarappa et al., 2008). Prefers N-formyl methionine peptides, such as Microcin C (of prokaryotic origin) to non formylated peptides (of eukaryotic origin) (Novikova et al., 2007).

YejABEF of Salmonella enterica
YejA (R) (Q8ZNK0)
YejB (M) (Q7CQ74)
YejE (M) (Q8ZNJ9)
YejF (C-C) (Q8ZNJ8)

The ABC peptide/signalling peptide transporter. OptA binds peptides of 3-6 aas; OptS binds dipeptides. OptB,C,D are most similar to 3.A.1.5.19.

The OptASBCDF transport system of Lactococcus lactis
OptS (R) (Q64K09)
OptA (R) (Q9CIL2)
OptB (M) (Q9CILI)
OptC (M) (Q9CIL0)
OptD (C) (Q9CIK9)
OptF (C) (Q9CIK8)

The glutathione transporter, OppA (Dasgupta et al., 2010). OppA binds glutathione and the nanopeptide, bradykinin. Also regulates cytokine release, apoptosis and the innate immune response of macrophages infected with M. tuberculosis (Dasgupta et al., 2010).

Peptide transporter of Mycobacterium tuberculosis
OppA (R) (P66771)
OppD (C) (P63395)
OppC (M) (P66964)
OppB (M) (P66966)

The glutathione uptake porter, DppBCDF with the glutathione binding protein, DppA (GbpA; HbpA). Takes up reduced (GSH) and oxidized (GSSG) but not bulky glutathione S conjugates or glutathione derivatives with C-terminal modifications (Vergauwen et al., 2010).

DppABCDF of Haemophilus influenzae
DppA (R) (P33950)
DppB (M) (P45096)
DppC (M) (P51000)
DppD (C) (P45095)
DppF (C) (P45094)

The Nickel (Ni2+) uptake porter, NikZYXWV (Howlett et al., 2012).

NikZYXWV of Campylobacter jejuni 
NikZ (R) (Q0P844)
NikY (M) (Q0P845)
NikX (M) (Q0P846)
NikW (C) (Q0P847)
NikV (C) (Q0P848) 

Probable xylan oligosaccharide porter (Conners et al. 2005). Induced by cylan and xylose. Regulated by xylose-responsive regulator XylR (Kazanov et al. 2012).

XtpELKGF of Thermotoga maritima
XtpE (R) (TM0056) (Q9WXR2)
XtpL (C) (TM0057) (Q9WXR3)
XtpK (C) (TM0058) (Q9WXR4)
XtpG (M) (TM0059) (Q9WXR5)
XtpF (M) (TM0060) (Q9WXR6)

Putative fucose-glucose oligosaccharide porter. Binds xyloglucan hepta-, octa-, nonasaccharides with beta-1,4- tetraglucosyl backbones (Conners et al., 2005)

GloEFGKL of Thermotoga maritima
GloE (R) (TM0300) (Q9WYD6)
GloF (M) (TM0301) (Q9WYD7)
GloG (M) (TM0302) (Q9WYD8)
GloK (C) (TM0303) (Q9WYD9)
GloL (C) (TM0304) (Q9WYE0)  

Predicted galactoside porter. Induced by lactose (Conners et al., 2005)

LtpE (R) (TM1199) Q9X0S6 LtpF (M) (TM1198) Q9X0S5 LtpG (M) (TM1197) Q9X0S4 LtpK (C) (TM1196) Q9X0S3 LtpL (C) (TM1194) Q9S5X6

ABC α-galactoside uptake porter.  Most highly induced by stachyose (Andersen et al. 2012).

ABC α-galactoside uptake porter of Lactobacillus acidophilus
F0TFS5 (R)
F0TFS6 (R)
F0TFS7 (M)
F0TFS8 (M)
F0TFS9 (C)
F0TFT0 (C)

The Nickel (Ni2+) uptake porter, NikABCDE (Hiron et al. 2010)

NikABCDE of Staphylococcus aureus 
NikA (R) (G8V0I4)
NikB (M) (I0C488)
NikC (M) (I0C487)
NikD (C) (I0C7E8)
NikE (C) (I0C7E7) 

Putative oligopeptide uptake porter. Induced by S-adenosylmethionine. Deletion caused impaired sporulation and impaired the enhancing activity of S-adenosylmethionine on actinorhodin (but not undecylprodigiosin) production (Shin et al. 2007).

Putative oligopeptide uptake porter of Streptomyces coelicolor
Sco_5476 (M) (O86571)
Sco_5477 (R) (O86572)
Sco_5478 (M) (O86573)
Sco_5479 (C) (O86574)
Sco_5480 (C) (O86575) 

Putative peptide transporter encoded adjacent to the putative transport system with TC#3.A.1.5.36. The orthologue controls aerial mycelium formation in S. griseus (Akanuma et al. 2011).

Sco_5117-Sco_5121 of Streptomyces coelicolor
Sco_5117 (R) (Q9F353)
Sco_5118 (M) (Q9F352)
Sco_5119 (M) (Q9F351)
Sco_5120 (C) (Q9F350)
Sco_5121 (C) (Q9F349)

Peptide transporter encoded adjacent to the putative transport system with TC#3.A.1.5.35 (Akanuma et al. 2011). Induced by exogenous S-adenosylmethionine (SAM) at a concentration of 2muM which also enhanced antibiotic production and inhibited morphological development (Park et al. 2005). SAM can be imported into cells. Mutants in the bldK genes confer resistance to the toxic tripeptide, bialaphos (Nodwell et al. 1996).

BldKA-D and Sco_5116 of Streptomyces coelicolor 
BldKA (Sco_5112) (M) (Q93IU3)
BldKB (Sco_5113) (R) (Q93IU2)
BldKC (Sco_5114) (M) (Q93IU1)
BldKD (Sco_5115) (C) (Q93IU0)
Sco_5116 (C) (Q8CJS2) 

The ABC BldKA-E (SGR_2418-2414) oligopeptide transport system. It controls aerial mycelium formation on glucose media. Probably involved in extracellular peptide signalling (Akanuma et al. 2011).  Probably orthologous to 3.A.1.5.35.

BldKA-E of Streptomyces griseus
SGR_2417; BldKA (M) (B1W1M1)
SGR_2418; BldKB (R) (B1W1M2)
SGR_2419; BldKC (M) (B1W1M0)
SGR_2420; BldKD (C) (B1W1L9)
SGR_2421; BldKE (C) (B1W1L8) 

The putative D-alanyl-D-alanyl dipeptide permease, DdpABCDF; encoded within an operon that includes the D-ala-D-ala peptidase, DdpX (VanX, YddT). May also interact with the YegQ peptidase (P76403).

DdpABCDF of E. coli
DdpA (R)
DdpB (M)
DdpC (M)
DdpD (C)
DdpF (C)  

Di- and tri-peptide transporter, DppBCDF with periplasmic substrate binding receptors, A1, A3, A5, A7 and A9, each with differing specificities for peptides (Pletzer et al. 2014).

Dpp transporter of Pseudomonas aeruginosa
DppB, (M)
DppC (M)
DppD (C)
DppF (C)
DppA1 (R)
DppA3 (R)
DppA5 (R)
DppA7 (R)
DppA9 (R)

Nickel uptake porter, NikAB(CD)E (Benoit et al. 2013).

NikAB(CD)E of Helicobacter hepaticus
NikA (R)
NikB (M)
NikCD (M-C)
NikE (C)

Oligopeptide transporter, OppABCDF/MppA/YgiS.  MppA is a murein peptide receptor, and YgiS is a bile acid (e.g., cholate, deoxycholate) receptor that may use the Opp system for uptake.  YgiS mRNA is degraded by the toxin, MgsR, which is regulated by the antitoxin, MgsA, and this loss of the mRNA protects the cell against bile acid stress (Kwan et al. 2015). oppA translation is activated by MicF through a mechanism of action involving facilitated access to a translation-enhancing region in oppA 5'UTR.  MicF activation of oppA translation depends on cross-regulation by negative trans-acting effectors, the GcvB sRNA and the RNA chaperone protein Hfq (Carrier et al. 2023).

OppABCDF/MppA/YgiS system of E. coli
OppA (R)

OppB (M)
OppC (M)
OppD (C)
OppF (C)
MppA (R)
YgiS (R)

Peptide transporter, SapABCDF

SapABCDF of E. coli
SapA (R)
SapB (M)
SapC (M)
SapD (C)
SapF (C)

The metal-staphylopine (nicotianamine-like metalophore) complex uptake system, CntABCDF.  Staphylopine binds divalent nickel, cobalt, zinc, copper and iron (Ghssein et al. 2016).

Metal-staphylopine uptake system, CntABCDF of Staphylococcus aureus

Peptide transporter, SapABCDF. Mutants are more sensitive than the wild type to wheat alpha-thionin and to snakin-1, which is the most abundant antimicrobial peptide from potato tubers. They were also less virulent than was the wild-type strain in potato tubers: lesion areas were 37% that of the control, and the growth rate was two orders of magnitude lower. Thus, the interaction of antimicrobial peptides from the host with the sapA-F operon from the pathogen plays a similar role in animal and in plant bacterial pathogenesis (López-Solanilla et al. 1998).

SapABCDF of Dickeya chrysanthemi (Pectobacterium chrysanthemi) (Erwinia chrysanthemi)
SapA, 540 aas, R
SapB, 313 aas, M
SapC, 296 aas, M
SapD, 330 aas, C
SapF, 269 aas, C

Uncharacterized 5 component peptide uptake transporter with a receptor, two transmembrane proteins and two ATPases, as is common for this family of ABC porters. The five genes encoding this system, from metagenomic data for an uncultured Lokiarchaeon, occur adjacent to each other in the genome (Zaremba-Niedzwiedzka et al. 2017).

Candidatus Lokiarchaeota
UP of Lokiarchaeum sp. GC14_75

Putative oligopeptide transporter, OppA1A2BCDF. The two membrane proteins (OppB and OppC, of 564 and 670 aas with 13 and 15 TMSs, respectively (M-subunits)) and the two ATPases (C-subunits of 342 and 369 aas, respectively) map together, but the 4 potential receptors (R) map elsewhere on the chromosome. Two of them appear to be complete and have 734 and 738 aas, respectively, each with 2 TMSs, one N-terminal and one C-terminal.  There are two other potential receptors that may not have complete sequences.  They are OLS21443 (721 aas with only 1 C-terminal TMS) and OLS22122 (353 aas with only 1 N-terminal TMS).

Candidatus Heimdallarchaeota
Putative oligopeptide transporter of six probable subunits, 2 Rs, 2 Ms, and 2 Cs, of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

Peptide uptake porter, DppABCDF (Asai et al. 2018).

DppABCDF of Treponema denticola

Putative peptide uptake porter, DppABCD where A is a periplasmic receptor (R) B and C are membrane proteins (M) and D is a cytoplasmic ATPase (C) (Mandal et al. 2021).

DppABCD of Mycobacterium tuberculosis
DppA, R, 541 aas, I6X811
DppB, M, 266 aas, L0TEV4
DppC, M, 308 aas, I6YGV9
DccD, C, 548 aas, I6Y482

YejABEF with four subunits as indicated with YejA, a periplasmic peptide binding protein of 610 aas and 1 N-terminal TMS, YejB, a membrane protein with 360 aas and 6 TMSs, YejE, a membrane protein with 377 aas and 6 TMSs, and YejF, and an ATPase with 542 aas.

YejABEF of Sinorhizobium meliloti (Rhizobium meliloti)
3.A.1.6:  The Sulfate/Tungstate Uptake Transporter (SulT) Family

Sulfate/thiosulfate porter

Sbp (sulfate receptor)-CysP (thiosulfate receptor)-CysTWA of E. coli
Sbp (R)
CysP (R)
CysT (M)
CysW (M)
CysA (C)

Tungstate porter. (TupA, the receptor, exhibits an extremely high affinity for tungstate (Kd <1 nM) and discriminates between tungstate and molybdate (Andreesen and Makdessi, 2007))

TupABC of Eubacterium acidaminophilum
TupA (R)
TupB (M)
TupC (C)

Sulfate porter
CysAWT SubI-sulfate porter of Mycobacterium tuberculosis
CysA (C)
CysW (M)
CysT (M)
SubI (R)

Vanadate porter (Pratte and Thiel, 2006) (most similar to TupABC (3.A.1.6.2))
VupABC of Anabaena variabilis ATCC29413
VupA (R) (ABA23645)
VupB (M) (ABA23644)
VupC (C) (ABA23643)

Tungsten (KM=20pM)/molybdate (KM=10nM) porter (Bevers et al., 2006)
WtpABC of Pyrococcus furiosus
WtpA (R) (Q8U4K5)
WtpB (M) (Q8U4K4)
WtpC (C) (Q8U4K3)

The Molybdate/Tungstate Transporter, ModA-C (Zhang and Gladyshev, 2008).
ModABC of Pyrobaculum calidifontis
ModA (R) (A3MW02)
ModB (M) (A3MW01)
ModC (C) (A3MW00)

The chloroplast sulfate transporter, SulP/SulP2/Sabc/Sbp (Melis & Chen et al., 2005).

Viridiplantae, Chlorophyta
Chloroplast sulfate uptake permease of Chlamydomonas reinhardtii
SulP (M) (Q8RVC7)
SulP2 (M) (Q6QJE2)
Sabc (C) (Q6QJE1)
Sbp (R) (Q6QJE0)

Molybdate/tungstate transport system, ModABC (WtpABC) (ModA binds to ModBC with high affinity (0.11%u03BCM) and dissociates slowly; the complex is destabilized by nucleotide and substrate binding (Vigonsky et al. 2013).

ModABC of Archeoglobus fulgidus
ModB (M; 12 TMSs; type I fold) (O30143)
ModC (C) (O30144)
ModA (R) (O30142)

The putative molybdate, tungstate, selenite transporter, WtpBC (Kim and Whitman 1999).
WtpB of 249 aas (M) (Q58763)
WtpC of 297 aas (C) (Q58762)
WtpA of 346 aas (R) (Q58586)

WtpBC of Methanocaldococcus jannaschii (Methanococcus jannaschii)

Tungstate uptake porter with three subunits, R, M and C (Mandal et al. 2019).

Tungstate porter of Thermus thermophilus

High affinity tungstate-specific uptake porter (Km = 1 pM) (Smart et al. 2009).

Tungstate porter of Campylobacter jejuni
TupA, R, 269 aas and 1 N-terminal TMS
TupB, M, 239 aas and 6 TMSs
TupC, C, 331 aa

Putative (partial) sulfate/thiosulfate uptake porter (Choi and Ford 2021).  An ATPase and a membrane protein are known, but the other constituents are not known.  These proteins are most similar to the chloroplast sulfate uptake transporter (TC# 3.A.1.6.7) in TCDB, but the receptor and one membrane constituent are not known.

Viridiplantae, Streptophyta
CysA/CysT of Marchantia polymorpha (Liverwort) (Marchantia aquatica)
3.A.1.7:  The Phosphate Uptake Transporter (PhoT) Family

Phosphate porter, PhoSPstABC.  Serves as both a transporter and a sensor for transcriptional activation of the pho regulon in the presence of low external phosphate.  The unphosphorylated EIIANtr protein of the PTS (TC# 4.A) activates PhoR, the senor kinase that phosphorylates the response regulator, PhoB, that activates the pho regulon (Lüttmann et al. 2012).

PhoS (phosphate receptor)-PstABC of E. coli
PhoS (R)
PstA (M)
PstC (M)
PstB (C)

Phosphate transporter, PstSCAB (Gebhard and Cook, 2007).
PstSCAB of Mycobacterium smegmatis
PstS (R) (Q7WTY8)
PstC (M) (Q7WTY7)
PstA (M) (Q7WTY6)
PstB (C) (P0C560)

High-affinity phosphate-specific permease, PstAB/PhoS. The 3-d structure of PhoS = (PBP) = PfluDING) has been solved at high resolution by x-ray crystallography (Ahn et al. 2007) with phosphate bound (4F1U and 4F1V; 0.95Å resolution) and with arsenate bound (4F18 and 4F19; 0.88Å resolution) (Elias et al. 2012). Phosphate binds with 500-fold higher affinity than arsenate due to a dense and rigid network of ion-dipole interactions (Elias et al. 2012). The PBP from Halomonas sp. GFAJ-1 has a phosphate affinity 5000-fold higher than that of arsenate (Elias et al. 2012).

PstAB/PhoS of Pseudomonas fluorescens
PstA (C) (C3KCB5)
PstB (M) (C3KCB6)
PstC (PBP) (R) (D0VWY2) 

High specificity inorganic phosphate porter, PstABCS (Sarin et al. 2001). May also function as a regulator of extracellular vesicle formation via the SenX3/RegX3 two component system (White et al. 2018).

PstABCS of Mycobacterium tuberculosis 
PstA2 (M) (P0A627)
PstB2 (C) (P95302)
PstC2 (M) (P0A630)
PstS2 (R) (O05870) 

The phosphate transporter, PstABCS.  The structure of PstS is known to 1.3Å resolution (Brautigam et al. 2013).

PstABCS of Borrelia burgdorferii
PstA (M) (O51235)
PstB (C) (O51236)
PstC (M) (O51234)
PstS (R) (O51233)

High affinity phosphate-specific transporter, PstABCS, where PstA (AAZ57802) = 304 aas with 6 TMSs, PstB (AAZ57801) = 267 aas with 0 TMSs (the ATPase), PstC (AAZ57803) = 317 aas with 6 TMSs, PstS (Q46L27 or AAX46970) = 321 aas and 1 N-terminal TMS; this PstS homolog is encoded by Prochlorococcus phage P-SSM3 (Zhao et al. 2022).

PstABCS of Prochlorococcus NATL2A
3.A.1.8:  The Molybdate Uptake Transporter (MolT) Family

Molybdate porter consisting of three proteins.  Molybdate, after transport into cells by the ModABC proteins, is metabolized by the products of the mol gene(s) (Maupin-Furlow et al. 1995). The repressor of the mod operon is ModE (Grunden et al. 1996).

ModABC of E. coli
ModA (R)
ModB (M)
ModC (C)

The molybdate/tungstate ABC transporter, ModABC. The trans-inhibited 3-d structure of ModABC, is available (3D31.A and 3D31.B)(Gerber et al., 2008)

ModABC of Methanosarcina acetivorans
ModA (Q8TTV0)
ModB (M) (Q8TJ86)
ModC (C) (Q8TTV2)

Molybdate uptake porter with three components, R, M and C (Mandal et al. 2019).

Molybdate porter of Thermus thermophilus

Molybdate/tungstate uptake porter, ModABC with a Km of 4 - 8 μM for its two substrates (Smart et al. 2009).

ModABC of Campylobacter jejuni
ModA, R, 133 aas and 1 N-terminal TMS
ModB, M, 224 aas and 5 TMSs
ModC, C, 294 aa

Molybdenum (MoO42-) uptake porter with three subunits, the receptor, R, ModA, of 261 aas (P9WGU3), the membrane protein, M, ModB, of 264 aas and 6 TMSs (P9WG13), and the cytoplasmic ATPase, C, ModC, of 369 aas (P9WQL3) (Mandal et al. 2021).

ModABC of Mycobacterium tuberculosis
ModA, R
ModB, M
ModC, C
3.A.1.9:  The Phosphonate Uptake Transporter (PhnT) Family

Phosphonate/organophosphate ester porter (broad specificity). Reviewed by Hinz & Tampé (2012).

PhnCDE of E. coli
PhnC (C)
PhnD (R)
PhnE (M)

Putative phosphonate/phosphite/phosphate porter, PhnDCE (Gebhard and Cook, 2007)

PhnDCE of Mycobacterium smegmatis
PhnC (C) (A0QQ70)
PhnD (R) (A0QQ71)
PhnE (M) (A0QQ68)

Phosphite uptake porter, PhnDCE of 252 aas (PhnC; Q119J0; C), 298 aas and 1 N-terminal TMS (PhnD; Q119I9; R) and 272 aas and 6 TMSs (PhnE; Q119I8; M) (Polyviou et al. 2015).

PhnCDE of Trichodesmium erythraeum

Phosphite/phosphonate/hypophosphite ABC transporter, HtxBCDE (Metcalf and Wolfe 1998; White and Metcalf 2004). HtxC residue F210 is a "gatekeeper" for this transporter (Hirota et al. 2022).

HtxBCDE of Pseudomonas stutzeri (Pseudomonas perfectomarina)
HtxB, R, O69061, 298 aas and 1 N-terminal TMS
HxtC, M, O69062, 282 aas and 5 or 6 TMSs
HxtD, C, O69063, 341 aas and 0 TMSs
HxtE, M, O69064, 261 aas and 5 or 6 TMSs
3.A.1.10:  The Ferric Iron Uptake Transporter (FeT) Family

Ferric iron (Fe3+) porter, SfuABC (Angerer et al. 1990). These iron uptake systems have been reviewed (Angerer et al. 1992). Delepelaire 2019 reviewed structural and functional aspects of iron ABC transporters with emphasis on their substrate binding proteins.

SfuABC of Serratia marcescens
SfuA (R)
SfuB (M)
SfuC (C)

Ferric iron (Fe3+) porter
Fut A1A2BC of SynechocystisPCC6803
FutA1 (R)
FutA2 (R)
FutB (M)
FutC (C)

Ferric iron (Fe3+) porter, FbpABC or HitABC (selective for trivalent cations, Fe3+, Ga3+ and Al3+) (Anderson et al., 2004)

FbpABC (HitABC) of Haemophilus influenzae
FbpA (R) (AAC21773)
FbpB (M) (AAC21774)
FbpC (C) (AAC21775)

The Fe-hydroxamate-type siderophore uptake porter (transports Fe+3 bound to ferrioxamine, ferrichrome or pyoverdine siderophores) (Vajrala et al., 2010).

NitABC of Nitrosomonas europaea
NitA (R) (Q82VN7)
NitB (M) (Q82VN6)
NitC (C) (Q82VN5)

Siderophore-independent iron uptake system, AfuABC (Saken et al. 2000).

AfuABC of Yersinia enterocolitica
AfuA (R)
AfuB (M)
AfuC (C)

Fe3+ uptake porter consisting of 3 subunits, R, 330 aas, M, 516 aas and 12 TMSs, and C, 350 aas (Mandal et al. 2019).

Fe3+ uptake porter of Thermus thermophilus with 3 subunits.
3.A.1.11:  The Polyamine/Opine/Phosphonate Uptake Transporter (POPT) Family

Polyamine (putrescine/spermidine) uptake porter.  Plays a role in biofilm formation (Zhang et al. 2013).  Spermidine-preferring (Igarashi and Kashiwagi 1996).

PotABCD of E. coli
PotA (C)
PotB (M)
PotC (M)
PotD (R)

Putrescine porter (Igarashi and Kashiwagi 1996).

PotGHIF of E. coli
PotG (C)
PotH (M)
PotI (M)
PotF (R)

Mannopine porter
MotABCD of Agrobacterium tumefaciens plasmid pTi15955
MotA (R)
MotB (C)
MotC (M)
MotD (M)

Chrysopine porter
ChtGHIJK of Agrobacterium tumefaciens
ChtG (C)
ChtH (R)
ChtI (R)
ChtJ (M)
ChtK (M)

2-aminoethyl phosphonate porter
PhnSTUV of Salmonella typhimurium
PhnS (R)
PhnT (C)
PhnU (M)
PhnV (M)

The γ-aminobutyrate (GABA) uptake system, GtsABCD (White et al., 2009).
GtsABCD of Rhizobium leguminosarum
GtsA (R) (Q1M7Q4)
GtsB (M) (Q1M7Q3)
GtsC (M) (Q1M7Q2)
GtsD (C) (Q1M7Q1)

PotABCD of Streptococcus pneumoniae
PotA (C) 385 aas
PotB (M) 275 aas (also called PotH)
PotC (M) 257 aas
PotD (R) 356 aas

The spermine/spermidine uptake porter, PotABCD.

PotABCD of Staphylococcus aureus
PotA (C)
PotB (M)
PotC (M)
PotD (R)  

Putative polyamine (spermidine/putrescine) uptake porter, YdcSTUV (Moussatova et al. 2008). May also be involved in the uptake of double stranded DNA (Sun 2018).

YdcSTUV of E. coli
YdcS (R; 381 aas)
YdcT (C; 337 aas)
YdcU (M; 313 aas)
YdcV (M; 264 aas)

The 3-component polyamine uptake transporter, PotABD. Transports homospermidine and possibly other polyamines. Inactivation of the potADB gene cluster (potADB) disrupted diazotrophic growth, clearly suggesting the importance of polyamine homeostasis in Anabaena. (Burnat et al. 2018). 

PotABD of Anabaena variabilis
3.A.1.12:  The Quaternary Amine Uptake Transporter (QAT) Family (Similar to 3.A.1.16 and 3.A.1.17)

Glycine betaine/proline porter, ProU or ProVWX (also transports proline betaine, carnitine, dimethyl proline, homobetaine, γ-butyrobetaine and choline with low affinity).  Contributes to the regulation of cell volume is response to osmolarity.  A reconsituted system shows osmotic strength-gating (Gul and Poolman 2012).

ProVWX of E. coli
ProW (M)
ProX (R)
ProV (C)

Glycine betaine OpuAA/AB/AC porter (also transports dimethylsulfonioacetate and dimethylsulfoniopropionate).  The system has been reconstituted in nanodiscs and shows substrate-dependent ionic stringth-gated gating and energy coupling dependent on anionic lipids (Karasawa et al. 2013).

OpuAA, AB, AC of Bacillus subtilis
OpuAA (C)
OpuAB (M)
OpuAC (R)

Choline porter
OpuBA, BB, BC, BD of Bacillus subtilis
OpuBA (C)
OpuBB (M)
OpuBC (R)
OpuBD (M)

Uptake system for choline, L-carnitine, D-carnitine, glycine betaine, proline betaine, crotonobetaine, γ-butyrobetaine, dimethylsulfonioacetate, dimethylsulfoniopropionate, ectoine and choline-O-sulfate
OpuCA, CB, CC, CD of Bacillus subtilis
OpuCA (C)
OpuCB (M)
OpuCC (R)
OpuCD (M)

Uptake system for glycine-betaine (high affinity) and proline (low affinity) (OpuAA-OpuABC) or BusAA-ABC of Lactococcus lactis). BusAA, the ATPase subunit, has a C-terminal tandem cystathionine β-synthase (CBS) domain which is the cytoplasmic K+ sensor for osmotic stress (osmotic strength)while the BusABC subunit has the membrane and receptor domains fused to each other (Biemans-Oldehinkel et al., 2006; Mahmood et al., 2006; Gul et al. 2012). An N-terminal amphipathic α-helix of OpuA is necessary for high activity but is not critical for biogenesis or the ionic regulation of transport (Gul et al., 2012). ATP and glycine betaine dependences of conformational changes have been examined (Tassis et al. 2020).

BusAA-AB of Lactococcus lactis
BusAB (M-R)

Uptake system for hisitidine, proline, proline-betaine and glycine-betaine
HutXWV of Sinorhizobium meliloti
HutX (R)
HutW (M)
HutV (C)

High affinity (3 μM) choline-specific uptake system (Dupont et al., 2004)
ChoXWV of Sinorhizobium meliloti
ChoX (R) (AAM00244)
ChoW (M) (AAM00245)
ChoV (C) (AAM00246)

A proline/glycine betaine uptake system. Also reported to be a bile exclusion system that exports oxgall and other bile compounds, BilEA/EB or OpuBA/BB (required for normal virulence) (R.D. Sleator et al., 2005).
OpuBA/BB or BilEA/EB of Listeria monocytogenes
OpuBA (C) (Q93A35)
OpuBB (M-R) (Q93A34)

The salt-induced glycine betaine OtaABC transporter (Schmidt et al., 2007)
OtaABC of Methanosarcina mazei Go1
OtaA (C) Q8U4S5
OtaB (M) Q8U4S4
OtaC (R) Q8U4S3

The OpuC transporter selective for glycine betaine > choline, acetylcholine, carnitine and proline betaine (contains tandem cystathionine-β-synthase (CBS) domains in the ABC component of OpuC that are required for osmoregulatory function (Chen and Beattie, 2007)).
OpuCA, CB, CC of Pseudomonas syringae
OpuCC (R) (Q87WH3)
OpuCB (M) (Q87WH4)
OpuCA (C) (Q87WH5)

The glycine betaine uptake porter, GbpABCD (Saum et al., 2009).
GbpABCD of Methanosarcina mazei
GbpA (R) (Q8Q040)
GbpB (M) (Q8Q043)
GbpC (M) (Q9Q042)
GbpD (C) (Q8Q041)

The CbcWV/CbcX (choline)/CaiX (carnitine)/BetX (betaine) transporter with 3 binding receptors for distinct quaternary ammonium compounds. Only the ligand-bound receptor binds to the transporter with high affinity (Chen et al., 2010; Thomas et al., 2010).

CbcWV/CbcX/CaiX/BetX of Pseudomonas aeruginosa
CbcW (M) (Q9HTI7)
CbcV (C) (Q9HTI8)
CbcX (R) (Q9HTI6)
CaiX (R) (Q9HTH6)
BetX (R) (Q9HZ04)

High affinity (2mμM) choline uptake porter. The choline binding receptor exhibits a venus fly trap mechanism of substrate binding. (ChoX binds acetyl choline and betaine with low affinity (80μM and 470μM, respectively) (Aktas et al., 2011) (most similar to 3.A.1.12.7)

ChoVWX of Agrobacterium tumefaciens 
ChoX (R) (Q7CXG0)
ChoW (M) (Q7CXG1)
ChoV (C) (A9CI32)

OsmU (OsmVWXY) transporter for glycine betaine and choline-O-sulfate uptake. Induced by osmotic stress (0.3M NaCl) (Frossard et al., 2012). Also called OpuCA/CB1/CB2/CC.

OsmU or OsmVWXY of Salmonella enterica 
OsmV (STM1491) (C) (Q8ZPK4)
OsmW (STM1492) (M) (Q8ZPK3)
OsmX (STM1493) (R) (Q8ZPK2)
OsmY (STM1494) (M) (Q8ZPK1) 

Putative osmoprotectant (glycine/betaine/choline) uptake transporter, YehWXYZ.  Induced by osmotic stress and growth into the stationary phase; under RpoS (σS) control (Ibanez-Ruiz et al. 2000; Checroun and Gutierrez 2004).  YehZ is also called OsmF.

YehWXYZ of E. coli
YehW (M) 243 aas
YehX (C) 308 aas
YehY (M) 385 aas
YehZ or OsmF (R) 305 aas

Glycine betaine/carnitine/choline/proline transporter, OpuABC. It is not a dominant proline transporter which in S. aureus are, however, PutP and ProT (Lehman et al. 2023). The sequence of OpuB, the membrane component of the system, is not included here. The 3-d structure of OpuC (or a part of it) has been solved (5IIP_A-D).


OpuABC of Staphylococcus aureus
3.A.1.13:  The Vitamin B12 Uptake Transporter (B12T) Family (Similar to 3.A.1.14)

Vitamin B12 porter. The 3-D structure of BtuCDF has been solved to 2.6 Å (Hvorup et al., 2007). The conformational transition pathways of BtuCD has been revealed by targeted molecular dynamics simulations (Weng et al., 2012). Asymmetric states of BtuCD are not discriminated by its cognate substrate binding protein BtuF (Korkhov et al., 2012).  ATP hydrolysis occurs at the nucleotide-binding domain (NBD) dimer interface, whereas substrate translocation takes place at the translocation pathway between the TM subunits, which is more than 30 angstroms away from the NBD dimer interface.  Hydrolysis of ATP appears to facilitate substrate translocation by opening the cytoplasmic end of translocation pathway (Pan et al. 2016). The molecular mechanism of ATP hydrolysis by BtuCD-F may proceeds in a stepwise manner (Prieß et al. 2018). First, nucleophilic attack of an activated lytic water molecule at the ATP gamma-phosphate yields ADP + HPO42-. A conserved glutamate located close to the gamma-phosphate transiently accepts a proton acting as a catalytic base. In the second step, the proton transfers back from the catalytic base to the gamma-phosphate, yielding ADP + H2PO4-. These two reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The overall free energy change of the reaction is close to zero, suggesting that ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing. ATP hydrolysis resets the conformational cycle (Prieß et al. 2018).

BtuCDF of E. coli
BtuC (M)
BtuD (C)
BtuF (R)

Putative cobalamin (vitamin B12) uptake porter, BtuFCD (Rodionova et al. 2015).

BtuFCD of Chloroflexus aurantiacus
BtuF (R; 1 TMS)
BtuC (M; 9 TMSs)
BtuD (C; 0 TMSs)
3.A.1.14:  The Iron Chelate Uptake Transporter (FeCT) Family (Similar to 3.A.1.13 and 3.A.1.15)

Iron (Fe3+) or ferric-dicitrate porter, FecBCDE (Braun and Herrmann, 2007). The Mycobacterium tuberculosis (Mtb) ortholog has two substrate binding proteins, FecB and FecB2 (de Miranda et al. 2023).  The crystallographic structures of Mtb FecB and FecB2 were determined to 2.0 Å and 2.2 Å resolution, respectively, and they show distinct ligand binding pockets. In vitro ligand binding experiments for FecB and FecB2 were performed with heme and bacterial siderophores from Mtb and other species, revealing that both FecB and FecB2 bind heme, while only FecB binds the Mtb sideophore ferric-carboxymycobactin (Fe-cMB). Subsequent structure-guided mutagenesis of FecB identified a single glutamate residue-Glu339-that significantly contributes to Fe-cMB binding (de Miranda et al. 2023).

FecBCDE of E. coli
FecB (R)
FecC (M)
FecD (M)
FecE (C)

Iron (Fe3+)-enterobactin porter

FepBCDG of E. coli
FepB (R) (C8U2V6)
FepC (C) (P23878)
FepD (M) (P23876)
FepG (M) (P23877)

Iron (Fe3+)-hydroxamate (ferrichrome, coprogen, aerobactin, ferrioxamine B, schizakinen, rhodotorulic acid) porter, albomycin porter.  A FtsZ inhibitor can utilize siderophore-ferric iron uptake transporter systems, FepA, CirA (outer membrane transporters) and FhuBC (inner membrane transporter) for activity against Gram-negative bacterial pathogens (Bryan et al. 2024).

FhuBCD of E. coli
FhuB (M-M; 20 TMSs; 10+10)
FhuC (C)
FhuD (R)

Iron-chrysobactine porter
CbrABCD of Erwinia chrysanthemi
CbrA (R)
CbrB (M)
CbrC (M)
CbrD (C)

Heme (hemin) uptake porter. The receptor, HmuT, binds two parallel stacked heme molecules, and two are transported per reaction cycle (Mattle et al., 2010).

HmuTUV of Yersinia pestis
HmuT (R) (Q56991)
HmuU (M) (Q56992)
HmuV (C) (Q56993)

The iron-vibriobactin/enterobactin uptake porter
ViuPDGC of Vibrio cholerae
ViuP (R)
ViuD (M)
ViuG (M)
ViuC (C)

Iron (Fe3+)-hydroxamate porter (transports Fe3+-ferrichrome and Fe3+-ferrioxamine B with FhuD1, and these compounds plus aerobactin and coprogen with FhuD2).  FhuB may function with FhuG (A6QEV8) together with FhuD2 to form a ferrichrome transporter where FhuB and FhuG have conserved arginine residues (R71 and R61, respectively) that form essential salt bridges with FhuD2 (Vinés et al. 2013).

FhuBCD1D2 of Staphylococcus aureus
FhuB (M)
FhuC (C)
FhuD1 (R)
FhuD2 (R)

The iron-vibrioferrin uptake porter (Tanabe et al., 2003)
PvuBCDE of Vibrio parahaemolyticus
PvuB (R) (BAC16540)
PvuC (M) (BAC16541)
PvuD (M) (BAC16542)
PvuE (C) (BAC16543)

The Corrinoid porter, BtuCDE (Woodson et al., 2005)
BtuCDE of Halobacterium sp. strain NRC-1
BtuC (M) (AAG19698)
BtuD (C) (NP_444218)
BtuE (R) (AAG19697)

The heme porter, Shp/SiaABC (HtsABC). Shp is a cell surface heme binding protein that transfers the heme directly to HstA (Nygaard et al., 2006). The crystal structure of the heme binding domain of Shp has been solved (Aranda et al., 2007). HtsABC is required for the uptake of staphyloferrin A (Beasley et al. 2009). The Shp cell surface heme receptor feeds iron-heme to the transporter in preparation for uptake (Sun et al. 2010; Ouattara et al., 2010). 

Shp/HtsABC of Streptococcus pyogenes
Shp (R1) (291 aas; Q1J548)
HtsA (R2) (294 aas; Q99YA2)
HtsB (M) (340 aas; Q99YA3)
HtsC (C) (278 aas; Q99YA4)

The molybdate/tungstate ABC transporter, MolABC.  For MolC; HI1470(C)/MolB; HI1471(M), the 3D structure is known at 2.4 Å resolution; Pinkett et al., 2007).  MolA binds to MolBC with low affinity (50 - 100μM), forming a transient complex that is stabilitzed by ligand binding (Vigonsky et al. 2013).

MolABC of Haemophilus influenzae
MolC; HI1470 (C) (Q57399)
MolB; HI1471 (M; 10 TMSs; type II fold) (Q57130)
MolA; HI1472 (R) (E3GUW2)

Desferrioxamine B uptake porter, DesABC (Barona-Gomez et al., 2006)

DesABC of Streptomyces coelicolor
DesA (R) (1 TMS) (Sco7499; Q9L178)
DesB (M-M) (18 TMSs; 9 9 TMSs) (Sco7498; Q9L179)
DesC (C) (0 TMSs) (Sco7400; Q9L177)

Ferric iron-coelichelin uptake porter, CchCDEF (Barona-Gomez et al., 2006).

CchCDEF of Streptomyces coelicolor
CchC (M) (Sco0497) (Q9RK09)
CchD (M) (Sco0496) (Q9RK10)
CchE (C) (Sco0495) (Q9RK11)
CchF (R) (Sco0494) (Q9RK12)

The Fe3+ /Fe3+ferrichrome/Fe3+heme uptake porter; SiuABDG (FtsABCD) (Montañez et al., 2005; Hanks et al. 2005; Li et al. 2013).  A similar system has been characterized in S. iniae (Wang et al. 2013).

SiuABDG (FtsABCD) of Streptococcus pyogenes
SiuA; FtsA (C) (Q9A197)
SiuD; FtsB (R) (Q9A199)
SiuB; FtsC (M) (Q9A198)
SiuG; FtsD (M) (Q06A41) 

Uptake transporter for the catecholic trilactone (2, 3-dihydroxybenzoate-glycine-threonine)3 siderophore bacillibactin (for ferric iron scavenging), FeuABC (Gaballa and Helmann, 2007; Miethke et al., 2006).

FeuABC of Bacillus subtilis
FeuA (R) (P40409)
FeuB (M) (P40410)
FeuC (M) (P40411)

The heme-specific uptake porter, HemTUV (Létoffé et al., 2008).

HemTUV of Serratia proteamaculans
HemT (R) - (A8GDS8)
HemU (M) - (A8GDS7)
HemV (C) - (A8GDS6)

Heme acquisition ABC uptake transporter, IsdDEF (Liu et al., 2008)
IsdDEF of Staphylococcus aureus
IsdD (?) (358aas, 2TMSs) (Q5HGV2)
IsdE (R) (295aas, 1TMS) (Q7A652)
IsdF (M) (273aas; 8TMSs) (Q7A651)

The heme uptake porter, ShuTUV (Burkhard and Wilks, 2008). Transports a single heme per reaction cycle (Mattle et al., 2010). (3-d structure of ShuT is known (2RG7).

ShuTUV of Shigella dysenteriae
ShuT(R) (Q32AX9)
ShuU(M) (Q32AY2)
ShuV(C) (Q32AY3)

Heme uptake porter, HugBCD (Villarreal et al., 2008); also called HmuTUV.
HugBCD of Plesiomonas shigelloides
HugB (R) (Q93SS3)
HugC (M) (Q93SS2)
HugD (C) (Q93SS1)

Heme-iron (hemin) utilization transporter BhuTUV ( Brickman et al., 2006; Vanderpool and Armstrong, 2004).  The crystal structures of BhuUV with or without the periplasmic haem-binding protein BhuT have been solved (Naoe et al. 2016). The TMSs show an inward-facing conformation, in which the cytoplasmic gate of the haem translocation pathway is completely open. Since this conformation is found in both the haem- and nucleotide-free form, the structure of BhuUV-T provides the post-translocation state and the missing piece in the transport cycle of type II importers.

BhuTUV of Bordetella pertussis
BhuT (R) (Q7VSQ6)
BhuU (M) (Q7W024)
BhuV (C) (Q7W025)

The heme uptake porter, PhuTUV (transports one heme per reaction cycle) (Mattle et al., 2010).

PhuTUV of Pseudomonas aeruginosa
PhuT (R) (Q9HV90)
PhuU (M) (O68878)
PhuV (C) (O68877)

The putative ferric iron-desferrioxamine E uptake porter, DesEFGH.  The DesE binding receptor has been characterized (Barona-Gómez et al. 2006).  The remaining three (desFGH) genes cluster together without a gene encoding a receptor (R).  They are believed to function with DesE based on sequence similarity and phylogenetic analyses (Getsin et al., 2013).

DesEFGH of Streptomyces coelicolor
DesE (Sco2780) (R) (349 aas; 1 TMS) (Q9L074)
DesF (Sco1785) (C) (301 aas; 0 TMSs) (Q9S215)
DesG (Sco1786) (M) (375 aas; 9 TMSs) (Q9S214)
DesH (Sco1787) (M) (345 aas; 9 TMSs) (Q9S213)

Two components of a vitamin B12 (cobalamin) uptake porter, BtuCD.  BtuAB must exist but have not been identified (Deutschbauer et al. 2011). 

BtuCD of Shewanella oneidensistu
BtuC (M) of 380 aas
BtuD (C) of 314 aas

FecB1CDE iron siderophore uptake transporter. Transports iron chelated dihydroxamate xenosiderophores, either ferric schizokinen (FeSK) or a ferric siderophore of the filamentous cyanobacterium Anabaena variabilis ATCC 29413 (a schizokinen derivative, SAV), as the sole source of iron in a TonB-dependent manner (Obando S et al. 2018). The gene schT encodes the TonB-dependent outer membrane transporter (TC# 1.B.14.9.6).

FecB1CDE of Synechocystis sp. PCC 6803
FecB1 (R), 315 aas, P72593
FecC (M), 343 aas, 9 TMSs
FecD (M), 349 aas, 9 TMSs
FecE (C), 268 aa

Heme uptake porter with three subunits (Mandal et al. 2019).

Heme porter of Thermus thermophilus

Cyanocobalamin uptake porter with 3 components, R, M and C (Mandal et al. 2019).

Cyanocobalamin porter of Thermus thermophilus

Heme transporter with three components, HmuU (M), HmuV (C) and HmuT (R).  Chemo-mechanical coupling in the transport cycle has been proposed with outward open, inward open and occluded states (Tamura et al. 2019).

HmuUVT of Burkholderia cenocepacia (Burkholderia cepaci)
HmuU, B4EKB4 (M)
HmuV, B4EKB5 (C)
HmuT, B4EKB3 (R)

Iron-siderophore (staphylobactin, made by S. aureus) uptake system, SirABCD (A = periplasmic receptor (R); B and C = membrane proteins with 9 or 10 TMSs (M), and D (IsdC) is likely to be the periplasmic auxiliary protein with 2 TMSs, N- and C-terminal (Dale et al. 2004). This last protein is also given the TC# 9.A.39.1.2 as a member of its own family. The ATPase subunit is not known, but it could be the protein with genbank acc# WP_001080807.1.

SirABCD of Staphylococcus aureus
3.A.1.15:  The Manganese/Zinc/Iron Chelate Uptake Transporter (MZT) Family (Similar to 3.A.1.12, 3.A.1.14 and 3.A.1.16)

Manganese (Mn2+) porter
MntABC of Synechocystis 6803
MntA (C)
MntB (M)
MntC (R)

Manganese (Mn2+) and zinc (Zn2+) porter
ScaABC of Streptococcus gordonii
ScaA (R)
ScaB (M)
ScaC (C)

Zinc (Zn2+) porter, AdcABC/AII

AdcABC of Streptococcus pneumoniae
AdcA (R)
AdcB (M)
AdcC (C)
AdcAII (Lmb) (R)

Iron and manganese porter
YfeABCD of Yersinia pestis
YfeA (R)
YfeB (C)
YfeC (M)
YfeD (M)

Zinc (Zn2+) porter of E. coli, ZnuABC.  Required for Zn2+ homeostasis and virulence in the close E. coli relative, Salmonella enterica (Ammendola et al., 2007).

ZnuABC (YebLMI) of E. coli
ZnuA (R)
ZnuC (C)
ZnuB (M)

Iron (Fe2+)/Zinc (Zn2+)/Copper (Cu2+) porter
MtsABC of Streptococcus pyogenes
MtsA (R)
MtsB (C)
MtsC (M)

Manganese (Mn2+) (Km=0.1 μM) and iron (Fe2+) (5 μM) porter (inhibited by Cd2+ > Co2+ > Ni2+, Cu2+) (most similar to YfeABCD of Yersinia pestis (TC #3.A.1.15.4)). Important for virulence in Salmonella (Karlinsey et al., 2010).

SitABCD of Salmonella typhimurium
SitA (R)
SitB (C)
SitC (M)
SitD (M)

Manganese (Mn2+), zinc (Zn2+) and possibly iron (Fe2+) uptake porter, TroABCD (Hazlett et al., 2003).  Transcription of the operon is controlled by the Mn2+-activated (not Zn2+- or Fe2+-activated) repressor, TroR (153 aas, acc# F7IW50;) TroR contains a metal-binding domain homologous to the YtgC-R protein (3.A.1.15.12) which has the membrane domain of this ABC transporter (N-terminus) fused to the repressor domain (C-terminus) (Liu et al. 2013).  TroA (Tromp1), the periplasmic metal binding protein, was originally reported to be an outer membrane porin (Zhang et al. 1999), but this proved to be incorrect.

TroABCD of Treponema pallidum
TroA (R) P96116
TroB (C) P96117
TroC (M) P96118
TroD (M) P96119

Manganese (Mn2+) and Iron (Fe2+) porter, SitABCD (Davies and Walker, 2007)
Sit ABCD of Sinorhizobium meliloti
SitA (R) - (Q92LL5)
SitB (M) - (Q92LL4)
SitC (C) - (Q92LL3)
SitD (M) - (Q92LL2)

The Mn2+/Zn2+ transporter MntABC (KB of Mn2+ and Zn2+ is 0.1μM which bind with equal affinity to the same site (Lim et al., 2008)
MntABC of Neisseria meningitidis:
MntA (C) (A1IQK5)
MntB (M) (A1IQK4)
MntC (R) (Q5FA63)

The zinc uptake porter, YcdHI-YceA; AdcA/AdcC/AdcB (Gaballa et al., 2002).

YcdHI-YceA of Bacillus subtilis
AdcA (YcdH) (R) (O34966)
AdcC (YcdI) (C) (O34946)
AdcB (YceA) (M) (O34610)

Metal ion (probably iron) uptake permease , YtgABC-RD. The third gene in the ytg operon is fused, the N-terminal membrane domain being fused to the C-terminal transcriptional regulator homologous to the diphtheria toxin repressor, DtxR. These two domains may be proteolitically processed yielding the two active proteins (Thompson et al. 2012). 

YtgABC-RD of Chlamydia trachomatis 
YtgA (R) (O9S529)
YtgB (C) (084071)
YtgC-R (M-R) (084072)
YtgD (M) (084073) 

The ZnuA18/ZnuA08/ZnuB/ZnuC zinc (Zn2+) uptake system (Hudek et al. 2013).  ZnuB (M) and ZnuC (C) can function with either of two zinc ion receptors, ZnuA18 (R) which is encoded in the znuACB operon, and ZnuA08 (R) which is encoded elsewhere on the chromosome.  ZnuA18 is more efficient that ZnuA08 in promoting uptake (Hudek et al. 2013).

Zn2+ uptake system of Nostoc punctiforme
ZnuA18 (R) (B2IWS9)
ZnuA08 (R) (B2J0B7)
ZnuB (M) B2IWT1)
ZnuC (C) (B2IWT0)

High affinity Mn2+ uptake complex, PsaABC (Lisher et al. 2013). The crystal structure of the manganese transporter PsaBC from Streptococcus pneumoniae has been solved in an open-inward conformation (Neville et al. 2021). The type II transporter has a tightly closed transmembrane channel due to "extracellular gating" residues that prevent water permeation and ion reflux. Below these residues, the channel contains a metal coordination site, which is essential for manganese translocation. Mutagenesis of the extracellular gate perturbs manganese uptake, while coordination site mutagenesis abolishes import. These structural features are well conserved in metal-specific ABC transporters and are represented throughout the kingdoms of life. Collectively, these results define the structure of PsaBC and reveal the features required for divalent cation transport (Neville et al. 2021).

PsaABC of Streptococcus pneumoniae
PsaA (R; 309 aas)
PsaB (C; 240 aas)
PsaC (M; 282 aas)

High affinity Mn2+ uptake complex, MntABC.  The 3-d structure of MntC has been  solved to 2.2Å resolution (Gribenko et al. 2013).

MntABC of Staphylococcus aureus 
MntA of 247 aas (C)
MntB of 278 aas (M)
MntC of 309 aas (R)

ZnuABC Zinc/Manganese/iron uptake porter

ZnuABC of Leptospira sp.
ZnuA (R) 345 aas
ZnuB (M) 275 aas
ZnuC C) 210 aas

ZnuABC Zinc/Manganese/Iron uptake porter

  ZnuABC of Bdellovibrio bacteriovorus
ZnuA (R)
ZnuB (M)
ZnuC (C)

ABC high affinity Zinc (Zn2+) uptake porter, ZnuABC.  The similar system from Y. pestis has been characterized (Bobrov et al. 2014; Neupane et al. 2018). ZnuA (R) of that systems can bind up to 5 zinc ions with high affinity.

ZnuABC of Yersinia pseudotuberculosis
ZnuA, 318 aas, Q66AT6
ZnuB, 261 aas, Q66AT8
ZnuC, 253 aas, Q66AT7

Zinc ion ABC uptake system, AztABCD, where AztD is a periplasmic chaparone protein that feeds Zn2+ into AztC, the periplasmic receptor/binding protein for the transporter (Neupane et al. 2018).

AztABCD of Paracoccus denitrificans
AztA, 309 aas, R, (A1B2F3)
AztB, 288 aas, 9 TMSs, M, (A1B2F2)
AztC. 263 aas, C, (A1B2F1)
AztD, 408 aas, Periplasmic chaparone (A1B2F4)

ABC uptake transporter specific for Mn2+ and Fe2+, SloABC (Paik et al. 2003). The system is repressed by Mn2+ together with the SloR repressor, encoded by a gene downstream of sloABC.

SloABC of Streptococcus mutans

Mn2+ ABC uptake system, MntABC. Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A (Kuznetsova et al. 2021). Zinc is a high-affinity inhibitor. The transmembrane metal permeation pathway is lined with six titratable residues that can coordinate the positively charged metal, and mutagenesis studies showed that they are essential for manganese transport. Modelling suggested that access to these titratable residues is blocked by a ladder of hydrophobic residues, and ATP-driven conformational changes open and close this hydrophobic seal to permit metal binding and release. The conservation of this arrangement of titratable and hydrophobic residues among ABC transporters of transition metals suggests a common mechanism (Kuznetsova et al. 2021).

MntABC of Bacillus cereus
MntA, R, 311 aas, 1 N-terminal TMSs, Q4V0W6
MntB, C, 249 aas, 0 TMSs, Q4V0W4
MntC, M, 288 aas, 7 TMSs, Q4V0W5
3.A.1.16:  The Nitrate/Nitrite/Cyanate Uptake Transporter (NitT) Family (Similar to 3.A.1.12 and 3.A.1.17)

Four component nitrate/nitrite porter (Kikuchi et al. 1996).  It's synthesis occurs in response to nitrite, not nitrate in a nitrate reductase mutant (Kikuchi et al. 1996).

NrtABCD of Synechococcus sp. (PCC 7942)
NrtA (R)
NrtB (M)
NrtC (C)
NrtD (C)

Bispecific cyanate/nitrite transporter (functions in both cyanate and nitrite assimilation; Maeda and Omata, 2009).
CynABD of Synechococcus PCC7942
CynA (R)
CynB (M)
CynD (C)

Bicarbonate porter (activated by low [CO2] mediated by CmpR; (Nishimura et al., 2008))
CmpABCD of Synechococcus sp.
CmpA (R)
CmpB (M)
CmpC (C)
CmpD (C)

Nitrate uptake system, NrtABCD (Frías et al., 1997). Molecular interactions within the nitrate uptake system of Anabaena PCC7120 have been reported (but are a bit confusing) (Swapnil et al. 2021).

NrtABCD of Anabaena (Nostoc) sp. PCC 7120
NrtA (R) (Q44292)
NrtB (M) (Q8YRV7)
NrtC (C-R) (Q8YRV8)
NrtD (C) (Q8YZ25)
3.A.1.17:  The Taurine Uptake Transporter (TauT) Family (Similar to 3.A.1.12 and 3.A.1.16)

Taurine (2-aminoethane sulfonate) porter
TauABC of E. coli
TauA (R)
TauB (C)
TauC (M)

Aromatic sulfonate porter
SsuABC of Pseudomonas putida
SsuA (R)
SsuB (C)
SsuC (M)

Putative hydroxymethylpyrimidine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch. Potentially takes up a pyrimidine moiety of thiamin.

ThiXYZ of Haemophilus influenzae
ThiZ (C) (P44656)
ThiX (M) (Q57306)
ThiY (R) (P44658)

The taurine uptake system, TauABC (Krejcík et al., 2008).

TauABC of Neptuniibacter caesariensis
TauA (R) (Q2BM68)
TauB (C) (Q2BM69)
TauC (M) (Q2BM70)

The phthalate uptake system, OphFGH (Chang et al. 2009).
OphFGH of Burkholderia capacia
OphF (R) (C0LZR7)
OphG (M) (C0LZR8)
OphH (C) (C0LZR9)

Putative hydroxymethylpyrimidine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch. Potentially takes up a pyrimidine moiety of thiamin. ThiY is homologous to the yeast THI5 HMP-P synthase (P43534) (Bale et al., 2010).

ThiXYZ of Pasteurella multocida
ThiX (M) (Q9CLG9)
ThiY (R) (Q9CLH1)
ThiZ (C) (Q9CLG8)

Putative riboflavin transport system, RibXY. Regulated by an FMN riboswitch (Vitreschak et al. 2002).

RibXY of Roseiflexus castenholzii
RibX (M) (A7NLS3)
RibY (R) (A7NLS2)

Putative thiamine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch.

ThiXYZ of Roseiflexus castenholziThiX (M) (A7NH43)ThiY (R) (A7NH44)ThiZ (C) (A7NH45)

Uncharacterized membrane protein of 733 aas and 12 TMSs. The other constituents of the system have not been identified.

UP of Chondrus crispus

Aliphatic sulfonate (alkanesulfonate) import permease, SsuABC (YcbOEM) and is regluated by the transcriptional activator, Cbl (van Der Ploeg et al. 1999; Eichhorn and Leisinger 2001).

SsuABC of E. coli
SsuA (YcbO), (R), 319 aas
SsuB (YcbE), (C), 255 aas
SsuC (YcbM), (M), 263 aa  

Putative ABC transporter specific for riboflavin, RibXYZ. RibY is called "NMT1/THI5 like domain protein" (Anderson et al. 2015).

Riboflavin transporter, RibXYZ, of Thermobaculum terrenum
RibY, 1 N-terminal TMS; R (D1CEG8)
RibX, 7 TMSs, M (D1CEG9)
RibZ, unknown

Sulfonate and sulfonate ester uptake transporter, SsuABC (Koch et al. 2005).

SsuABC of Corynebacterium glutamicum
SsuA (R)
SsuB (C)
SsuC (M)

Putative thiamine (vitamin B1)-specific transporter, ThiXYZ (Rodionova et al. 2015).

ThiXYZ of Chloroflexus aurantiacus
ThiX, (M, 5 TMSs) (A9WDS0)
ThiY, (R, 1 TMS) (A9WDR9)
ThiZ, (C, 0 TMSs) (A9WDR8)

Riboflavin uptake porter, RibXY (RibX, 168 aas and 6 TMSs; RibY, 351 aas) (Gutiérrez-Preciado et al. 2015).

RibXY of Chloroflexus aurantiacus
3.A.1.18:  The Cobalamin Precursor/Cobalt (CPC) Family

The putative cobalamin precursor/cobalt (CPC) transporter family includes proteins of about 190 aas with 4-6 TMSs. These proteins are encoded in operons that are subject to regulation by vitamin B12 (Rodionov et al. 2003). These and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Putative ECF transporter, EcfSTA; regulated by a cobalamin riboswitch.

EcfSTA of Roseifluxes sp. RS-1
EcfS (S) (A5UXW2)
EcfT (T) (A5UXW1)
EcfA (A) (A5UXW0)

Putative Co2+ ECF transporter, EcfSTA

EcfSTA of Gloeobacter violaceus
EcfS (S) (Q7NIY0)
EcfT (T) (Q7NIX9)
EcfA (A) (Q7NIX8)

Putative Co2+ ECF transporter, EcfSTA

EcfSTA of Syntrophobotulus glycolicus
EcfS (S) (F0SWZ4)
EcfT (T) (F0SWZ5)
EcfA (A) (F0SWZ6)
3.A.1.19:  The Thiamin Uptake Transporter (ThiT) Family (Most similar to 3.A.1.10, 3.A.1.6 and 3.A.1.8 in that order)

Thiamin, thiamin monophosphate and thiamin pyrophosphate porter. The 2.25 Å structure of ThiB (TbpA) has been solved (Soriano et al., 2008).
ThiBPQ of Salmonella typhimurium (functionally characterized and partially sequenced) and E. coli (fully sequenced but not functionally characterized)
ThiB; TbpA (R)
ThiP; YabK (M)
ThiQ; YabJ (C)

The thiamine pyrophosphate (TPP) uptake porter (Bian et al., 2011).

TPP transporter of Treponena denticola TDE0143/TDE0144/TDE0145
TDE0143 (R) (Q73RE6)
TDE0144 (M) (Q73RE5)
TDE0145 (C) (Q73RE4)

ABC transporter of unknown function. The three genes encoding this system are adjacent to a gene homologous to a mycothiol maleylpyruvate isomerase.

ABC transporter of Streptomyces hygroscopicus
Periplasmic binding protein (R) (H2JXL4)
Permease (M) (H2JXL5)
ATPase (C) (H2JXL6)

The putative sulfate/thiosulfate transporter, YnjBCD. YnjB has 12 TMSs. The three genes encoding this system are adjacent to one encoding a thiosulfate:sulfur transferase or a rhodanese (B7L6N1).  Also considered to be a thiamine transporter (Moussatova et al. 2008).

YnjBCD of E. coli
YnjB (possible receptor, R) (B7L6M8)
YnjC (M) (B7L6M9)
YnjD (C) (B7L6N0)

Putative ABC transporter, WtpB1/C1: molybdate/tungstate transport system.

ABC transporter of Deinococcus deserti
Permesae (M) (C1CWI2)
ATPase (C) (C1CWI3)
Possible periplasmic receptor (R) (C1CWI4)

Probable 4 component ABC transporter with two ATPase of 387 and 368 aas, respectively, both annotated as MalK, one membrane protein that maps together with the two ATPases and is annotated CysW, and one receptor that maps separately for the other three and is designated MalE. It is not established that this repector maps with the other three constituents, but this has been inferred by the similarities of the two ATPases to MalK. 

Candidatus Heimdallarchaeota
Putative 4 component ABC uptake porter of unknown specificity, CysW/MalK/MalK/MalE of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
3.A.1.20:  The Brachyspira Iron Transporter (BIT) Family (Most similar to 3.A.1.6, 3.A.1.8 and 3.A.1.11)

The iron transporter, BitABCDEF (Dugourd et al. 1999).

BitABCDEF of Brachyspira (Serpulina) hyodysenteriae
BitA (R)
BitB (R)
BitC (R)
BitD (C)
BitE (M)
BitF (M)

Hexose-phosphate transporter.  Transports glucose-6-phosphate (Km = 0.3 υM) and fructose-6-phosphate (1.3 υM).  Sugar phsophates can be used as both carbon and phosphate sources (Moisi et al. 2013).

Sugar phosphate uptake permease, FbpABC of Vibrio cholerae
FbpA 344 aas (R) (Q9KLQ7)
FbpB 700 aas (M) (Q9KLQ6)
FbpC 351 aas (C) (Q9KLQ5)

Iron (Fe3+) uptake porter, AfuABC (FbpABC) (Chin et al. 1996). AfuA has been characterized (Willemsen et al. 1997).

AfuABC (FbpABC) of Actinobacillus pleuropneumoniae
AfuA (R)
AfuB (M)
AfuC (C)


Putative glycerol phosphodiester uptake transporter.  The three genes encoding this system are in an operon with a gene encoding a glycerophosphodiester phosphodiesterase, providing the evidence that this transporter might function to take up such substrates.

Putative glycerol phosphodiester uptake porter of Bdellovibrio exovorus A11Q_2445 (R), 344 aas and 1 TMS
A11Q_2446 (M), 541 aas and 12 TMSs
A11Q_2447 (C), 245 aas and 0 TM  

Possibly a Mg2+-citrate uptake porter with three components, R, M and C, as suggested by Mandal et al. 2019.  However, this system appears more likely to be a ferric iron uptake system, based on sequence similarity studies (see other members of TC sub-family 3.A.1.20).

Fe3+ or Mg2+-citrate porter of Thermus thermophilus
3.A.1.21:  The Siderophore-Fe3+ Uptake Transporter (SIUT) Family

The Fe3+-Yersiniabactin uptake transporter, YbtPQ (Brem et al., 2001; Fetherston et al., 1999). YbtPQ is a virulence factor in the highly inflammatory microenvironment characteristic of high-titer cystitis in E. coli (Koh et al. 2016). The E. coli and Y. pestis YbtP proteins are 99.7% identical. Multiple structures of the yersiniabactin importer YbtPQ from uropathogenic Escherichia coli (UPEC) have been solved in inward-open conformations of both apo and substrate-bound states by cryo-EM (Wang et al. 2020). YbtPQ does not adopt a known fold of typical ABC importers, but instead exhibits the fold of an ABC exporter. It has two unique features: unwinding of a transmembrane helix in YbtP upon substrate release and tightly associated nucleotide-binding domains without bound nucleotides (Wang et al. 2020). This ABC porter is similar to FrpBC of Vibrio anguillarum (Lages et al. 2022).

YbtPQ of Yersinia pestis
YbtP (M-C)
YbtQ (M-C)

The Fe3+-mycobactin/carboxymycobactin transporter, IrtAB (Rodriguez and Smith, 2006). IrtA contains an FAD-binding domain (Ryndak et al., 2010). M. tuberculosis produces two classes of siderophores, lipid-bound mycobactin and water-soluble carboxymycobactin. Iron-loaded carboxymycobactin is imported into the cytoplasm by IrtAB which has an additional cytoplasmic siderophore interaction domain that may serve as a periplasmic receptor. Membrane-reconstituted IrtAB is sufficient for the import of mycobactins, which are then reduced by the siderophore interaction domain to facilitate iron release (Arnold et al. 2020). Structure determination by X-ray crystallography and cryo-EM not only confirmed that IrtAB has an ABC exporter fold (as indicated by TC-BLAST searches), but also revealed structural peculiarities at the transmembrane region of IrtAB that result in a partially collapsed inward-facing substrate-binding cavity. The siderophore interaction domain is positioned in close proximity to the inner membrane leaflet, enabling the reduction of membrane-inserted mycobactin. Enzymatic ATPase activity and in vivo growth assays revealed that IrtAB has a preference for mycobactin over carboxymycobactin as its substrate (Arnold et al. 2020). The large transporter (Rv1348-1349) of 859 aas seems to have three domains, an extracytoplasmic receptor domain (IrtA), a central membrane domain of 6 TMSs (IrtB) and a C-terminal ATPase (IrtC). If so, there may be two potential receptors (see Mandal et al. 2021 for a review). Cryo-EM structures for the M. tuberculosis iron-loaded siderophore transporter IrtAB has been reported (Sun et al. 2023). It adopts the canonical type IV exporter fold. The structures of unliganded Mtb IrtAB in complex with ATP, ADP, or the ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the TMDs, and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-EM structures and ATP hydrolysis assays showed that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB (Sun et al. 2023).

IrtAB of Mycobacterium tuberculosis
IrtA (M-C) (P63391)
IrtB (M-C) (P63393)
3.A.1.22:  The Nickel Uptake Transporter (NiT) Family

Putative nickel (Ni2+) and/or Cobalt (Co2+) porter with 4 components, CbiKMQO. CbiM and CbiQ probably have 6 TMSs, but TMSs 3 and 4 are close together.

CbiKMQO of Actinobacillus pleuropneumoniae
CbiK (R)
CbiM (M)
CbiQ (M)
CbiO (C)

The ABC exporter, CbiMNQ1O1. CbiM and CbiQ1 both have 6 TMSs in a 2 + 2 + 2 TMS arrangement.

ABC exporter of Desulfobacterium autotrophicum
CbiM, 203 aas and 6 TMSs (M)
CbiN, 186 aas and 2 TMSs (N- and C-terminal) (Probable auxiliary subunit)
CbiQ1, 251 aas and 6 TMSs (M)
CbiO1, 244 aas and 0 TMSs (C)
3.A.1.23:  The Nickel/Cobalt Uptake Transporter (NiCoT) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Nickel (Ni2+) porter (Chen and Burne, 2003)

UreMQO of Streptococcus salivarius
UreM (M) (Q79CJ1)
UreQ (M) (Q79CJ0)
UreO (C) (Q79CI9)

Putative cobalt (Co2+) porter (Chen and Burne, 2003)
CbiMQOK of Clostridium acetobutylicum
CbiM (M) (AAK79333)
CbiQ (M) (AAK79335)
CbiO (C) (AAK79336)
CbiK (Auxiliary?) (AAK79334)

Cobalt (Co2+) porter 

Cbi M(N)OQ of Geobacter sulfurreducens 
Cbi M(N) (D7AE13)
CbiO (D7AE10)
CbiQ (D7AE11) 

The NikM2 (230 aas; 5 TMSs)/NikN2 (110 aas; 2 TMSs) pair is part or all of a nickel transporter.  The crystal structure of NikM2 is known (PDB 4M5C; 4M58).  It possesses an additional TMS at its N-terminal region not present on other ECF transporter of known structure, resulting in an extracellular N-terminus. The highly conserved N-terminal loop inserts into the center of NikM2 and occludes a region corresponding to the substrate-binding sites of the vitamin-specific S component. Nickel binds to NikM2 by coordination to four nitrogen atoms in Met1, His2 and His67. These nitrogens form a square-planar geometry, similar to that of the metal ion-binding sites in the amino-terminal Cu2+- and Ni2+-binding (ATCUN) motif (Yu et al. 2013).  Constituents other than NikN2 and NikM2 are not known but may be required for activity (T. Eitinger, personal communication).

NikM2N2 of Thermoanaerobacter tengcongensis  (Caldanaerobacter subterraneus subsp. tengcongensis)

Putative Ni2+/Co2+ uptake porter, NikMNOQ (Yu et al. 2013).

NikMNOQ of Thermoanaerobacter tengcongensis

Cobalt (Co2+) porter (Rodionov et al., 2006).  CbiMN is a bipartite S-subunit with 8 TMSs (Siche et al. 2010). Dynamic interactions of CbiN and CbiM trigger activity of the transporter (Finkenwirth et al. 2019). Substrate binding (S) components rotate within the membrane to expose their binding pockets alternately to the exterior and the cytoplasm. In contrast to vitamin transporters, metal-specific systems rely on additional proteins with essential functions. CbiN, with two TMSs tethered by an extracytoplasmic loop of 37 amino-acid residues is the auxiliary component that temporarily interacts with the CbiMQO2 Co2+ transporter. CbiN induces Co2+ transport activity in the absence of CbiQO2 in cells producing the S component CbiM plus CbiN or a Cbi(MN) fusion. Finkenwirth et al. 2019 showed that any deletion in the CbiN loop abolished transport activity. Protein-protein contacts between segments of the CbiN loop and loops in CbiM were demonstrated, and an ordered structure of the CbiN loop was shown. The N-terminal loop of CbiM, containing three of four metal ligands was partially immobilized in wild-type Cbi(MN) but completely immobile in inactive variants with CbiN loop deletions. Thus, CbiM-CbiN loop-loop interactions facilitate metal insertion into the binding pocket (Finkenwirth et al. 2019).

CbiMNOQ of Salmonella typhimurium
CbiM (M) (Q05594)
CbiN (Essential auxillary subunit) (Q05595)
CbiO (C) (Q05596)
CbiQ (M) (Q05598)

Ni2+, Co2+ uptake transporter, NikMNOQ (subunit sizes: NikMN, 347 aas, 9 TMSs; NikQ, 284 aas, 4 TMSs; NikO, 254 aas, 0 TMS.  NikMN can take up Ni2+ without NikQ or NikO (Kirsch and Eitinger 2014).

NikMNQO of Rhodobacter capsulatus
NikMN (M; 9 TMSs)
NikQ  (M; 5 TMSs)
NikO (C; 0 TMSs)

Ni2+/Co2+ uptake porter, CbiMNOQ (CbiM, 222 aas, 5 TMSs; CbiN, 103 aas, 2 TMSs; CbiO, 280 aas, 0 TMSs; CbiQ, 244 aas, 5 TMSs).  CbiMN can take up Ni2+ without CbiO or CbiQ (Kirsch and Eitinger 2014).

CbiMNOQ of Rhodobacter capsulatus
CbiM (M)
CbiN (M)
CbiO (C)
CbiQ (M)  
3.A.1.24:  The Methionine Uptake Transporter (MUT) Family (Similar to 3.A.1.3 and 3.A.1.12)

The L- and D-methionine porter (also transports formyl-L-methionine and other methionine derivatives) (Zhang et al., 2003). The 3.7A structure of MetNI has been solved. An allosteric regulatory mechanism operates at the level of transport activity, so increased intracellular levels of the transported ligand stabilize an inward-facing, ATPase-inactive state of MetNI to inhibit further ligand translocation into the cell (Kadaba et al., 2008).  The structure of an MetQ homologue in Neisseria meningitidis has been solved at 2.25 Å resolution revealing a bound methionine in the cleft between the two domains (Yang et al. 2009). Conformational changes in MetQ provide substrate access through the binding protein to the transmembrane translocation pathway. MetQ likely mediates uptake of methionine derivatives through two mechanisms: in the methionine-bound form, substrate is delivered from the periplasm to the transporter (the canonical mechanism) and in the apo form, it facilitates ligand binding when complexed to the transporter (the noncanonical mechanism). This dual role of substrate-binding proteins was proposed to provide a kinetic strategy for ABC transporters to transport both high- and low-affinity substrates present in a physiological concentration range (Nguyen et al. 2018).

MetNIQ (abc-yaeE-yaeC) of E. coli
MetN (C) AAC73310
MetI (M) AAC73309
MetQ (R) AAC73308

The L- and D-methionine porter (also transports methionine sulfoxide (Hullo et al., 2004)
MetNPQ (YusCBA) of Bacillus subtilis
MetN (C) CAB15264
MetP (M) CAB15263
MetQ (R) CAB15262

The methionine porter, AtmBDE (Sperandio et al., 2007)
AtmBDE of Streptococcus mutans
AtmB (R) (Q8K8K9)
AtmD (C) (Q8K8K8)
AtmE (M) (Q8K8K7)

L-Methionine uptake porter, MetQNI
MetQNI of Corynebacterium glutamicum
MetQ (R) (Q8NSN1)
MetN (C) (Q8NSN2)
MetI (M) (Q8NSN3)

L-Histidine uptake porter, MetIQN (Johnson et al. 2008)

MetIQN of Pseudomonas aeruginosa
MetI (M) (Q9HT69)
MetQ (R) (Q9HT68)
MetN (C) (Q9HT70)

Putative peptide transporter, PepABC.  The three components of this system are encoded in an operon with a gene encoding a peptidase (Q04MS7), providing the only tentative evidence for the substrate transported.  However the similarity with the methionine transporter of Streptococcus mutans (TC# 3.A.1.24.3) suggests that this porter may also be a methionine uptake porter.

PepABC of Streptococcus pneumoniae
PepA (R; 284 aas)
PepB (C; 353 aas)
PepC (M; 230 aas)
3.A.1.25:  The Biotin Uptake Transporter (BioMNY) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


The biotin uptake porter (binding receptor lacking) (see also the VUT or ECF family; BioY; 2.A.88.1.1) (Rodionov et al., 2006; Hebbeln et al., 2007). BioN (the EcfT component of the biotin transporter) appears to be required for intramolecular signaling and subunit assembly (Neubauer et al., 2009). The Ala-Arg-Ser and Ala-Arg-Gly signatures in BioN are coupling sites to the BioM ATPases (Neubauer et al., 2011).  Subunit stoicheometries have been estimated with the prediction that there are oligomeric forms of BioM and BioY in the BioMNY complex (Finkenwirth et al. 2010).

BioMNY of Rhizobium etli
BioM (C) (226 aas; 0 TMSs; Q6GUB2)
BioN (M) (202 aas; 5 TMSs; Q6GUB1)
BioY (M) (189 aas; 6 TMSs; Q6GUB0)

Putative biotin Ecf transporter, EcfSAA'T (function assigned based on genome context analyses). 

Putative Ecf transporter, EcfSAA'T, of Methanospirillum hungatei 
EcfS (M) (Q2FUL6)
EcfA (C) (Q2FUL5)
EcfA' (C) (Q2FUM0)
EcfT (M) (Q2FNH6) 

Putative biotin Ecf transporter, EcfSAA'T (function assigned based on genome context analyses).

The putative EcfSAA'T transporter of Methanocorpusculum labreanum
EcfS (A2SPQ3)
EcfA (A2SPQ4)
EcfA' (A2SPQ5)
EcfT (A2SPQ6) 

The biotin uptake system, BioMNY. The 3-d structure of the EcfS subunit, BioY, at 2.1Å resolution is known (Berntsson et al., 2012). BioY and ThiT from L. lactis show similar N-terminal structures for interaction with the ECF module but divergent C-terminal structures for substrate binding. BioY alone binds biotin but doesn''t transport it (Berntsson et al., 2012).  Ala-Arg-Ser and Ala-Arg-Gly signatures in BioN are probably coupling sites to the two BioM ATPase subunits (Neubauer et al., 2011Neubauer et al., 2011).

BioMNY of Lactococcus lactis 
BioM (A) (A2RI01)
BioN (T) (A2RI03)
BioY (S) (A2RMJ9) 

Biotin/Riboflavin ECF transport system, EcfAA'T/RibU/BioY (Karpowich and Wang 2013). RibU binds riboflavin with high affinity, and the protein-substrate complex is exceptionally stable in solution. The crystal structure of riboflavin-bound RibU reveals an electronegative binding pocket at the extracellular surface in which the substrate is completely buried (Karpowich et al. 2016).

EcfAA''T/RibU/BioY of Thermatoga martima
EcfA (C) (Q9WY65)
EcfA'' (C) (Q9X1Z1)
EcfT (M) (Q9X2I1)
BioY (M) (Q9X1G6)
RibU (M) (Q9WZQ6)

Riboflavin ECF transport system, EcfAA'T/RibU (Karpowich and Wang 2013).

EcfAA'T/RibU of Streptococcus thermophilus 
EcfA (C) (Q5M244)
EcfA' (C) (Q5M243)
EcfT (M) (Q5M245)
RibU (M) (Q5M614)

The riboflavin uptake system, BioMNY.  BioM, EtcA, ATPase, 234 aas;  BioN, EtcT, 190 aas, 5 TMSs; BioY, EtcS, 210 aas, 5 TMSs BioY can also function as a secondary carrier and is therefore listed separately under TC# 2.A.88.1.3.  ATP-dependent conformational changes drive substrate capture and release when BioMNY are together in a complex (Finkenwirth et al. 2015).

RibMNY of Rhodobacter capsulatus

An ECF ABC transporter with 4 subunits, EcfS/EcfT/EcfA/EcfA'.  EcfS is also called RibU; EcfT is also called CbiQ, EcfA is also called Cbi01, and EcfA' is also called Cbi02.  This system can take up riboflavin and possibly other vitamins (Karpowich et al. 2015). ATP binding to the EcfAA' ATPases drives a conformational change that dissociates the S subunit from the EcfAA'T ECF module. Upon release from the ECF module, the RibU S subunit then binds the riboflavin transport substrate.  S subunits for distinct substrates compete for the ATP-bound state of the ECF module (Karpowich et al. 2015). RibU appears to be capable of exporting riboflavin, FMN and FAD (Light et al. 2018). More recently, this system has been shown to functioin in three capacities; all use EcfA (Ecf1), EcfB (Ecf2), both ATPases. Two of them also use RibU (EcfS).  The first complex uses EcfT and RibU and imports FAD; the second uses FmnA and RibU and takes up vitamin B2 (riboflavin derivatives); the third uses FmnA and EetB and exports FAD (Rivera-Lugo et al. 2023). Thus, these three systems are partially redundant. FmnA is also called AuxA and can be found under TC# 9.B.414.1.1.

EcfSTAA' complex of
LIsteria monocytogenes
EcfS, RibU, 203 aas and 5 TMSs
EcfT, CbiQ, 265 aas and 6 TMSs
EcfA, Cbi01, 279 aas
EcfA', Cbi02, 288 aas
EetB, 180 aas and 5 TMSs (S5LID4)  This protein is also in a family of homologs of unknown functions; see TC# 5.B.14.1.1. These proteins may serve as alternative subunits of this type of ABC porters (see Rivera-Lugo et al. 2023 ).
Another putative subunit, FmnA or AuxA, is found in TCDB with the TC# 9.B.414.1.1.
3.A.1.26:  The Putative Thiamine Uptake Transporter (ThiW) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


The putative thiazole ABC porter (COG4732), ThiW; 718 aas; 5 TMSs; domain order: M-C-C; plus the putative ATPase binding subunit, CbiQ homologue (binding receptor unknown) (Rodionov et al., 2009)

ThiW/CbiQ of Chloroflexus aurantiacus
CbiQ M (T) (A9WGA9)

ThiW homologue/CbiQ homologue (ThiW: 647 aas; M-C-C; 5-6TMSs) (Rodionov et al., 2009)

ThiW/ChiQ of Methanocorpusculum labreanum
CbiQ M (T) (A2SPE9)

ThiW homologue (711 aas; M-C-C) (No known binding receptor) plus a CbiQ homologue (Rodionov et al., 2009)

ThiW/CbiQ homologues of Actinomyces odontolyticus
CbiQ M (T) (A7BAX3)

ThiW/CbiQ homologues (ThiW: 697 aas; M-C-C) (No known binding receptor) (Rodionov et al., 2009)

ThiW/CbiQ homologues of Mycobacterium tuberculosis
ThiW MCC (SAA) (P63399)
CbiQ M (T) (P64997)

ThiW/CbiQ/CbiO homologues (ThiW: 174 aas; 5 putative TMSs).  Possible thiamin uptake porter (Rodionov et al., 2009).

ThiW/CbiQ/CbiO homologues of Roseiflexus castenholzii
ThiW (M) (S) (A7NRF9)
CbiQ (M) (T) (A7NRG1)
CbiO C-C (A-A) (A7NRG0)

The ThiW/CbiQ/CbiO1/CbiO2 homologues (ThiW: 184 aas; 1-6 TMSs) (Rodionov et al., 2009)

ThiW/CbiQ/CbiO1/CbiO2 homologues of Aeropyrum pernix
ThiW M (S) (Q9Y974)
CbiQ M (T) (Q9Y982)
CbiO1 C (A) (Q9Y979)
CbiO2 C (A) (Q9Y977)

The putative hydroxyethyl thiazole (biosynthetic precursor of thiamine) porter, ThiW-EcfA1-A2-EcfT (this is a group II ECF transporter which uses a universal energy-coupling module (EcfA1-EcfA2-EcfT) in many firmicutes; Rodionov et al., 2002).

ThiW-EcfA1-EcfA2-EcfT of Enterococcus faecalis
ThiW (M) (Q830K3)
EcfA1 (C) (Q839D5)
EcfA2 (C) (Q839D4)
EcfT (M) (Q839D3)

Putative biotin Ecf transporter, EcfSAT

Putative Ecf transpoter, EcfSAT, of Archaeoglobus fulgidus 
S-subunit (M) (O29098) 
A-subunit (C) (O29097) 
T-subunit (M) (O29096) 

The folate transporter, FolT/EcfAA''T (The 3-d structure is known to 3.0Å resolution (Xu et al. 2013; 4HUQ).  This transporter uses the same ECF energy coupling complex (AA''T) as 3.A.1.28.2.

FolT/EcfAA'T of Lactobacillus brevis
FolT (M; EcfS subunit) (Q03S56)
EcfA (C) (Q03PY6)
EcfA' (C) (Q03PY7)
EcfT (M) (Q03PY5)

ATP-dependent folic acid uptake porter, FolT/EcfT/EcfA1/EcfA2.  The crystal structure of FolT has been solved to 3.2 Å resolution in substrate-bound and free conformations, revealing a potential gating mechanism (Zhao et al. 2015).

FolT/EcfT/EcfA1/EcfA2 of Enterococcus faecalis
FolT, 182 aas, 5 TMSs
EcfT, 264 aas, 6 TMSs
EcfA1, 279 aas
EcfA2, 289 aas

Putative pantothenate uptake porter, PanT/EcfA/EcfA'/EcfT (Rodionova et al. 2015).

Putative ABC (Ecf) pantothenate transporter of Ktedonobacter racemifer
PanT, (M, substrate binding subunit)
EcfA, (C)
EcfA', (C)
EcfT, (M, transducer subunit)

Chloroplast heavy metal ion uptake porter with at least two components, ABCI10, 271 aas (C) and ABCI12, 391 aas (M), present in the inner chloroplast envelope. Loss of ABCI10 and ABCI11 gene products in Arabidopsis leads to dwarfed, albino plants showing impaired chloroplast biogenesis and deregulated metal homeostasis. The membrane-intrinsic protein ABCI12 may be the interaction partner for ABCI10. Thus, ABCI12 may insert into the chloroplast inner envelope membrane with five or six predicted TMSs (Voith von Voithenberg et al. 2019).

Viridiplantae, Streptophyta
ABCI10 and ABC12 of Arabidopsis thaliana
3.A.1.27:  The γ-Hexachlorocyclohexane (HCH) Family (Similar to 3.A.1.12 and 3.A.1.24)

The γ-hexachlorocyclohexane (γHCH) uptake permease, LinKLMN (most similar to 3.A.1.12.4, the QAT family) (Endo et al., 2007)
LinKLMN of Sphingobium japonicum
LinK (M) (BAF51698)
LinL (C) (BAF51699)
LinM (R) (BAF51700)
LinN (lipoprotein) (BAF51701)

The chloroplast lipid (trigalactosyl diacyl glycerol (TDG)) transporter, Tdg1,2,3 (Lu et al., 2007). Lipids such as mono- and digalactolipids are synthesized in the endoplasmic reticulum (ER) of plant cells and transferred to the thylakoid membranes of chloroplasts. Mutations in an outer chloroplastic envelope protein with 350 aas and 7 putative TMSs in the last 250 residues may catalyze translocation as part of a lipid transfer complex (Xu et al., 2003; Roston et al. 2012).

Viridiplantae, Streptophyta
Tdg 1,2,3 of Arabidopsis thaliana:
Tdg1 (M) (Q8L4R0)
Tdg2 (R) (Q3EB35)
Tdg3 (C) (Q9AT00)

ABC transporter maintaining outer membrane (OM) lipid asymmetry, MlaABCDEF (YrbABCDEF) (Malinverni and Silhavy, 2009). MlaA (VacJ) is a "spreading" protein, essential for Shigella pathogenicity (Suzuki et al., 1994).  The ABC transporter, MlaEFBD, provides energy for maintaining OM lipid asymmetry via the transport of aberrantly localized phospholipids (PLs) from the OM to the inner membrane (IM) (Thong et al. 2016). MlaD spans the periplasm, forms stable hexamers within the complex, functions in substrate binding with strong affinity for PLs within a channel that spans the periplasm, and modulates ATP hydrolytic activity. MlaB plays critical roles in both the assembly and activity of the transporter.  MlaA forms a complex with OmpC and OmpF in the outer membrane to extract PLs from the outer leaflet of the OM (Chong et al. 2015). MlaA is a monomeric 2 α-helical TMS OM protein that functions as a phospholipid translocation channel, forming a ~20-Å-thick doughnut embedded in the inner leaflet of the OM with a central, amphipathic pore (Abellón-Ruiz et al. 2017). This architecture prevents access of inner leaflet phospholipids to the pore, but allows outer leaflet phospholipids to bind to a pronounced ridge surrounding the channel. Members of the mammalian cell entry (MCE) protein family, one of which is MlaD, form hexameric assemblies with a central channel capable of mediating lipid transport across the periplasm (Ekiert et al. 2017). MlaD forms a ring associated with the ABC transporter complex in the inner membrane. A soluble lipid-binding protein, MlaC ferries lipids between MlaD and an outer membrane protein complex. EM structures of two other E. coli MCE proteins show that YebT (LetB) forms an elongated tube consisting of seven stacked MCE rings, and PqiB adopts a syringe-like architecture. Both YebT and PqiB create channels of sufficient length to span the periplasmic space. These homologs transport lipids between the two membranes of Gram-negative bacteria, some eukaryotic organelles and possibly actinobacteria (Ekiert et al. 2017). MCE systems mediate phospholipid trafficking across the periplasm. ~3.5 Å cryo-EM structures of the E. coli MCE protein LetB reveals an ~0.6 megadalton complex that consists of seven stacked rings, with a central hydrophobic tunnel sufficiently long to span the periplasm (Isom et al. 2020). Lipids bind inside the tunnel, suggesting that it functions as the pathway for lipid transport. Cryo-EM structures in the open and closed states revealed a dynamic tunnel lining with implications for gating and substrate translocation. These results support a model in which LetB establishes a physical link between the two membranes and creates a hydrophobic pathway for the translocation of lipids across the periplasm (Isom et al. 2020). The transmembrane subunit, MlaE, has minimal sequence similarity to other transporters. Coudray et al. 2020 reported the cryo-EM structure of MlaFEDB at 3.05 Å resolution, revealing distant relationships to the LPS and MacAB transporters, as well as members of the eukaryotic ABCA/ABCG families. A continuous transport pathway extends from the MlaE substrate- binding site, through the channel of MlaD, and into the periplasm. Two phospholipids are bound to MlaFEDB, suggesting that multiple lipid substrates may be transported each cycle. The structure provides mechanistic insight into substrate recognition and transport by MlaFEDB (Coudray et al. 2020). Structures of both the E. coli and P. aeruginosa MlaFEDB complexes have been determined by cryoEM (Zhou et al. 2021). The structures show that the MlaFEBD complex contains a total of twelve protein molecules with a stoichiometry of MlaF2E2B2D6, and binds a plethora of phospholipids (PLs) at different locations. In contrast to canonical ABC transporters, nucleotide binding fails to trigger significant conformational changes of both MlaFEBD and MlaFEB in the nucleotide-binding and transmembrane domains, correlated with their low ATPase activities exhibited in both detergent micelles and lipid nanodiscs. PLs or detergents appeared to relocate to the membrane-proximal end from the distal end of the hydrophobic tunnel formed by the MlaD hexamer in MlaFEBD upon addition of ATP, indicating that retrograde PL transport might occur in the tunnel in an ATP-dependent manner. Site-specific photocrosslinking experiment confirmed that the substrate-binding pocket in the dimeric MlaE and the MlaD hexamer are able to bind PLs in vitro, in line with the notion that the MlaFEBD complex functions as a PL transporter (Zhou et al. 2021).  Mla uses a shuttle-like mechanism to move lipids between the MlaFEDB inner membrane complex and the MlaA-OmpF/C OM complex, via a periplasmic lipid-binding protein, MlaC. MlaC binds to MlaD and MlaA (MacRae et al. 2023). They mapped the MlaC-MlaA and MlaC-MlaD protein-protein interfaces, suggesting that the MlaD and MlaA binding surfaces on MlaC overlap to a large extent, leading to a model in which MlaC can only bind one of these proteins at a time. Low-resolution cryo-EM maps of MlaC bound to MlaFEDB suggested that at least two MlaC molecules can bind to MlaD at once, in a conformation consistent with AlphaFold2 predictions (MacRae et al. 2023). The Mla system of the diderm Firmicute, Veillonella parvula, reveals an ancestral transenvelope bridge for phospholipid trafficking (Grasekamp et al. 2023).

MlaABCDEF of E. coli
MlaA, YrbA, OM lipoprotein component (251aas) (P76506)
MlaB, YrbB cytoplasmic STAS component (97aas) (P64602)
MlaC, YrbC periplasmic binding receptor (R) (211aas) (P0ADV7)
MlaD, YrbD anchored periplasmic binding receptor (R) (183aas) (P64604)
MlaE, YrbE inner membrane permease component (M) (260aas) (P64606)
MlaF, YrbF ATP binding protein (C) (269aas) (P63386)

The cholesterol uptake porter (Mohn et al., 2008). Takes up cholesterol, 5-α-cholestanol, 5-α-cholestanone, β-sitosterol, etc. (It is not established that all of these proteins comprise the system or that other gene products are not involved.)

Cholesterol uptake porter of Rhodococcus jostii
YrbE4A (ro04696; 254aas; 5-6 TMSs) (M) (Q0S7K4)
YrbE4B (ro04697; 283aas; 5 TMSs) (M) (Q0S7K3)
MceE4A (ro04698; 391aas; 1 N-terminal TMS) (R) (Q0S7K2)
MceE4B (ro04699; 338aas; 1 N-terminal TMS) (R) (Q0S7K1)
MlkA (ro01974; 363aas; 0 TMSs) (C) (Q0SFA1)
MlkB (ro01744; 346aas; 0 TMSs) (C) (Q0SD37)  

The Mce/Yrb/Mlk (Mammalian cell entry) ABC-type putative steroid uptake transporter (involved in several aspects of mycobacterial pathogenesis) (Mohn et al., 2008; Joshi et al., 2006).

The Mce transporter of Mycobacterium tuberculosis H37Rv
YrbE4A (M) (254aas; 6 TMSs) (O53546)
YrbE4B (M) (280aas; 5 TMSs) (O53545)
MceA (R) (242aas; 1 TMS) (O06356)
MceB (R) (244aas; 1 TMS) (O07422)
Mlk (C) (Mkl; MceG; 359aas; 0 TMSs) (P63357)

Mce1A-F hetero-hexameric uptake porter for mycolic acid and fatty acids. The structure of Mce1A is known (Asthana et al. 2021); MceE = LprK. Each of the four Mce complexes in Mtb (Mce1-4) comprises six substrate-binding proteins (SBPs; MceA-F), each of which contains four conserved domains (N-terminal transmembrane, MCE, helical and C-terminal unstructured tail domains). In the crystal structure of the MCE domain of Mce4A (MtMce4A39-140) a domain-swapped conformation is observed. The fact that there are six SBPs in each Mtb mce operon suggests that the MceA-F SBPs from Mce1-4 may form heterohexamers. The helical domains interact with the detergent micelle, suggesting that when assembled, the helical domains of MceA-F may form a hydrophobic pore for lipid transport, as observed in PqiB of E. coli (Asthana et al. 2021). 

Mce1A-F of Mycobacterium tuberculosis
Mce1A, 454 aas and 3 TMSs, Q79FZ9
Mce1B, 346 aas and 1 N-terminal TMS, O07414
Mce1C, 515 aas and 1 N-terminal TMS, O07415
Mce1D, 530 aas and 1 N-terminal TMS, O07416
Mce1E = LprK, 390 aas and 1 N-terminal TMS, O07417
Mce1F, 515 aas and 1 N-terminal TMS, L0T2W6


Mce2A-F hetero-hexameric receptor complex of a lipid-transporting ABC uptake system. A Mycobacterium bovis Δmce2 double deletion mutant protects cattle against a challenge with virulent M. bovis (Blanco et al. 2013). The expression ratio of all selected mce operon genes in all M. tuberculosis isolates was reduced at the initial phase and increased substantially at a later phase of growth. Higher expression of mce1 operon genes was found in all M. tuberculosis isolates as compared to other mce operon genes (mce2 and mce3 operons) at stationary growth phase (Singh et al. 2016).

Mce2A-F of Mycobacterium tuberculosis
Mce2A, Q79FY7, 404 aas
Mce2B, O07788, 275 aas
Mce2C, O07787, 481 aas
Mce2D, A5TZX3, 508 aas
Mce2E (IprL), I6Y461, 402 aas
Mce2F, O07784, 516 aas
3.A.1.28:  The Queuosine (Queuosine) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


The putative queuosine uptake transporter, QrtTUVW (Rodionov et al., 2009).

QrtTUVW of Salmonella enterica su. typh.
QrtT (M) (Q8XGV9)
QrtU (M) (Q8Z3V9)
QrtV (C) (Q8Z3V8)
QrtW (C) (Q8Z3V7)

The folate transporter, FolT/EcfAA''T (The 3-d structure is known to 3.0Å resolution (Xu et al. 2013; 4HUQ).  Thiamine and riboflavin may also be substrates.

EcfAA'ST of Lactobacillus brevis
EcfA (C) (Q03PY5)
EcfA' (C) (Q03PY6)
EcfS (M) (Q03NM0)
EcfT (M) (Q03PY7)
3.A.1.29:  The Methionine Precursor (Met-P) Family

The putative methionine precursor/uptake transporter, MtsTUV (T is most similar to 3.A.1.23.2; U is most similar to 2.A.36.7.1 and 3.A.1.14.2; V is most similar to 3.A.1.23.2 and 3.A.1.25.1) (Rodionov et al., 2009)

MtsTUV of Lactobacillus johnsoni
MtsT (M) (Q74I63)
MtsU (C) (Q74I62)
MtsV (M) (Q74I61)

This ABC uptake porter of unknown substrate specificity is unusual in that all four subunits of a typical ECF transporter occur in a single polypeptide chain of 1148 aas with the domain order as follows: (1) a hydrophilic domain of ~200 aas, (2) the S (substrate binding) domain, (3) the first ATPase domain, (4) another hydrophilic domain, (5) the second ATPase domiain, (6) the T (transducer) domain. It is not unusual for eukaryotes to fuse domains of an ABC porter together, but this is the first one we have observed in this type of ABC transporter. Based on its similarity with TC# 3.A.1.29.1, it may transport Methionine, but the entry in NCBI indicates possible substrates to be Co2+ or riboflavin (based only on sequence similarity).

Fungi, Ascomycota
ECF-type ABC transporter of Hortaea werneckii
3.A.1.30:  The Thiamin Precursor (Thi-P) Family

The putative thiamin precursor uptake transporter, YkoEDC (Rodionov et al., 2009) (E is most similar to 3.A.1.4.3; D is most similar to 3.A.1.26.2; C is most similar to 3.A.1.23.2).

YkoEDC of Bacillus subtilis
YkoE (M) (O34738)
YkoD (C-C) (O34362)
YkoC (M) (O34572)

Putative thiamin transporter

Potential thiamin transporter of Streptococcus pneumoniae 
Membrane Protein 1 (Q97RJ2) 
ABC ATPase (Q97RS3)
Membrane Protein 2 (Q97RS4) 
3.A.1.31:  The Unknown-ABC1 (U-ABC1) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


The putative uptake transporter of unknown substrate specificity, HtsTUV (Rodionov et al., 2009)

HtsTUV of Bifidobacterium longum
HtsT (M) (Q8G6E7)
HtsU (M) (Q8G6E8)
HtsV (C-C) (Q8G6E9)

EcfSTAA of unknown function.

EstSTA of Treponema denticola
EstS (Q73JF1)
EstT  (Q73JF2)
EstAA  (Q73JF3)  

RLI1 ATPase of 608 aas and 0 TMSs, ABCE.  Binds to the ribosome, IF3, IF5 and IF2 to promote preinitiation complex assembly (Dong et al. 2004). ABCE proteins are present in eukaryotes and archaea and are encoded by a single gene in most genomes, or by two genes in a few cases. Functional analysis of ABCE genes, primarily in Saccharomyces cerevisiae, has shown that ABCE proteins have essential functions as part of the translational apparatus. Navarro-Quiles et al. 2018 summarized ABCE protein functions in ribosome biogenesis and recycling, with a particular focus on their known and proposed developmental roles in different species. The ABCE proteins might represent another class of factors contributing to the role of the ribosome in gene expression regulation.

Fungi, Ascomycota
RLI1 of

RNase L inhibitor of 599 aas, ABCE1; lacks a TMS, and is not a transporter.  It antagonizes the binding of 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) by RNase L through direct interaction with RNase L and therefore inhibits its endoribonuclease activity. It may  also play a central role in the regulation of mRNA turnover (Le Roy et al. 2001). It antagonizes the anti-viral effect of the interferon-regulated 2-5A/RNase L pathway, and may act as a chaperone for post-translational events during HIV-1 capsid assembly (Martinand et al. 1999).

Metazoa, Chordata
ABCE1 of Homo sapiens
3.A.1.32:  The Cobalamin Precursor (B12-P) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


The putative cobalamin precursor uptake transporter, CbrTUV (Rodionov et al., 2009) (CbrT is most similar to 2.A.1.15.1; CbrU is most similar to 3.A.1.26.1 (MFS; e-4); CbrV is most similar to 2.A.53.11.1 and 3.A.1.2.2 (score of 0.035)) (CbrT has 6 putative TMSs; CbrV has 8-10 putative TMSs).
CbrTUV of Streptomyces coelicolor
CbrT (M) (Q9KXJ5)
CbrU (C-C) (Q9KXJ6)
CbrV (M) (Q9KXJ7)

Putative vitamin transporter, EcfSTAA

Putative vitamin transporter of Methanosphaera stadtmanae, EcfSTAA'
EcfT (M) (Q2NFA7)
EcfA-A' (C) (Q2NFA8)
EcfS (M) (Q2NFA9) 

Putative cobalamin (vitamin B12) uptake porter, CbrVUT (Rodionova et al. 2015). The ATPase subunit has not been identified.

CbrVUT of Chloroflexus aurantiacus
CbrV (M, 9 TMSs)
CbrU (R, 1 TMS)
CbrT (M, 6 TMSs)

ECF ABC transporter of unknown function with three subunits, EcfS, EcfT (both with 7 putative TMSs) and EcfA.

ECF transporter, EcfSTA of Moorella sp. Hama-1

Putative substrate binding membrane (S) subunit of 4 or 5 TMSs of the heavy metal/vitamin transporter subclass of the ABC superfamily.  It is an ECF-ribofla-tS domain.  An ATPase and a T-subunit have not been found, but these S-membrane proteins can also function as secondary carriers (see TC family 2.A.88).

Candidatus Lokiarchaeota
S-subunit of a putative ABC transporter or secondary carrier of Lokiarchaeum sp. GC14_75 (marine sediment metagenome)
3.A.1.33:  The Methylthioadenosine (MTA) Family

The putative methylthio adenosine uptake transporter (Rodionov et al., 2009).  MtaTUV (MtaT and MtaU are most similar to 3.A.1.26.1 (ThiW); MtaV is most similar to 3.A.1.25.1 (BioN) and 3.A.1.23.2 (CbiQ)).
MtaTUV of Thermoanaerobacter tengcongensis
MtaT (M) (Q8R9M1)
MtaU (C-C) (Q8R9L8)
MtaV (M) (Q8R9L9)

Possible cobalt ion transporter of three subunits, Q8TSC7 (S-subunit, DUF1616, with 550 aas and 8 probable TMSs in a 1 (N-terminus) + 7 (C-terminus) arrangement), Q8TSC8 (A-subunit, ATPase, with 641 aas) and Q8TSC9 (T-subunit, 297 aas, probably with 6 or 7 TMSs).  The protein with UniProt acc. # Q8TSC6, encoded adjacent to the three genes encoding the transporter, is CobN, a Co2+/Mg2+ celatase of 1302 aas, and adjacent thereto is a gene encoding a PQQ enzyme of 570 aas with 1 N-terminal TMS.

EcfSAT of Methanosarcina acetivorans
3.A.1.34:  The Tryptophan (TrpXYZ) Family

The putative tryptophan uptake transporter, TrpXYZ. Regulated by tryptophan-specific T-box (Vitreschak et al. 2008)

TrpXYZ of Streptococcus pyogenes
TrpX (R) (Q99ZY6)
TrpY (M) (Q99ZY4)
TrpZ (C) (Q99ZY3)
3.A.1.101:  The Capsular Polysaccharide Exporter (CPSE) Family

Capsular polysaccharide exporter
KpsMT of E. coli KpsM
KpsM (M) - (P24584)
KpsT (C) - (P24586)

Vi polysaccharide exporter, VexBC (Hashimoto et al, 1993).
VexBC of Salmonella typhi
VexB (M) - (P43109)
VexC (C) - (P43110)

Capsular polysialate exporter, CtrC/D (functions with 1.B.18.2.3 (OMA) and 1.B.4.2.1 (MPA2)) (Larue et al., 2011).

CtrABCD of Neisseria meningitidis
CtrC (M) (B3FHE1)
CtrD (C) (B3FHE0) 
3.A.1.102:  The Lipooligosaccharide Exporter (LOSE) Family

Lipooligosaccharide exporter (nodulation proteins, NodIJ)
NodIJ of Rhizobium galegae
NodJ (M)
NodI (C)

NodIJ nodulation factor transporter.  Involved in lipo-chitooligosaccharide secretion (Fernández-López et al. 1996).

NodIJ of Azorhizobium caulinodans
NodI, C, Q07756
NodJ, M, Q07757
3.A.1.103:  The Lipopolysaccharide Exporter (LPSE) Family

Lipopolysaccharide exporter
RfbAB of Klebsiella pneumoniae
RfbA (M)
RfbB (C)

Heteropolysaccharide O-antigen exporter, Wzm/Wzt (Feng et al., 2004). The C-terminal cytoplasmic domain of Wzt (an IgG-like β-sandwich) determines the specificity of the transporter for either O8 or O9a O-PS (Cuthbertson et al., 2007). The transporter structure reveals a continuous transmembrane channel in a nucleotide-free state (Caffalette et al. 2019). Upon ATP binding, large structural changes within the nucleotide-binding and transmembrane regions push conserved hydrophobic residues at the substrate entry site towards the periplasm and provide a model for polysaccharide translocation. With ATP bound, the transporter forms a large transmembrane channel with openings toward the membrane and periplasm. The channel's periplasmic exit is sealed by detergent molecules that block solvent permeation. Molecular dynamics simulation data suggest that, in a biological membrane, lipid molecules occupy this periplasmic exit and prevent water flux in the transporter's resting state (Caffalette et al. 2019).

Wzm/Wzt of E. coli
Wzm (M) (AAS99164)
Wzt (C) (AAS99165)

ABC transporter required for O-antigen biosynthesis and multicellular development, RfbAB (Guo et al. 1996). Functions with the RfbC glycosyl transferase (TC#4.D.1.3.4). 

RfbAB of Myxococcus xanthus 
RfbA (M) 260aas (Q50862)
RfbB (C) 437aas (Q50863) 

RfbAB lipopolysaccharide exporter (Guo et al. 1996).

RfbAB of Myxococcus xanthus.
RfbA (MXAN_4623) (M)
RfbB (MXAN_4622) (C) 

ABC transporter mediating ethanol tolerance, Slr0977 (M)/Slr0982 (C) (Zhang et al. 2015).  Present in a gene cluster with (lipo)polysaccharide biosynthetic enzymes, so could be a cell surface carbohydrate export system.

Ethanol tolerance transporter of Synechocystis sp. (strain PCC 6803 / Kazusa)

Two component lipopolysaccharide exporter, Wzm/Wzt.  Wzm is the membrane component (265 aas with 6 TMSs) which forms a ring-like large ion conductance channel. The ATPase, Wzt, functions both as the energizer and regulator (Mohammad et al. 2016).

Wzm/Wzt of Pseudomonas aeruginosa

ABC-type polysaccharide/polyol phosphate export systems, permease componentof 262 aas and 6 or 7 TM

Transporter of Acidovorax sp. MR-S7

ABC transporter of 258 aas and 6 TMSs.

Candidatus Moranbacteria
ABC transporter of Moranbacteria bacterium

ABC O-antigen lipopolysaccharide/polysaccharide export transporter, Wzm/Wzt of 253 aas and 6 TMSs (Wzm; also called AbcT3) and 396 aas and 0 TMSs (Wzt). The crystal structure is available (PDB 6AN7) (Bi et al. 2018) for the Wzm-Wzt homologue from Aquifex aeolicus in an open conformation. The transporter forms a transmembrane channel that is sufficiently wide to accommodate a linear polysaccharide. Its nucleotide-binding domain and a periplasmic extension form 'gate helices' at the cytosolic and periplasmic membrane interfaces that probably serve as substrate entry and exit points (Bi et al. 2018). O antigen structures are serotype specific and form extended cell surface barriers endowing many pathogens with survival benefits. In the ABC transporter-dependent biosynthesis pathway, O antigens are assembled on the cytosolic side of the inner membrane on a lipid anchor and reoriented to the periplasmic leaflet by WzmWzt for ligation to the core lipopolysaccharides. This process depends on the chemical modification of the O antigen's nonreducing terminus, sensed by WzmWzt via a carbohydrate-binding domain (CBD) that extends its nucleotide-binding domain (NBD). Caffalette and Zimmer 2021 provided the cryoEM structure of this full-length WzmWzt transporter bound to ATP in a lipid environment, revealing a highly asymmetric transporter organization. The CBDs dimerize and associate with only one NBD. Conserved loops at the CBD dimer interface straddle a conserved peripheral NBD helix. The CBD dimer is oriented perpendicularly to the NBDs and its putative ligand-binding sites face the transporter to likely modulate ATPase activity upon O antigen binding. A closed WzmWzt conformation in which an aromatic belt near the periplasmic channel exit seals the transporter in a resting, ATP-bound state. The sealed transmembrane channel is asymmetric, with one open and one closed cytosolic and periplasmic portal (Caffalette and Zimmer 2021). 


Wzm/Wzt of Aquifex aeolicus

Wzm (M; 280 aas; 6 or 7 TMSs in a 2 + 3 + 1 or 2 TMS arrangement)-Wzt (C) ABC lipid-linked galactan precursor exporter. Deletion of the encoding genes results in severe morphological changes and the accumulation of an aberrantly long galactan precursor. A model for coupled synthesis and export of the galactanpolymer precursor in mycobacteria has been proposed (Savková et al. 2021). The two encoding genes are separated by a gene that encodes a galactofuranosyltransferase, GlfT1.

Wzm-Wzt of Mycobacterium tuberculosis
Wzm, M, P72049 (Rv3783)
Wzt, C, P72047 (Rv3781)
3.A.1.104:  The Teichoic Acid Exporter (TAE) Family

Teichoic acid exporter, TagGH.  It is present in a large complex with the teichoic acid precursor synthetic enzymes (Formstone et al. 2008).  The substrate may be the diphospholipid-linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011).  3-d structural studies have been reported (Ko et al. 2016) showing that TagG and TagH are localized on the cytoplasmic membrane in a patch, and the TMS of TagH is important for normal transport activity (Yamada et al. 2018). The crystal structure of the N-terminal domain of TagH reveals a potential drug targeting site (Yang et al. 2020). The ATPase activity of TagH-N was inhibited by clodronate, a bisphosphonate, in a non-competitive manner, consistent with the proposed wall teichoic acid-binding site for drug targeting (Yang et al. 2020).

TagGH of Bacillus subtilis
TagG (M)
TagH (C)

The teichoic acid precursor exporter, TarGH. May be specific for the diphospholipid linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011). TarG is the target of a small antimicrobial inhibitor of S. aureus growth (Swoboda et al. 2009). TarGH is a WTA transporter and has been purified and reconstituted in proteoliposomes (Matano et al. 2017). They showed that a new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG, near the opposite side of the membrane. These are the first ABC transporter inhibitors to block ATPase activity by binding to the transmembrane domain.

TarGH of Staphylococcus aureus 
TarG (M) (D1GQ18)
TarH (C) (D1GQ17) 
3.A.1.105:  The Drug Exporter-1 (DrugE1) Family

Daunorubicin, doxorubicin etc. (multidrug resistance) exporter, DrrAB.  DrrB binds drugs with variable affinities and contains multiple drug binding sites. The two asymmetric nucleotide binding sites in DrrA have strikingly different binding affinities. Long-range conformational changes occur between DrrA and DrrB. The transduction pathway from the nucleotide-binding DrrA subunit to the substrate binding DrrB subunit includes the Q-loop and CREEM motifs in DrrA and the EAA-like motif in DrrB (Rahman and Kaur 2018).

DrrAB of Streptomyces peucetius
DrrA (C), 330 aas
DrrB (M), 283 aas and 6 TM

Oleandomycin (drug resistance) exporter
OleC4-OleC5 of Streptomyces antibioticus
OleC4 (C)
OleC5 (M)

The 4A-4E-O-dideacetyl-chromomycin A3 (biosynthetic precursor of chromomycin) exporter (may also export chromomycin and mithramycin (Menendez et al., 2007).

CmrAB of Streptomyces greseus
CmrA(C) (Q70J75)
CmrB(M) (Q70J76)

The pyoluteorin (a chlorinated polyketide) efflux pump, PltHIJKN (Brodhagen et al. 2005; Huang et al. 2006).

PltHIJKN of Pseudomonas sp. M18:
PltH (336aas; MFP) - (Q4VWD0)
PltI (589aas; C-C) - (Q4VWC9)
PltJ (377aas; M; COG0842; similar to 9.B.74.2 (ABC-2)) - (Q4VWC8)
PltK (372aas; M; The C-terminal hydrophobic half has 5TMSs and is most similar to PltJ, and then to 9.B.74.2, but it is also homologous to 3.A.1.105.2 and 3.A.1.102.1) - (Q4VWC7)
PltN (480aas; OMF) - (Q4VWC6)

AbcG homologue, Snustorr, sioform A, Snu, of 808 aas and 6 TMSs in a 1 + 5 TMS arrangement at the C-terminal part of the protein.  The N-terminal domain is the ATPase domain.  The protein therefore has a C-M domain arrangement.  Lipids in extracellular matrices (ECM) contribute to barrier function and stability of epithelial tissues such as the pulmonary alveoli and the skin. In insects, skin waterproofness depends on the outermost layer of the extracellular cuticle envelope that contains cuticulin, an unidentified water-repellent complex molecule composed of proteins, lipids and catecholamines. Based on live-imaging analyses of fruit fly larvae, Zuber et al. 2018 found that initially, envelope units are assembled within putative vesicles harbouring the ABC transporter Snu and the extracellular protein Snsl. In a second step, the content of these vesicles is distributed to cuticular lipid-transporting nanotubes named pore canals and to the cuticle surface, dependent on Snu function. The surface of snu and snsl mutant larvae is depleted of lipids and cuticulin. Consequently, these animals suffer uncontrolled water loss and penetration of xenobiotics. The data allude to a two-step model of envelope (i.e. barrier) formation. The proposed mechanism in principle parallels the events occurring during differentiation of the lipid-based ECM by keratinocytes in the vertebrate skin, suggesting establishment of analogous mechanisms of skin barrier formation in vertebrates and invertebrates (Zuber et al. 2018).

Metazoa, Arthropoda
AbcG homologue, Snu, of Drosophila melanogaster

The ABC-2-like transporter

ABC-2-like transporter of Dehalococcoides ethenogenes
ABC2 protein (M) (Q3Z8A7)
ATPase (C) (Q3Z8A8)

Putative ABC2 tranport system, SagGHI; may export streptolysin S.

Putative Streptolysin ABC2 tranport system, SagGHI.
SagG (C) (Q9A0K0)
SagH (M) (Q9A0J9)
SagI (M) (Q9A0J8)

ABC-2 transporter.  The two genes encoding this system are adjacent to one encoding an squalene-hopene cyclase that coverts squalene to hopene.  The substrate could therefore be hopene or a hydrocarbon triterpene derivative of it (Racolta et al. 2012).

ABC2 membrane protein (Q7UE57) and ATPase (Q7UE58) of Rhodopirellula baltica

ABC2 membrane proteins (J7ZHK9 and J8A8S6) with ATPase (J8ABC0) transporter

ABC2 transporter of Bacillus cereus

AbcG homologue, ABCH1 of 705 aas and 6 TMSs in a C-M arrangement.  May be involved in steroid or drug efflux (Popovic et al. 2010).  Of the vertbrates, it may be restricted to fish. 

Metazoa, Chordata
AbcH1 (C-M) of Danio rerio

ABC-2 transporter probably specific for a lantibiotic.  The genes for this system are adjacent to an S2P-M50 peptidase (G0Q3D2), probably involved in pro-lantibiotic processing, as well as a lantibiotic biosynthetic enzyme (G0Q3D1) and a lantibiotic dehydratase (G0Q3D0). 

ABC-2/ATPase of Streptomyces griseus
ABC-2 (M) (G0Q3D4)
ATPase (C) (G0Q3D3)

Three component ABC-2 transporter: (1) the membrane (M) subunit with a C-terminal CBS domain, (2) an ABC ATPase subunit and (3) an M50 peptidase (Zn2+-metalopeptidase) of 392 aas and 6TMSs. they may export a bacteriocin, and the protease cleaves off the signal peptide during export. The three encoding genes are in a single gene cluster.

ABC transporter
ABC2 (M) (F8D412)
ABC ATPase (C) (F8D413)
M50 peptidese,  (F8D414)

SclAB (Sco4359-60) (Gominet et al. 2011).

SclAB of Streptomyces coelicolor.
SclA (C)
SclB (M)

RagAB, involved in both aerial hyphae formation and sporulation (San Paolo et al. 2006).

RagAB of Streptomyces coelicolor.
RagA: Sco4075 (C)
RagB: Sco4074 (M) 

Putative drug exporter, YbhFGRS (Moussatova et al. 2008).

YbhFGRS of E. coli
YbhF, (C) (578 aas)
YbhG, (MFP) (332 aas)
YbhR, (M) (368 aas)
YbhS, (M) ((377 aas)

Putative ABC export system (MDR?), RbbA/YhhJ/YhiI (All three genes are in a single operon; this system may comprise a single ABC exporter with MFP; substrate unknown (Moussatova et al. 2008 and unpublished observations).


RbbA/YhhJ/YhiI of E. coli
RbbA (C-M; 911 aas; C8TJS4)
YhhJ (M; 374 aas; P0AGH1)
YhiI (MFP; 355 aas; P37626)

The putative polyketide drug exporter, YadGH.  May also transport phospholipids, participating in phospholipid trafficking together with the Mla complex. It interacts with MlaABCDEF (TC# 3.A.1.27.3) to preserve outer membrane asymmetry (Malinverni and Silhavy 2009; Babu et al. 2018).

YadGH of E. coli
YadG (C; 308 aas)
YadH (M, 256 aas)

Poorly characterized ABC exporter involved in bacterial competitiveness and bioflim morphology, YfiLMN (Stubbendieck and Straight 2017).

YfiLMN of Bacillus subtilis
YfiL (C) 311 aas, 0 TMSs
YfiM (M) 296 aas, 6 TMSs
YfiN (N) 385 aas, 6 TMSs

Putative 5 component ABC exporter with two membrane constituents, two cytoplasmic ATPases, and one membrane fusion protein (truncated at the N-terminus, probably because of an incorrect initiation codon assignment).

5-component ABC exporter of Bdellovibrio bacteriovorus
Q6MLX4 (M)
Q6MLX5 (M)
Q6MLX6 (C)
Q6MLX7 (C)

Uncharacterized ABC transporter with two components, a transmembrane protein with 6 TMSs and an ATPase. The substrate in unknown.

Candidatus Saccharibacteria
ABC system of Candidatus Saccharibacteria bacterium

Uncharacterized protein pair of a presumed ABC transporter. One is of 280 aas and 7 putative TMSs; the other is of 275 aas and 6 putative TMSs. The genes encoding these two proteins map adjacent to each other.  The ATPase has not been identified.

Candidatus Eisenbacteria
UP of Candidatus Eisenbacteria bacterium RBG_16_71_46 (subsurface metagenome)

Putative ABC exporter with two consitutents, M is of 256 aas and 6 TMSs; C is of 317 aas.  The genes encoding these two proteins are adjacent to each other.

ABC exporter of Armatimonadetes bacterium (groundwater metagenome)

Putative ABC exporter with two membrane constituents encoded by adjacent genes.  The ATPase does not map adjacent to these genes and has not been identified.

Candidatus Thermoplasmatota
Putative ABC exporter of Methanomassiliicoccus sp.

ATP-binding cassette transporter subfamily Gof 687 aas and 7 TMSs in a 1 + 6 TMS arrangement. 13 ABCG genes were identified in N. lugens, and expression levels of these ABCG transporter genes after treatment with thiamethoxam, abamectin, and cyantraniliprole has been examined.  Some increase in amounts while others do not (Yang et al. 2019).

Metazoa, Arthropoda
ABCG of Nilaparvata lugens (Brown plant leafhopper)

Putative ABC transporter with two membrane proteins, both with 6 TMSs, one with them in a 2 + 2 + 2 TMS arrangement, the other in a 2 + 3 + 1 TMS arrangement. The two genes encoding these proteins are next to each other on the chromosome.  The ATPase is fused to the first of these two membrane protein domains (acc # C7QI22). These two genes, presumable encoding an ABC exporter, are adjacent to lantibiotic biosynthesis genes. Therefore their function may be to export a lantibiotic. The N-terminal hydrophilic domain of C7QI22 is an S2P-M50-like peptidase (TC# 9.B.149) that may process the pro-lantibiotic during export.

ABC membrane transport proteins of Catenulispora acidiphila

Putative ABC exporter with two protein components, the first, a large protein with an N-terminal membrane domain with 6 TMSs in a 2 + 2 + 2 TMS arrangement, and a C-terminal ABC-type ATPase domain. The second protein is a smaller protein with only a membrane domain with 6 TMSs in a 2 + 3 + 1 TMS arrangement.  The two genes encoding these proteins are adjacent to each other, and are adjacent to a lantibiotic dehydrophenase gene. They may therefore export the newly synthesized lantibiotic.

ABC exporter of Catenulispora acidiphila

ABC-like transporter with 4 components, two integrals membrane ABC proteins (O26020 and O26021, 376 and 365 aas, respectively) , an MFP protein (OP94851; 329 aas) and a TolC-like protein (O026022; 510 aas). This system appears to play a role in flagellar stability and bacterial motility (Gibson et al. 2022).

4 component ABC-like transporter
3.A.1.106:  The Lipid Exporter (LipidE) Family

Phospholipid, LPS, lipid A and drug exporter, MsbA, which flips the substrate from the inner leaflet of the cytoplasmic membrane to the outer leaflet (Eckford and Sharom, 2010). MsbA also confers drug resistance to azidopine, daunomycin, vinblastine, Hoechst 33342 and ethidium (Reuter et al., 2003). Four x-ray structures, trapped in different conformations, two with and two without nucleotide, have been solved (Ward et al., 2007). They suggest an alternating accessibility mode of transport with major conformational changes.  The mechanism and conformational transitions have been discussed (Moradi and Tajkhorshid 2013).  MsbA is energized both by ATP hydrolysis and the H+ electrochemical gradient (Singh et al. 2016). Mi et al. 2017 used single-particle cryo-electron microscopy to elucidate the structures of lipid-nanodisc-embedded MsbA in three functional states. The 4.2 Å-resolution structure of the transmembrane domains of nucleotide-free MsbA revealed that LPS binds deeply inside MsbA at the height of the periplasmic leaflet. Two sub-nanometre-resolution structures of MsbA with ADP-vanadate and ADP revealed a closed and an inward-facing conformation, respectively. A  2.9 A resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealed an unanticipated mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains (Ho et al. 2018). Coupled ATPase-adenylate kinase activity in ABC transporters including MsbA has been demonstrated (Kaur et al. 2016). Close-proximity effects and structural coupling of the transmembrane domains with the NBDs has been suggested (Josts et al. 2019). Two first-generation inhibitors of MsbA, TBT1 and G247, induce opposite effects on ATP hydrolysis. Using single-particle cryo-electron microscopy and functional assays, TBT1 and G247 were found to bind adjacent yet separate pockets in the MsbA transmembrane domains (Thélot et al. 2021). MsbA adopts the wide inward-open conformation in E. coli cells (Galazzo et al. 2022).  Solid-state NMR spectroscopy rvealed that substantial chemical shift changes within both CH1 and CH2 occur upon substrate binding, in the ATP hydrolysis transition state, and upon inhibitor binding. CH2 is domain-swapped within the MsbA structure, and substrate binding induces a larger response in CH2 compared to CH1. These data show that CH1 and CH2 undergo structural changes as part of the TMD-NBD cross-talk (Novischi et al. 2024).

MsbA (M-C) of E. coli

The homodimeric Sav1866 multidrug exporter (transports doxorubicin, verapamil, ethidium, tetraphenylphosphonium, vinblastine and the fluorescent dye, Hoechst 33342; 3-D structure known at 3 Å resolution; Dawson and Locher, 2006; Velamakanni et al., 2008) The empty site opens by rotation of the nucleotide-binding domain whereas the ATP-bound site remains occluded (Jones and George, 2011). Conformational changes induced by ATP-binding and hydrolysis have been proposed (Becker et al. 2010; Oliveira et al., 2011). The alternating access mechanism and the flippase activity of this ABC exporter has been shown to be lipid-dependent (Becker et al. 2010; Oliveira et al., 2011). The alternating access mechanism and the flippase activity of this ABC exporter has been shown to be lipid-dependent (Immadisetty et al. 2019).

Sav1866 of Staphylococcus aureus (M-C) 2HYDA/2HYDB (578 aas)

The dimeric multidrug resistance exporter, ABC1/2 (exports the peptide antimicrobials, nisin and polymyxin; (Margolles et al., 2006) (both ABC1 and ABC2 also show striking similarity to family 3.A.1.117).

ABC1/2 of Brevibacterium longum:
ABC-1 (M-C) (ZP_00121338)
ABC-2 (M-C) (ZP_00121339)

The duplicated ABC transporter, CgR_1214 (1247 aas; MC(poorly conserved) MC(well conserved))
CgR_1214 of Corynebacterium glutamicum (MCMC) (A4QD95)

The heterodimeric multidrug efflux pump, SmdAB (exports norfloxacin, tetracycline, 4',6-diamidino-2-phenylindole (DAPI), and Hoechst 33342) (Matsuo et al., 2008).
SmdAB of Serratia marcescens:
SmdA (M-C) (A7VN01)
SmdB (M-C) (A7VN02)

Multidrug efflux pump, Rv0194 (exports & causes resistance to ampicillin, streptomycin and chloramphenicol by 32- to 64-fold and to vancomycin and tetracycline by 4- to 8-fold (Danilchanka et al., 2008)).
Rv0194 of Mycobacterium tuberculosis (MCMC) (O53645)

The Salmochelin/Enterobactin secretory exporter, IroC (Crouch et al., 2008; Müller et al. 2009).

IroC of Salmonella enterica (MCMC) (Q8RMB7)

The heterodimeric BmrC/BmrD (YheHI) MDR transporter.  Transports a wide range of structurally unrelated drugs including doxorubicin, mitoxantrone, ethidium, and hoechst 33342 (Torres et al., 2009). It activates the sensor kinase, KinA, during sporulation initiation (Fukushima et al. 2006). Large scale purification has been achieved (Galián et al. 2011).  It has been reconstituted in giant unilamellar vesicles (Dezi et al. 2013).  It exhibits an asymmetric configuration of catalytically inequivalent nucleotide binding sites. The two-state transition of the TMS domains, from an inward- to an outward-facing conformation, may be driven exclusively by ATP hydrolysis (Mishra et al. 2014). A novel intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. has been identified (Thaker et al. 2021). In the cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in an asymmetric head-to-tail arrangement. Deletion of the extracellular domain capping the substrate-binding chamber or mutation of Hoechst-coordinating residues abrogates cooperative stimulation of ATP hydrolysis. These findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters (Thaker et al. 2021). Lipid interactions with BmrCD modulate the energy landscape, suggesting a distinct transport model that highlights the role of asymmetric conformations in the ATP-coupled cycle with implications to the mechanism of ABC transporters in general (Tang et al. 2023).

BmrC/BmrD (YheHI) of Bacillus subtilis
YheH (M-C) (O07549)
YheI (M-C) (O07550)

SoxR regulon single protein ABC exporter, Sco7008, containing an N-terminal membrane domain and a C-terminal ATPase domain (Shin et al. 2011). SoxR responds to extracellular redox-active compounds.  Thus, it is induced in stationary phase during the production of the benzochromanequinone blue-pigmented antibiotic, actinorhodin (Naseer et al. 2014). Possibly an actinorhodin exporter.

Sco7008 (M-C) of Streptomyces coelicolor.

Involved in the export of a molecule required for the autochemotactic process. AbcA integrated permease/ATPase (M-C) protein, MXAN_1286 (Ward et al. 1998). 

MXAN_1286 (M-C) of Myxococcus xanthus.

HlyA/MsbA family transporter of 595 aas.  The gene for this protein is adjacent to and probably in the same operon as that encoding 3.A.1.106.12.  They both have 6 TMSs, so they may together comprise a single heterodimeric system. 

ABC exporter of Gloeobacter violaceus

HlyA/MsbA family transporter of 577 aas.  The gene encoding this protein is adjacent to and in the same operon with that encoding 3.A.1.106.11.  They both have 6 TMSs, so they may together comprise a single heterodimeric system. 

ABC exporter of Gloeobacter violaceus

Multidrug resistance-like ABC exporter, MdlAB; exports peptides of 6 - 21 aas (Moussatova et al. 2008).

MdlAB of E. coli
MdlA (M-C; 590 aas)
MdlB (M-C; 593 aas)

Lipid A exporter homologue of 593 aas and 6 TMSs (N-terminal with a C-terminal ATPase domain.  Essential for acid, salt and thermal tolerance (Matsuhashi et al. 2015).

Exporter of Synechocystis sp. PCC6803

Lipid flippase, PglK or WlaB, of 564 aas and 6 N-terminal TMSs with a C-terminal ATPase domain.  Mediates the ATP-dependent translocation of an undecaprenylpyrophosphate-linked heptasaccharide intermediate (LLO) across the cell membrane, an essential step during the N-linked protein glycosylation pathway. Transport across the membrane is effected via ATP-driven conformation changes. Most likely, only the polar and charged part of the glycolipid enter the substrate-binding cavity, and the lipid tail remains exposed to the membrane lipids during the transmembrane flipping process (Alaimo et al. 2006; Kelly et al. 2006; Perez et al. 2015). PglK may employ a "substrate-hunting" mechanism to locally increase the LLO concentration and facilitate its jump into the translocation pathway, for which sugars from the LLO head group are essential; the release of LLO to the outside occurs before ATP hydrolysis and is followed by the closing of the periplasmic cavity of PglK (Perez et al. 2019).

PglK (M-C) of Campylobacter jejuni

Probable integral membrane protein NMA1777 with 6 TMSs in a 2 + 2 + 2 arrangement, ; function and ATPase unknown.

UP of Klebsiella pneumoniae

ABC1 transporter

transporter of Acidobacterium capsulatum

Peptide and multidrug resistance porter of the ABC superfamily, TmrAB. TmrA (Q72J05; 600 aas with 6 N-terminal TMSs) and TmrB (Q72J04; 578 aas with 6 N-terminal TMSs) comprise this heterodimeric transporter, both proteins of the M-C structure.  The system has been found to export the dye, hoechst 33342, and to be inhibited by verapamil (Zutz et al. 2011). The subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy has been solved (Kim et al. 2015). A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Comparison between this structure and those of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations (Kim et al. 2015). A subset of annular lipids is normally invariant in composition, with negatively charged lipids binding tightly to TmrAB, suggesting that this exporter may be involved in glycolipid translocation (Bechara et al. 2015). Coupled ATPase-adenylate kinase activity in ABC transporters including TmrAB has been demonstrated (Kaur et al. 2016). A 2.7-Å X-ray structure of TmrAB has been determined. It not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. It adopts an asymmetric inward-facing state, and the C-terminal helices, arranged in a zipper-like fashion, play a role in guiding the conformational changes associated with substrate transport (Nöll et al. 2017). Conformational coupling and trans-inhibition have been characterized (Barth et al. 2018), and a  conserved motif in intracellular loop 1 stabilizes the outward-facing conformation of TmrAB (Millan et al. 2021). A strong entropy-enthalpy compensation mechanism enables the closure of the nucleotide-binding domains (NBDs) over a wide temperature range. This is mechanically coupled with an outward opening of the transmembrane domains (TMDs) accompanied by an entropy gain (Barth et al. 2020).  TmrAB undergoes a reversible transition in the presence of ATP with a significantly faster forward transition. The impaired degenerate NBS stably binds Mn2+-ATP, and Mn2+ is preferentially released at the active consensus NBS (Rudolf et al. 2023). ATP hydrolysis at the consensus NBS considerably accelerates the reverse transition. Both NBSs fully open during each conformational cycle, and the degenerate NBS may regulate the kinetics of this process (Rudolf et al. 2023).

TmrAB of Thermus thermophilus

ABC exporter.  It has been suggested that it might be a glycolate exporter (Braakman et al. 2017). However it's closest hit in TCDB (31% identity in the transmembrane domain) has TC# 3.A.1.106.18, which is probably a peptide/multidrug (and possibly glycolipid) exporter with broad substrate specificity. 

ABC exporter of Prochlorococcus marinus

MsbA of 582 aas and 6 TMSs in an M-C arrangement.  The X-ray structure at 2.8 Å resolution in an inward-facing conformation after cocrystallization with lipid A and using a stabilizing facial amphiphile has been reported (Padayatti et al. 2019). The structure displays a large amplitude opening in the transmembrane portal, which is likely to be required for lipid A to pass from its site of synthesis into the protein-enclosed transport pathway. Putative lipid A density is observed further inside the transmembrane cavity, consistent with a trap and flip model. Additional electron density attributed to lipid A is observed near an outer surface cleft at the periplasmic ends of the transmembrane helices (Padayatti et al. 2019). This protein is 96% identical to the E. coli ortholog, TC# 3.A.1.106.1.

MsbA of Salmonella enterica
3.A.1.107:  The Putative Heme Exporter (HemeE) Family

Putative heme exporter, CcmABC=CycVWZ (Note: CcmC may function independently of CcmAB) (Feissner et al., 2006; Christensen et al., 2007)
CycVWZ of Bradyrhizobium japonicum
CycV (C)
CycW (M)
CycZ (M)

The mitochondrial ABC transporter involved in cytochrome c maturation, CcmA/CcmB. (Note: CcmA is nuclearly encoded while CcmB is mitochondrially encoded) (Rayapuram et al., 2007)
Viridiplantae, Streptophyta
CcmA/CcmB of Arabidopsis thaliana
CcmA (C) (Q9C8T1)
CcmB (M) (P93280)

CcmABCD exporter; CcmD (69aas, 1TMS) is required for the release of CcmE (which binds heme in the periplasm) from CcmABC. CcmC (9.B.14.2.3) is required for the transfer of heme to CcmE in the periplasm (Richard-Fogal et al., 2008) In the presence of heme, CcmC and CcmE form a stable complex (Richard-Fogal & Kranz, 2010) as do CcmE and CcmF (San Francisco and Kranz 2014). The cytochrome c maturation system I, consisting of eight membrane/periplasmic proteins (CcmABCDEFGH), results in the attachment of heme to cysteine residues of cytochrome c proteins. Since all c-type cytochromes are periplasmic, heme is first transported to a periplasmic heme chaperone, CcmE. A large membrane complex, CcmABCD has been proposed to carry out this transport and linkage to CcmE. Li et al. 2022 described high resolution cryo-EM structures of CcmABCD in an unbound form, in complex with inhibitor AMP-PNP, and in complex with ATP and heme. The ATP-binding site in CcmA and the heme-binding site in CcmC were identified. They proposed a model of heme trafficking, heme transfer to CcmE, and ATP-dependent release of holoCcmE from CcmABCD. CcmABCD represents an ABC transporter complex using the energy of ATP hydrolysis for the transfer of heme from one binding partner (CcmC, see TC# 9.B.14.2.3) to another (CcmE) (Li et al. 2022). It appers that CcmC is in a complex with CcmABD but is not part of the ABC transporter. The same may be true of CcmD (see description above).

CcmABCD of E. coli
CcmA (C) (Q8XE58)
CcmB (M; 7 TMSs) (P0ABM0)
CcmC (M; 6 TMSs) (P0ABM1 = P0ABM3) (listed under TC# 9.B.14.2.3 not here)
CcmD (M; 1 TMS) (P0ABM7)

Cytochrome c maturation system (heme exporter?), CcmA/B

CcmAB of Pseudomonas virdiflava
CcmA (C) (K6BJ24)
CcmB (M) (K6BIH6)
3.A.1.108:  The β-Glucan Exporter (GlucanE) Family

β-Glucan exporter
NdvA (M-C) of Rhizobium meliloti
3.A.1.109:  The Protein-1 Exporter (Prot1E) Family

α-Hemolysin exporter. HlyB has an (inactive?) N-terminal C39 peptidase-like domain (Lecher et al., 2011).  It is essential for secretion and interacts with the unfolded HlyA, thereby protecting it from cytoplasmic degradation (Lecher et al. 2012). Type 1 secretion systems (T1SSs)  extruding protein substrates following synthesis of the entire polypeptide. The E. coli hemolysin A secretion system has three membrane proteins - an inner membrane ABC transporter HlyB, an adaptor protein HlyD TC# 8.A.1.3.1), and an outer membrane porin TolC (TC# 1.B.17.1.1). All are required for secretion. Cryo-EM structures determined in two conformations revealed that the inner membrane complex is a hetero-dodecameric assembly comprising three HlyB homodimers and six HlyD subunits. Oligomerization of HlyB and HlyD is essential for protein secretion, and polypeptides translocate through a canonical ABC transporter pathway in HlyB (Zhao et al. 2022).

HlyB (M-C) of E. coli

Cyclolysin exporter, CyaB (Glaser et al., 1988) (Possesses an N-terminal lysosomal sorting signal within the amino-terminal transmembrane domain; Kamakura et al., 2008).

CyaB (M-C) of Bordetella pertussis

LapA adhesin protein exporter, LapB (Hinsa et al., 2003)
LapB of Pseudomonas putida
LapB (MC) (AAN65800)

The biofilm inducible ABC drug (tobramycin, gentamycin, and ciprofloxacin) resistance pump, PA1875-PA1877 (Zhang and Mah, 2008).  It is specifically induced and is most active when  growing in a biofilm.

PA1875-PA1877 of Pseudomonas aeruginosa
PA1875 (OMF; 425 aas) (Q9I2M2)
PA1876 (ABC; M-C; 723 aas) (Q9I2M1)
PA1877 (MFP; 395 aas) (Q9I2M0)

Probable giant non-fimbrial adhesin, SiiE, exporter, SiiFDC.  SiiF interacts with SiiAB (TC# 1.A.30.4.1) which probably forms a proton channel homologous to that of MotAB (TC# 1.A.30.1.1) and facilitates energization of SiiE export using the pmf (Wille et al. 2013).

SiiFDC of Salmonella enterica
SiiF (M-C; 688 aas; E1WEV2)
SiiD (MFP; 425 aas; E1WEV0)
SiiC (OMF; 439 aas; E1WEU9)

Probable 2646 aa extracellular adhesin (acc# C6BWI7) ABC exporter of 715 aas.  Functions as a type I protein secretion system together with an MFP and an OMF which all are encoded within a single operon together with the adhesin and SiiAB homologues as for TC# 3.A.1.109.5.

ABC/MFP/OMF type I protein secretion system of Desulfovibrio salexigens
ABC protein (M-C; 715 aas; C6BWI0)
MFP protein (430 aas; C6BWj0)
OMF protein (513 aas; C6BWI6)

Leukotoxin export protein of 707 aas, LtxB (has a fused M-C structure with 6 TMSs) (Guthmiller et al. 1995). Functions with the MFP, LtxD (TC# 8.A.1.3.4) and the TolC-like protein, TdeA (TC# 1.B.17.3.11).

Leukotoxin exporter of Aggregatibacter (Actinobacillus; Haemophilus) actinomycetemcomitans
3.A.1.110:  The Protein-2 Exporter (Prot2E) Family

The multiple protein exporter, PrsD/PrsE (exports EPS glycanases, PlyA and PlyB, as well as Rhizobium adhering proteins) (Russo et al., 2006). 12 substrates have been identified; PrsDE provide the major route of protein export in R. leguminosarum (Krehenbrink and Downie, 2008).
PrsD/PrsE of Rhizobium leguminosarum
PrsD(M-C) (O05693)
PrsE(MFP) (O05694)

Alkaline protease exporter
AprD (M-C) of Pseudomonas aeruginosa

S-layer protein exporter
RsaD (M-C) of Caulobacter crescentus

Exporter for lipase LipA, protease PrtA and S-layer protein SlaA, LipBCD (Akatsuka et al. 1997).   LipABC is also called PrtDEF.

LipBCD of Serratia marcescens
LipB (M-C) (Q54456)
LipC (MFP) (Q54457)
LipD (OMF) (O87950)


Exporter for heme-binding protein, HasA and metaloprotease, PrtA.  Functions as a complex spanning the two membranes of the cell envelope: HasDEF (HasD = ABC protein; HasE = the MFP; HasF = the OMF (see 2.A.6.2.31 for HasF) (Akatsuka et al. 1997).

HasDEF of Serratia marcescens
HasD (M-C) (Q53368)
HasE (MFP) (Q57387)
HasF (OMF) (Q54452)   

Surface layer protein exporter
SapD (M-C) of Campylobacter fetus

Exporter of HasA lipase, and alkaline protease
HasD (M-C) of Pseudomonas fluorescens

The AlgE-type Mannuronan C-5-Epimerase exporter, EexD (PrtD) (Gimmestad et al., 2006).
EexD of Azotobacter vinelandii (C1DS84)

Secretion system for metalloprotease, PrtA, PrtDEF (Akatsuka et al. 1997). (PrtF=1.B.17.1.2)

PrtDEF of Erwinia chysanthemi 
PrtD (M-C) (P23596)
PrtE (MFP) (P23597) 

Thermostable lipase, TliA (Q9ZG91; 476 aas with a C-terminal region that shows similarity to members of the RTX toxin family (1.C.11)) exporter, TliDEF.  The wild type transporter has a temperature sensitive defect which can be corrected by a single mutation in TliD (Eom et al. 2016).

TliDEF of Pseudomonas fluorescens
TliD, 578 aas (M-C) and 6 N-terminal TMSs
TliE, 433 aas (MFP)
TliF, 481 aas (OMF)

Protein export system, PrtD of 564 aas and 6 TMSs. The 3.15 Å structure has been solved (Morgan et al. 2017).  The structure suggests a substrate entry window just above the transporter's nucleotide binding domains. Highly kinked transmembrane helices, which frame a narrow channel, not observed in canonical peptide transporters, are likely involved in substrate translocation. The PrtD structure supports a polypeptide transport mechanism distinct from alternating access (Morgan et al. 2017).

PrtD of Aquifex aeolicus
3.A.1.111:  The Peptide-1 Exporter (Pep1E) Family

Hemolysin/bacteriocin (cytolysin) exporter with associated proteolytic activity

CylT (M-C) (CylB) of Enterococcus faecalis

Subtilin (toxic peptide) exporter
SpaB (M-C) of Bacillus subtilis

Nisin exporter
NisT (M-C) of Lactococcus lactis

Bacteriocin immunity protein, SmbG (198 aas; 6TMSs in a 2+2+2 arrangement. (Exports bacteriocins and causes resistance to antibiotics such as tetracycline, penicillin and triclosan). Upregulated by exposure to antibiotics (Matsumoto-Nakano and Kuramitsu, 2006)
SmbG (M-C) of Streptococcus mutans (Q5TLL2)

The lacticin Q exporter, LcnDR3 (Yoneyama et al., 2009).
LcnDR3 (M-C) of Lactococcus lactis (P37608)

Salivericin 9 exporter, SivT (692 aas; 6 TMSs) (Wescombe et al., 2011)

SivT of Strepococcus salivarius (F8LI02)

Nukacin ISK-1 bacteriocin exporter, NukT of 694 aas and 6 TMSs.  The protease domain is N-terminal, the membrane domain is central, and the ATPase domain in C-terminal. NukT and its peptidase-inactive mutant have been expressed, purified, and reconstituted into liposomes for analysis of their peptidase and ATPase activities. The ATPase activity of the NBD (C) region is required for the cysteine-type peptidase activity, and leader peptide cleavage enhances the ATPase activity (Zheng et al. 2017).

NukT of Staphylococcus warneri (P-M-C)

Uncharacterized ABC export system of 608 aas and 6 N-terminal TMSs in a 2 + 2 + 2 TMS arrangement followed by the ATPase domain (M-C).  It is adjacent to a 10  protein where the TMSs are in a 5 + 5 TMS arrangement.  Possibly this latter protein is a chaparone protein for proper insertion and folding of the transporter (see TC# 9.B.29.2.17 whick seems to be a chaparone protein for insertion and folding of ABC transporter with TC# 3.A.1.122.2. 

ABC exporter of Lachnospiraceae bacterium
3.A.1.112:  The Peptide-2 Exporter (Pep2E) Family

Competence factor (CSF; a heptadecapeptide) exporter of 717 aas.  The transporter is fused to an N-terminal peptidase  domain and functions with an MFP  accessory protein, ComB (TC# 8.A.1.4.2) (Ishii et al. 2006). 

ComA (peptidase-M-C) of Streptococcus pneumoniae (functions with MFP accessory protein, ComB)

Pediocin PA-1 exporter
PedD (M-C) of Pediococcus acidilactici

Bacteriocin (lactococcin) exporter. 

LcnC (M-C) of Lactococcus lactis (functions with putative MFP accessory protein LcnD)

Sublancin exporter, SunT
SunT (M-C) of Bacillus subtilis

Exporter of the BlpC peptide pheromone (B5E242) and several bacteriocins, BlpAB (Kochan and Dawid 2013).

BlpAB of Streptococcus pneumoniae
BlpA (M-C) (B3E244)
BlpB (MFP) (B3E242)

Putative ABC transporter (6 TMSs)

ABC Transporter of Ureaplasma parvum (Q9PPY0)

Mesenterici Y105 (bacteriocin) ABC exporter and porcessing protease, MesD(E) of 722 aas and 6 TMSs (MesD) (Fremaux et al. 1995). MesDE can transport and catalyze maturation of the two pre-bacteriocins, mesentericin Y105 and B105 (Aucher et al. 2004).  Hydrophobic conserved amino acyl residues and the C-terminal GG doublet of the leader peptide of pre-mesentericin Y105 are critical for optimal secretion (Aucher et al. 2005).  MesE has TC# 8.A.1.4.1.

MesDE of Leuconostoc mesenteroides

ABC bacteriocin exporter with two peptidase domains, Pcat1. 3-D structures are known (4S0F, 6V9Z, 4RY2). The pathway for peptide export consists of an large α-helical barrel for small folded peptides.  ATP binding alternates access to the transmembrane pathway and reglates protease activity (Lin et al. 2015). Subunit asymmetry of the M3-M4 loops contribute to optimizing AChR activation through allosteric links to the channel and the agonist binding site (Shen et al. 2005). Structures were more recently determined in the absence and presence of ATP, revealing how ATP binding regulates the protease activity and access to the translocation pathway. Two substrate CtAs, 90-residue polypeptides, are bound via their N-terminal leader peptides, but only one is positioned for cleavage and translocation. The structures were determined in the absence and presence of ATP, revealing how ATP binding regulates the protease activity and access to the translocation pathway. It seems that substrate cleavage, ATP hydrolysis, and substrate translocation are coordinated in a transport cycle (Kieuvongngam et al. 2020). The N-terminal C39 peptidase (PEP) domain of PCAT1 processes its natural substrate, CtA, by cleaving a conserved -GG- motif to separate the cargo from the leader peptide prior to secretion. The ATP-mediated association between PEP and the transmembrane domains of PCAT1 offers a putative mechanism to optimize peptide cleavage by regulating the width and flexibility of the enzyme active site (Bhattacharya and Palillo 2021). Structures of the peptidase-containing ABC transporter PCAT1 under equilibrium and nonequilibrium conditions have been solved (Kieuvongngam and Chen 2022).

Pcat1 of Ruminiclostridium thermocellus (Clostridium thermocellum; Hungateiclostridium thermocellum)

Bacteriocin exporter of 721 aas and 7 TMSs. Residues 10 - 134: peptidase with N-terminal TMS; residues 167 - 446: TM domain; residues 480 - 715: ATPase.

Peptide exporter of Bacteroides salanitronis

Enterocin CRL35 exporter, MunB, of 674 aas and 6 TMSs in an M-C domain arrangement.  The specific receptor for Enterocin CRL35 (MunA; TC# 1.C.24.1.15) acts as a docking molecule, not a structural part of the pore, but the bacteriocin must be anchored to the membrane (Ríos Colombo et al. 2019).

Enterocin CRL35 exporter of Enterococcus mundtii

Colicin V exporter. The ATPase is a GTPase (Zhong and Tai 1998; ).

CvaB (M-C) of E. coli

Microcin E492 exporter, MceFGH (MceF has 5 - 7 TMSs and is most likely a CAAX amino terminal protease that might function in the processing of microcin E492; MceG has a short hydrophilic N-terminus, a centra 6 TMS ABC domain, and a C-terminal ABC ATPase domain; MceH has 1 N-terminal TMS) (Bieler et al., 2006; Lagos et al., 1999)

MceGH of Klebsiella pneumoniae
MceG (C-M-C) (Q93GK5)
MceH (MFP) (Q93GK4)
3.A.1.113:  The Peptide-3 Exporter (Pep3E) Family

Modified cyclic peptide (syringomycin) exporter, SyrD
SyrD (M-C) of Pseudomonas syringae

Pyoverdin (siderophore) exporter
PvdE (M-C) of Pseudomonas aeruginosa

The multidrug/microcin J25 (MccJ25; 21 aa cyclic peptide antibiotic; the precursor peptide is McjA) exporter, YojI (Delgado et al., 2005). TolC is also required for export; Vincent and Morero, 2009). This system exports many phytol derivatives (Upadhyay et al. 2014).  Also exports L-cysteine (Yamada et al., 2006).  This is one of two microcin J25 exporters, the other being McjD (TC# 3.A.1.118.1).

YojI of E. coli (P33941)
3.A.1.114:  The Probable Glycolipid Exporter (DevE) Family

Glycolipid exporter (under nitrogen control in heterocysts), DevABC-HgdD (Moslavac et al., 2007). Heterocyst envelope glycolipids (HGLs) function as an O2 diffusion barrier, being deposited over the heterocyst outer membrane, surrounded by an outermost heterocyst polysaccharide envelope. DevBCA and TolC form an ATP-driven efflux pump required for the export of HGLs across the Gram-negative cell wall (Staron et al., 2011). DevB, the MFP, must be hexameric to create a functional export complex.  This system is under NtcA and nitrogen control and is required for heterocyst development (Fiedler et al. 2001).

DevABC-HgdD of Anabaena variabilis (sp. strain PCC7120)
DevA (C)
DevB (MFP)
DevC (M)
HgdD (TolC like)
3.A.1.115:  The Na+ Exporter (NatE) Family

Na+ efflux pump NatAB. It is induced by ethanol andby protonophores (Cheng et al. 1997). A similar system was found in the alkaliphilic Bacillus firmus OF4 species (Wei et al. 1999). The Bacillus subtilis NatK-NatR two-component system regulates expression of the natAB operon (Ogura et al. 2007).

NatAB of Bacillus subtilis
NatA (M)
NatB (C)

Putative Na extrusion pump, NatAB.  NatB has an N-terminal NatB domain (residues 1 - 375) as well as a C-terminal CAAX protease domain (9.B.2; residues 380 - 650).

NatAB of Rhodopirellula baltica

ABC transporter of unknown function

Candidatus Saccharibacteria
ABC transporter
AKM79972, (M)
AKM79973, (C)

Probable two component Na+ efflux system, NatAB, where NatB is a 228 aa ATPase and NatA is a 416 aa membrane protein with 6 TMSs in a 1 + 5 TMS arrangement.

NatAB of Evansella cellulosilytica (Bacillus cellulosilyticus)
3.A.1.116:  The Microcin B17 Exporter (McbE) Family

Microcin B17 exporter
McbEF of E. coli
McbE (M)
McbF (C)
3.A.1.117:  The Drug Exporter-2 (DrugE2) Family

The multidrug exporter, LmrA (can also substitute for MsbA [TC #3.A.1.106.1] to export lipid A; Reuter et al., 2003).  Structural models have been presented (Ecker et al. 2004; Federici et al. 2007). Hoechst 33342 is a substrate (van den Berg and van Saparoea et al. 2005). Coupled ATPase-adenylate kinase activity in ABC transporters including LmrA has been demonstrated (Kaur et al. 2016). This efflux porter mediates efflux of hydrophobic cationic substrates including antibiotics. TMS 3 of one monomer probably contacts TMS 5 or TMS 6 of the opposite monomer where substrate-binding occurs at the monomer/monomer interface (Ecker et al. 2004).

LmrA (M-C) of Lactococcus lactis

Hop resistance protein, HorA. Reconstitution in phosphatidyl ethanolamine bilayers resulted in normal activity, but reconstitution in phosphatidyl choline resulted in uncoupling of ATP hydrolysis from transport and a change in the orientations of the TMSs (Gustot et al. 2010).

HorA (M-C) of Lactobacillus brevis

Multidrug resistance homodimeric efflux pump, BmrA (YvcC) of 589 aas (Dalmas et al. 2005).  The low resolution cryo-electron microscopy reconstitution suggests large conformational changes occur during it's catalytic cycle (Fribourg et al. 2014). Backbone NMR assignments of the nucleotide binding domain of BmrA in the post-hydrolysis state have been determined (Pérez Carrillo et al. 2022). The protein is homodimeric, and it's unfolding and themodynamic stability have been studied (Oepen et al. 2023).

BmrA of Bacillus subtilis
3.A.1.118:  The Microcin J25 Exporter (McjD) Family

The cyclic peptide antibiotic, microcin J25 (MccJ25; the precursor peptide is JcjA) exporter, the self immunity protein, McjD. TolC is also required for export; Vincent and Morero, 2009.  The 3-d structure has been determined to 2.7Å resolution in an outward occluded state (Choudhury et al. 2014).  Binding and efflux as well as stimulation of the ATPase activity upon binding of MccJ25 have been demonstrated (Choudhury et al. 2014).  This is one of two MCCJ25 exporters, the other being YojI (TC# 3.A.1.113.3).  The large conformational changes in some crystal structures may not be necessary even for a large substrate like MccJ25 (Gu et al. 2015).

McjD (M-C) of E. coli
3.A.1.119:  The Drug/Siderophore Exporter-3 (DrugE3) Family

5-Hydroxystreptomycin and other streptomycin-like aminoglycoside exporter, StrVW
StrVW of Streptomyces glaucescens
StrV (M-C)
StrW (M-C)

Tetracycline/oxytetracycline/oxacillin exporter, TetAB
TetAB (StrAB) of Corynebacterium striatum
TetA (M-C)
TetB (M-C)

Exochelin exporter, ExiT (Zhu et al. 1998).

ExiT of Mycobacterium smegmatis

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the gene is in a gene cluster encoding the recognized coelichelin uptake system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006).  Sco0493 may function together with Sco0540 which is another putative ABC exporter of similar equence (see TC# 3.A.1.119.5).  However, alternatively, these two genes may encode two distinct transport systems.

Putative coelichelin exporter, Sco0493, of Streptomyces coelicolor (M-C)

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the gene is in a gene cluster encoding the recognized coelichelin uptake system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006).  Sco0493  (see TC# 3.A.1.119.4) may function together with Sco0540, both of which are putative ABC exporters of similar sequence. Alternatively, these two genes may encode two distinct transport systems.

Sco0540 of Streptomyces coelicolor (M-C)
3.A.1.120:  The (Putative) Drug Resistance ATPase-1 (Drug RA1) Family

Macrolide ATPase (membrane constituent unknown)
SrmB (C-C) of Streptomyces ambofaciens

Tylosin ATPase (membrane constituent unknown)
TlrC (C-C) of Streptomyces fradiae

Oleandomycin resistance ATPase (membrane constituent unknown)
OleB (C-C) of Streptomyces antibioticus

Carbomycin resistance ATPase (membrane constituent unknown)
Carbomycin, CarA (C-C), protein of Streptomyces thermotolerans

The acetate resistance ABC acetate exporter (Nankano et al., 2006)
AatA (C-C) of Acetobacter aceti (BAE71146)

The Uup protein (required for bacterial competitiveness (Murat et al., 2008); 39% identical to 3.A.1.120.5).

Uup of E. coli (P43672)

ABC transporter, SgvT2 (ATP-hydrolyzing subunit of 551 aas. Functions to export griseoviridin and viridogrisein (etamycin) (Xie et al. 2017). However, it may also function as an ATP-binding cassette domain of elongation factor 3, interacting with the ribosome which stimulates its ATPase activity (Sasikumar and Kinzy 2014).

SgvT2 of Streptomyces griseoviridis

 ABC protein of 558 aas and 0 TMSs, Rv2477c.  It is a translation factor that gates the progression of the 70S ribosomal initiation complex (IC, containing tRNA (fMet) in the P site) into the translation elongation cycle by using a mechanism sensitive to the ATP/ADP ratio. Binds to the 70S ribosome E site where it modulates the state of the translating ribosome during subunit translocation. It is an ABC-F subfamily protein, members of which are implicated in diverse cellular processes such as translation, antibiotic resistance, cell growth and nutrient sensing. Daniel et al. 2018 showed that Rv2477c displays strong ATPase activity (Vmax = 45 nmol/mg/min; Km = 90 muM) that is sensitive to orthovanadate. The ATPase activity was maximal in the presence of Mn2+ at pH 5.2. The protein hydrolyzed GTP, TTP and CTPas well as ATP but at lower rates. Glutamate to glutamine substitutions of amino acid residues 185 and 468 in the two Walker B motifs severely inhibited its ATPase activity. The antibiotics, tetracycline and erythromycin, which target protein translation, were able to inhibit the ATPase activity. Daniel et al. 2018 postulated that Rv2477c is involved in mycobacterial protein translation and in resistance to tetracyclines and macrolides.

v2477c of Mycobacterium tuberculosis
3.A.1.121:  The (Putative) Drug Resistance ATPase-2 (Drug RA2) Family

Erythromycin ATPase (membrane constituent unknown)
MsrA (C-C) of Staphylococcus epidermidis

Pristinamycin resistance protein, VgaG
VgaB (C-C) of Staphylococcus aureus

Antibiotic (virginiamycin and lincomycin) resistance protein, VmlR
VmlR (C-C) of Bacillus subtilis (P39115)

ABC-type streptogammin A resistance exporter, VgaA of 522 aas and 0 TMSs (C-C arrangement).  Inhibited by pristinamycin IIA (Jacquet et al. 2008). A transport function is not known.

VgaA of Staphylococcus aureus

MsrD of 487 aas and 0 TMSs. Involved in macrolide resistance (Zhang et al. 2016). Two ATPase domains are present in tandem. A membrane constituent is not known. Iannelli et al. 2018 suggested that MefA (TC# 2.a.1.21.1) can function with MsrD, and therefore that this MFS exporter can function as an ABC drug exporter.  However, the data presented seem inconsistent with this suggestion. Nevertheless, the two genes encoding these two proteins are adjacent to each other, suggesting that they may somehow function together (Iannelli et al. 2018).

MsrD of Streptococcus pyogenes (C-C)

Putative ABC protein of 684 aas and 0 TMSs, ATCF1.  Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

ABCF1 of Trypanosoma brucei

ATP-binding cassette subfamily F member 1, ABCF1 or ABC50, of 845 aas and 0 TMSs. There is no transmembrane protein associated with ABCF1, and this protein does not function in transport.  It is required for efficient Cap- and IRES-mediated mRNA translational initiation, not in ribosome biogenesis (Paytubi et al. 2009). ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells (Cao et al. 2020).

Metazoa, Chordata
ABCF1 of Homo sapiens

ABCF3 of 709 aas and 0 TMSs. It is not a transporter, but is a translational regulator that also promotes apoptosis (Hirose and Horvitz 2014). It has an antiviral effect against flaviviruses (Sakamoto et al. 2019).

Metazoa, Chordata
ABCF3 of Homo sapiens

ABCF1 (out of 5 isoforms) of 595 aas and 0 TMSs. Functions as a ribosome regulator.

Viridiplantae, Streptophyta
ABCF1 of Arabidopsis thaliana (Mouse-ear cress)

ATP-binding cassette sub-family F member 2, ABCF2 of 623 aas and 0 TMSs.  Its function is unknown, but it is probably not a transporter (Sakamoto et al. 2019).

Metazoa, Chordata
ABCF2 of Homo sapiens
3.A.1.122:  The Macrolide Exporter (MacB) Family

Macrolide (14- and 15- but not 16-membered lactone macrolides including erythromycin) exporter, MacAB (formerly YbjYZ). Both MacA and MacB are required for activity (Tikhonova et al., 2007). MacAB functions with TolC to export multiple drugs and heat-stable enterotoxin II (enterotoxin STII) (Yamanaka et al., 2008). The crystal structure of MacA is available (Yum et al., 2009). MacB is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA (Lin et al., 2009). Xu et al. (2009) have reported the crystal structure of the periplasmic region of MacB which they claim resembles the periplasmic domain of RND-type transporters such as AcrB (TC# 2.A.6.2.2). Also exports L-cysteine (Yamada et al., 2006). The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by the MacB transporter (Modali and Zgurskaya, 2011). Fitzpatrick et al. 2017 presented an electron cryo-microscopy structure of the tripartite assembly (MacAB-TolC) at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges a TolC trimer in the outer membrane to a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA may act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism (Fitzpatrick et al. 2017). The structure of ATP-bound MacB has been solved, revealing precise molecular details of its mechanism (Crow et al. 2017). MacB has a fold that is different from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores (Greene et al. 2018).

MacAB of E. coli:
MacA(MFP) (P75830)
MacB(C-M) (P75831)

The SpdC antimicrobial peptide resistance efflux pump, YknXYZ (Butcher and Helmann, 2006).  YknW (TC# 9.B.29.2.17), a 5 TMS protein, interacts directly with YknXYZ and is essential for facilitation of its assembly, thus serving as an integral membrane chaparone  (Yamada et al., 2012). The MFP YknX requires the ATP-binding cassette (ABC) transporter YknYZ and the Yip1 family protein YknW to form a functional complex. YknX (MFP) is hexameric (Xu et al. 2017).

YknXYZ of Bacillus subtilis
YknX (MFP) (O31710)
YknY (C) (O31711)
YknZ (M) (O31712)

The enterocin AS-48 exporter, As-48FGH
As-48FGH on plasmid pMBL of Enterococcus faecalis:
As-48F (MFP) (Q7AUQ4)
As-48H (M) (Q8RKC0)
As-48G (C) (Q8RKC1)

Probable Heme exporter, HrtAB (Stauff et al., 2008)
HrtAB of Staphylococcus aureus:
HrtA (C) (Q7A3X3)
HrtB (M) (Q7A7X2)

ABC transporter of unknown function (DUF214 protein) (4TMSs)/ABC protein [Msed1528/Msed1530]
Msed1528/Msed1530 of Metallosphaera sedula (M) (A4YGY2)

ABC transporter of unknown function (DUF214 protein) (4TMSs)/ABC protein [MA2839/MA2840]
MA2839/MA2840 of Methanosarcina acetivorans
MA2839 (M) (Q8TM31)
MA2840 (C) (Q8TM30)

ABC transporter of unknown function (Duf214 protein (409aas; 4TMSs:1+3)/ABC protein)
Duf214 protein/ ABC protein of Methanococcus voltae:
Duf214 protein (M) (A8TDX0)
ABC protein (C) (A8TDW7)

Putative ABC3 permease, PC1,2,3.
PC1,2,3 of Treponema denticola:
PC1 (C) - Q73MJ2
PC2 (M) - Q73MJ3
PC3 (M) - Q73MJ4

Duf214 protein (405aas)/ ABC protein
Duf214/ABC system of Caldivirga maquilingensis:
Duf214 protein (M) (A8M8Z1)

Duf214 (423aas) ABC3 membrane protein with ABC-type ATPase (232 aas).  Sandwiched inbetween the genes encoding these two proteins is a large protein of 869 aas with 2 TMSs, N- and C-terminal. Some homologues are annotated as "S-layer domain protein".  It may be an ABC auxiliary protein.  Most members occur in archaea, but distant homologues are also found in bacteria.

Duf214/ABC system of Sulfurisphaera tokodaii (Sulfolobus tokodaii):
Duf214 protein (M) (Q973J4)
ATPase (C) (Q973J6)
Putative auxiliary protein (Q973J5)

The hemin resistance transporter, HrtAB. Expression is activated by hemin or hemoglobin via the ChrAS transmembrane sensor kinase/response regulator system (Bibb and Schmitt 2010). HrtBA extracts heme from the membrane and expells it.  HrtBA consists of two cytoplasmic HrtA ATPase subunits and two transmembrane HrtB permease subunits. A heme-binding site is formed in the HrtB dimer and is laterally accessible to heme in the outer leaflet of the membrane. The heme-binding site captures heme from the membrane using a glutamate residue of either subunit as an axial ligand and sequesters the heme within the rearranged transmembrane helix bundle. By ATP-driven HrtA dimerization, the heme-binding site is squeezed to extrude the bound heme (Nakamura et al. 2022).

HrtAB of Corynebacterium diphtheriae
HrtA (C) (H2GZC3)
HrtB (M) (H2GZC4) 

Arthrofactin efflux pump, ArfDE (Balibar et al. 2005).

ArfDE of Pseudomonas sp. MIS38
ArfD (MFP) (Q84BQ3)
ArfE (ABC) (A0ZUB1)

Putative ABC3-type antimicrobial peptide transporter, fused ATPase-porter protein, U-ABC3-1b (667aas; 4TMSs:1+3)
U-ABC3-1b of Lactobacillus brevis (CM) (Q03RZ6)

ABC transporter of unknown function, but aspects of its structure and mechanism of action are known (Yuan et al. 2001; Zoghbi and Altenberg 2013).  Nucleotide-binding domain dimerization occurs as a result of binding to the natural nucleotide triphosphates, ATP, GTP, CTP and UTP, as well as the analog ATP-gamma-S. All the natural nucleotide triphosphates are hydrolyzed at similar rates, whereas ATP-gamma-S is not hydrolyzed. The non-hydrolyzable ATP analog AMP-PNP, frequently assumed to produce the nucleotide-bound conformation, failed to elicit nucleotide-binding domain dimerization (Fendley et al. 2016).

ABC transporter of Methanocaldococcus jannaschii (Methanococcus jannaschii)
Membrane protein, MJ0797 (M) (Q58207)
ATPase, MJ0796 (C) (Q58206)

Putative heavy metal ion exporter, YbbAB (Moussatova et al. 2008).

YbbAB of E. coli
YbbA (C; 228 aas)
YbbB (M; 804 aas)

Putative macrolide-specific efflux system, MacAB

MacAB of Bifidobacterium longum

LolC/E family lipoprotein releasing system, transmembrane protein of 639 aas and 4 TMSs

Candidatus Saccharibacteria
LolC/E family lipoprotein releasing system, transmembrane protein of Candidatus Saccharibacteria bacterium

MacAB-TolC MDR effllux porter. Exports macrolide antibiotics, virulence factors, peptides and cell envelope precursors. The 3-d crystal structure of MacB has been solved at 3.4 Å resolution (Okada et al. 2017). MacB forms a dimer in which each protomer contains a nucleotide-binding domain and four TMSs that protrude in the periplasm into a binding domain for interaction with the membrane fusion protein MacA. It has unique structural features (Okada et al. 2017).

MacAB of Acinetobacter baumannii
MacA, Q2FD52, 445 aas and 1 TMS
MacB, N9J6M5, 664 aas and 4 TMSs

ABC3-type efflux porter, YtrEF, encoded within an operon, ytrABCDEF, apparently encoding two ABC exporters, one, YtrBCD, with TC# 3.A.1.153.1, and the other, this one. The operon is induced in early stationary phase under the control of YtrA, a GntR-type HTH transcriptional regulator, probably a repressor (Yoshida et al. 2000). These authors suggest this operon may be involve in acetoin secretion and/or reutilization.

YtrEF of Bacillus subtilis
YtrE, C, 231 aas; O34392
YtrF, M, 436 aas; O35005

MacAB-MFP complex of 3 subunits involved in the resistance of antibiotics and antimicrobial peptides. Yang et al. 2018 reported the crystal structures of Spr0694-0695 (MacAB) at 3.3 Å and Spr0693 (MFP; TC# 8.A.1) at 3.0 Å resolution, revealing a MacAB-like efflux pump. The dimeric MacAB adopts a non-canonical fold, the transmembrane domain of which consists of a dimer with eight tightly packed TMSs (4 per subunit) with an extracellular domain between the first and second helices, whereas Spr0693 (the MFP) forms a nanotube channel docked onto the ABC transporter. Structural analyses, combined with ATPase activity and antimicrobial susceptibility assays, enabled the proposal of a putative substrate-entrance tunnel with lateral access controlled by a guard helix (Yang et al. 2018).

MacAB-MFP of Streptococcus pneumoniae
MacA, Spr0694, 233 aas (C)
MacB, Spr0695, 419 aas (M)
MFP, Spr0693, 399 aas, (MFP)

ABC transport system with a type 3 ABC membrane protein (386 aas and 4 TMSs; B8GHI1) and an ABC ATPase (234 aas; B8GHI2).  The encoding genes are adjacent to those encoding a putative transport system with TC# 9.B.29.2.7.

ABC transporter of Methanocorpusculum labreanum

Uncharacterized ABC exporter of two subunits, a 4 TMS membrane subunit of 177 aas, and an ATPase of 229 aas

Candidatus Lokiarchaeota
UP ABC exporter
(M) 177 aas and 4 TMSs, KKK40843
(C)  229 aas and ) TMSs, KKK48044

Uncharacterized ABC exporter

Candidatus Thorarchaeota
Uncharacterized ABC exporter of Candidatus Thorarchaeota
(M) 173 aas and 4 TMSs, RDE13437
(C) 225 aas, RDE13438

Uncharacterized ABC exporter

Candidatus Odinarchaeota
ABC exporter of Candidatus Odinarchaeota
(M) 166 aas and 4 TMSs, OLS17116
(C)  232 aas, OLS17115

3-component ABC3-type transporter with two 4 TMS membrane proteins and one ATPase, all encoded within a single operon with the three genes next to each other.

ABC exporter of Corallococcus coralloides

Uncharacterized two comoponent ABC3-type efflux transporter of 805 aas and 8 TMSs in a 1 + 3 + 1 +3 TMS arrangement. The ATPase is a distinct protein of 250 aas.

Candidatus Heimdallarchaeota
Uncharacterized ATP-energized exporter of Candidatus Heimdallarchaeota
ABC3-type membrane protein of 805 aas and 8 TMSs (M)
ATPase of 250 aas (C).

Putative ABC3-type transporter with an ATPase and a possible auxiliary protein encoded by a gene sandwiched in between the membrane protein and the ATPase. Some homologues of the auxiliary protein are annotated as S-layer domain proteins. This system resembles 3.A.1.122.10 which also has such an auxiliary protein.

ABC3-type transporter
E6NBB1 (M), 413 aas with 4 TMSs in a 1 + 3 TMS arrangement
E6NBB0 (C), 236 aas
E6N374 (Putative auxiliary protein), 597 aas and 1 TMS at the C-terminus

ABC3 exporter including a membrane protein of 392 aas and 4 TMSs in a 1 + 3 TMS arrangement and a putative auxiliary transport protein of 944 aas and 1 C-terminal TMS. It is annotated as an S-layer domain protein. While these two recognized proteins are encoded by adjacent genes, an ATPase was not encoded nearby, and it has not been identified.

Putative incomplete ABC3 exporter of Ignicoccus hospitalis

ABC3-type exporter with 3 components, the permease of 457 aas with 4 TMSs, an ATPase of 236 aas, and a putative auxiliary protein of 805 aas and 2 TMSs, N-and C-terminal. The permease subunit is annotated as an ABC-type lipoprotein release transport system, and the auxiliary protein is a COG1361 protein.

ABC3 porter of Anaerobacterium chartisolvens

ABC3 exporter with three constituents, the 4 TMS membrane protein of 529 aas, the ATPase of 251 aas, and an auxiliary protein of 431 aas and 2 TMSs, N-terminal and C-terminal.

ABC3 exporter of Bifidobacterium longum subsp. infantis

Uncharacterized ABC porter with a single membrane protein of 224 aas and 4 TMSs, plus two ATPases, of 237 and 243 aas, respectively.

Candidatus Heimdallarchaeota
ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
Porter, M, OLS20810
ATPase, C, OLS20809
ATPase, C, OLS20808

Putative 3-component ABC exporter with two uncharacterized homologous membrane proteins of 930 aas and 1090 aas, both with 10 TMSs in a 1 + (3 +2 +1) +3 TMS arrangement, plus an ATPase.

Uncharacterized  ABC exporter of Cellulomonas flavigena

Putative 3 component ABC transporter with two membrane proteins of 907 and 1113 aas plus an ATPase of 319 aas.  Both membrane proteins have 10 TMSs in a 1 + (3 + 2 + 1) + 3 TMS arrangement.

ABC exporter of Streptomyces coelicolor

Uncharacterized putative ABC exporter of 4 components, all encoded by adjacent genes: one membrane protein, two ATPases and one membrane fusion protein (MFP).

ABC exporter of Paenibacillus mucilaginosus

The MacAB drug exporter.  MacB is an ABC transporter that collaborates with the MacA adaptor protein (a membrane fusion protein, MFP) and the TolC exit duct to drive efflux of antibiotics and enterotoxin STII out of the bacterial cell. Crow et al. 2017 presented the structure of ATP-bound MacB and reveal precise molecular details of its mechanism. The MacB transmembrane domain lacks a central cavity through which substrates could be passed, but instead conveys conformational changes from one side of the membrane to the other, a process termed mechanotransmission. Comparison of ATP-bound and nucleotide-free states revealed how reversible dimerization of the nucleotide binding domains drives opening and closing of the MacB periplasmic domains via concerted movements of the second transmembrane segment and the major coupling helix. They proposed that the assembled tripartite pump acts as a molecular bellows to propel substrates through the TolC exit duct, driven by MacB mechanotransmission. Homologs of MacB that do not form tripartite pumps, but share structural features underpinning mechanotransmission, include the LolCDE lipoprotein trafficking complex and FtsEX cell division signaling protein. The MacB architecture serves as a blueprint for understanding the structure and mechanism of an entire ABC transporter superfamily and the many diverse functions it supports (Crow et al. 2017). The crystal structure of MacA has been solved (Yum et al. 2009).

MacAB of Aggregatibacter actinomycetemcomitans (Actinobacillus actinomycetemcomitans)

ABC-type antimicrobial peptide transport system with two components, one having a domain structure of C-M and 653 aas with 4 TMSs, and the other being a membrane fusion protein (see TC# 8.A.1) (Cho and Kang 2012). A mutant showed significant reduction in secretion of syringomycin (74%) and syringopeptin (71%), as compared to the parental strain (Cho and Kang 2012). The PseEF efflux system has a role in secretion of syringomycin and syringopeptin, and is required for full virulence in P. syringae pv. syringae.

PseEF of Pseudomonas syringae

ABC transporter permease of 831 aas and 8 TMSs in a 1 + 3 + 1 + 3 TMS arrangement.

ABC permease of Gemmatimonadota bacterium (marine sediment metagenome)
3.A.1.123:  The Peptide-4 Exporter (Pep4E) Family

Pep5 lantibiotic exporter, PepT

PepT (M-C) of Staphylococcus epidermidis

Aureocin A70 multipeptide bacteriocin (AurA, AurB, AurC, AurD) exporter, AurT
AurT (M-C) of Staphylococcus aureus

The one component lantibiotic exporter, GdmT (Sibbald et al., 2006)
GdmT (M-C) of Staphylococcus gallinarum (A3QNP2)
3.A.1.124:  The 3-component Peptide-5 Exporter (Pep5E) Family

The 3-component nisin immunity exporter, NisFEG. Contains an essential E-loop (Okuda et al., 2010).

NisFEG of Lactococcus lactis
NisF (C)
NisE (M)
NisG (M)

The 3-component subtilin immunity exporter, SpaEFG
SpaEFG of Bacillus subtilis
SpaE (M)
SpaF (C)
SpaG (M)

The lantibiotic Nukacin ISK-1 (TC# 1.C.21.1.5)/NukH (BAD01013; 92aas) exporter, NukEFG (Okuda et al., 2008)
NukEFG of Staphylococcus warneri
NukE (M) (Q75V14)
NukF (C) (Q75V15)
NukG (M) (Q75V13)

The macedocin exporter, McdEFG (Papadelli et al., 2007)
McdEFG of Streptococcus macedonicus
McdE (M; 254 aas) (A6MER6)
McdG (M; 245 aas) (A6MER7)
McdF (C; 304 aas) (A6MER5)

The salivaricin exporter, SboEFG (Hyink et al., 2007)
SboEFG of Streptococcus salivarius
SboE (M; 249 aas) (Q09IH9)
SboF (C; 303 aas) (Q09II0)
SboG (M; 242 aas) (Q09IH8)

CprABC antimicrobial peptide resistance ABC exporter.  Exports both mammalian and bacterial toxic peptides (McBride and Sonenshein 2011).

CprABC of Clostridium difficile
CprA (C, 235 aas)
CprB (M, 238 aas, 6 TMSs)
CprC (M, 252 aas, 6 TMSs)
3.A.1.125:  The Lipoprotein Translocase (LPT) Family (This TC subfamily overlaps with TC# 3.A.1.122)

Lipoprotein translocation system (translocates lipoproteins from the inner membrane to periplasmic chaperone, LolA, which transfers the lipoproteins to an outer membrane receptor, LolB, which anchors the lipoprotein to the outer membrane of the Gram-negative bacterial cell envelope) (see 1.B.46; Narita et al., 2003; Ito et al., 2006; Watanabe et al., 2007). The structure of ligand-bound LolCDE has been solved (Ito et al., 2006). LolC and LolE each have 4 TMSs (1+3). Unlike most ATP binding cassette transporters mediating the transmembrane flux of substrates, the LolCDE complex catalyzes the extrusion of lipoproteins anchored to the outer leaflet of the inner membrane. The LolCDE complex is unusual in that it can be purified as a liganded form, which is an intermediate of the lipoprotein release reaction (Taniguchi and Tokuda, 2008). LolCDE has been reconstituted from separated subunits (Kanamaru et al., 2007).  LolE binds the outer membrane lipoprotein, PAL (Mizutani et al. 2013). The mechanism of LolCDE as a molecular extruder of bacterial triacylated lipoproteins has been reported (Sharma et al. 2021) who determined the cryo-EM structures of nanodisc-embedded LolCDE in the nucleotide-free and nucleotide-bound states at 3.8-Å and 3.5-Å resolution, respectively. The structural analyses, together with biochemical and mutagenesis studies, uncovered how LolCDE recognizes its substrate by interacting with the lipid and N-terminal peptide moieties of the lipoprotein, and identify the amide-linked acyl chain as the key element for LolCDE interaction. Upon nucleotide binding, the transmembrane helices and the periplasmic domains of LolCDE undergo large-scale, asymmetric movements, resulting in extrusion of the captured lipoprotein. Comparison of LolCDE and MacB revealed the conserved mechanism of type VII ABC transporters and emphasized the unique properties of LolCDE as a molecule extruder of triacylated lipoproteins (Sharma et al. 2021).

LolCDE of E. coli
LolC (M)
LolD (C)
LolE (M)

Putative lipoprotein LolCDE homologue LolCE (10TMSs:1+6+3)/LolD
LolCE/LolD of Mycobacterium tuberculosis
LolCE (M) (Q7D911)
LolD (C) (O53899)

Duf214 protein (843aas; 10TMSs:1+6+3)
Duf214 protein/ ABC protein of Frankia sp. CcI3:
Duf214 protein (M) - Q2J9P4
[LolD/FtsE/SalX]-type ABC protein (C) - Q2J9P5

Uncharacterized ABC transporter with two consituents, a 4 TMS (in a 1 + 3 TMS arrangement) membrane (M) protein and an ATPase (C). 

Uncharacterized ABC transporter of Opitutus terrae

Putative ABC transporter, LolCDE, with three components, similar to (but substantially different from) LolC, LolD and LolE of E. coli. The three genes encoding these proteins are adjectent to each other on the bacteria chromosome, but there is no direct experimental evidence that they function together as lipoprotein exporters.

Candidatus Heimdallarchaeota
LolCDE of Candidatus Heimdallarchaeota archaeon LC_3
LolC, 690 aas and 4 TMSs in a 1 + 3 TMS arrangement (MC)
LolD, 236 aas with 2 or 3 TMSs followed by a hydrophilic C-terminal domain (MC)
LolE, 1106 aas and 12 TMSs in a 1 + 3 + 4 +1 + 3 TMS arrangement (MM)

ABC-type transport system, possibly involved in lipoprotein release. There are two and possibly three protein constituents. First, there is a permease component of 1004 aas with 13 TMSs in a 2 (N-terminal) + 3 +4 + 1 + 3 TMS arrangement (I2F7A7)).  This protein is unusual because it has 2 N-terminal TMSs rather than the usual 1, and between the two 1 + 3 TMS repeat units, there are 4 TMSs rather than the more usual 0 or 2 TMSs. Second, there is an ABC-type ATPase (I2F7A6) and third, there is a possible auxiliary subunit of 183 aas and 4 TMSs in a 2 + 2 TMS arrangement that appears to be two repeated 2 TMS sequences, one near the N-terminus and one near the C-terminus; I2F7A5).  Adjacent to these genes is one annotated as a "PRC barrel protein" (with a single N-terminal TMS and is a conserved, ubiquitous, chromo domain, shared by photosynthetic reaction center subunits and proteins of RNA metabolism (Anantharaman and Aravind 2002); I2F7A4) of unknown function, and adjacent to that gene are two genes encoding putative chromate resistance efflux (transport) protein, ChrA (I2F7A3 and I2F7A1; see TC family 2.A.51).

ABC type 3 transporter of Mesotoga prima MesG1 Ag.4.2  

FtsX-type ABC transporter of 902 aas and 10 TMSs in a 1 + 3 + 2 + 1 + 3 TMS arrangement.

ABC transporter of Vescimonas coprocola

ABC transporter of 1253 aas and 9 TMSs in a 1 + 3 +2 + 2 + 1 TMS arrangement.

ABC transporter of Exiguobacterium undae
3.A.1.126:  The β-Exotoxin I Exporter (βETE) Family

Exporter of β-exotoxin I, BerAB
β-exotoxin exporter, BerAB, of Bacillus thuringiensis
BerA (C)
BerB (M)

Putative ABC transporter with a 6 TMS membrane protein and an ATPase of the ABC-type encoded by the adjacent gene.

Putative ABC transporter of Arthrobacter (Paenarthrobacter) aurescens (A1R938)

Putative exporter of polyketide antibiotic-like protein (~12 TMSs) with an ABC ATPase encoded by the adjacent gene.

Putative exporter of Amycolicicoccus (Hoyosella) subflavus (F6EHL8)

6TMS putative ABC transporter protein with an ABC-type ATPase encoded by the adjacent gene.  This memebrane protein also maps adjacent to protein fragments that show similarity to ABC transport proteins as well as a protease (9.B.218.1.4; D4TYE3).

Putative ABC transporter system of Actinomyces odontolyticus (D4TYE0)

Polyether inonophore exporter, NarAB:  NarA, ATPase (C) of 293 aas and NarB, membrane protein (M) of 537 aas and 12 TMSs. The polyether ionophores, narasin, salinomycin, and maduramicin, but not monensin, are actively exported (A-O Naemi et al., NarAB Is an ABC-type Transporter That Confers Resistance to the Polyether Ionophores Narasin, Salinomycin, and Maduramicin, but Not Monensin, 2020 Front Microbiol.).

NarAB of Enterococcus faecium

Cereulide (cyclic depsipeptide) K+ ionophore exporter, CerCD. CerC is 291 aas without TMSs, while CerD is 268 aas with 5 or 6 TMSs (Yuan et al. 2024).

CerCD of the Bacillus cereus group
3.A.1.127:  The AmfS Peptide Exporter (AmfS-E) Family

Exporter of AmfS extracellular peptidic morphogen (Chater and Horinouchi, 2003; Ueda et al., 2002)
AmfS exporter, AmfAB of Streptomyces griseus
AmfA (MC) (BAA33537)
AmfB (MC) (BBA33538)
3.A.1.128:  The SkfA Peptide Exporter (SkfA-E) Family

Exporter of SkfA processed peptide (spO31422), SkfEF (González-Pastor et al., 2003)

SkfEF (YbdAB) of Bacillus subtilis
SkfE (C) O31427
SkfF (M-M) O31438

Putative ABC exporter, Teth 514-0346 & 0347
Teth 514-0346 & 0347 of Thermoanaerobacter sp. x514:
Teth514-0346 (C) (B0K2P2)
Teth514-0347 (M-M) (B0K2P3)

Putative ABC exporter, CLK2533/CLK2534
CLK2533/CLK2534 of Clostridium botulinum
CLK2533 (M-M) (B1L0U0)
CLK2534 (C) (B1L0U1)

Putative ABC exporter Tiet1371/1372
Tiet1371/72 of Thermotoga lettingae
Tiet1371 (M-M) (A8F6Z4)
Tiet1372 (C) (A8F6Z5)

Putative ABC transporter.  The genes encoding this system map adjacent to a beta-lactamase (A9BGZ6) gene and one encoding a C4 anaerobic dicarboxylate carrier (A9BGZ7).

Putative ABC transporter of Petrotoga mobilis

Putative ABC exporter

ABC exporter of Pyrococcus horikoshii
Membrane protein (M) (O58947)
ATPase (C) O58948)

Uncharacterized ABC permease, TA0065/TA0066

Candidatus Thermoplasmatota
UP of Thermoplasma acidophilum
TA0065 (M-M; permease; 515 aas, 12 TMSs)
TA0066 (C; ATPase)

ABC transporter encoded by two adjacent genes, a membrane protein and an ABC ATPase.

Candidatus Thorarchaeota
ABC transporter
(M) KXH73395
(C)  KXH73394

Three component ABC transport system of unknown function.

ABC porter of Paenibacillus larvae subsp. pulvifaciens

Apparent two component ABC transporter, probably an exporter of the sporulation killing factor, SkfB. The membrane component has 12 TMSs, and therefore is probably either due to an intragenic duplication of the usual 6 TMS domain protein or a fusion of two such proteins that are more usual for this subfamily of ABC exporters.  This system acts in conjunction with a CAAX protease (EMI14127; TC# 9.B.2.13.1) that presumably processes SkfB to the mature form. The two genes of this ABC system are preceded by a gene coding for a 174 aa proteins possibly involved in SkfB synthesis and/or export.

ABC SkfB exporter of Bacillus stratosphericus

ABC exporter, possibly for the sporulation killer factor SkfB.

ABC exporter of Parageobacillus thermoglucosidasius
3.A.1.129:  The CydDC Cysteine Exporter (CydDC-E) Family

Heme transporter (previously proposed to be a thiol (cysteine/glutathione) exporter, CydDC; CydC is also called MdrH (periplasmic cysteine is required for cytochrome bd assembly) (Cruz-Ramos et al., 2004).  The purified asymmetric heterodimer exhibits low ATPase activity which is activated by both thiols and heme (e.g., heme b) (Yamashita et al. 2014).  Bacterial redox homoeostasis during nitrosative stress is influenced by CydDC.  Periplasmic low molecular weight thiols restore haem incorporation into a cytochrome complex (Holyoake et al. 2016). Iron-bound cyclic tetrapyrroles (hemes) are redox-active cofactors in bioenergetic enzymes. Wu et al. 2023 used cellular, biochemical, structural and computational methods to characterize CydDC which is a heme transporter required for functional maturation of cytochrome bd. The conformational landscape of CydDC during substrate binding and occlusion was revealed. Heme binds laterally from the membrane space to the transmembrane region of CydDC, enabled by a highly asymmetrical inward-facing CydDC conformation. During the binding process, heme propionates interact with positively charged residues on the surface and later in the substrate-binding pocket of the transporter, causing the heme orientation to rotate 180° (Wu et al. 2023).

CydDC of E. coli
CydD (M-C) (P29018)
CydC (M-C) (P23886)
3.A.1.130:  The Multidrug/Hemolysin Exporter (MHE) Family

The multidrug/hemolysin exporter, CylA/B (note: CylK (AAF01071) may influence its activity)(Gottschalk et al., 2006)
CylA/B of Streptococcus agalactiae
CylA (C) (Q9X432)
CylB (M) (Q9X433)

ABC export system, possibly an MDR pump, consisting of two proteins, and membrane protein of 293 aas and 6 TMSs, and an ATPase of 301 aas.

ABC exporter of Acidipropionibacterium virtanenii

ABC exporter with two constituents, a membrane protein of 263 aas and 6 TMSs, and an ATPase of 310 aas.

ABC exporter of Lactobacillus hokkaidonensis
3.A.1.131:  The Bacitracin Resistance (Bcr) Family

The 2 or 3 component bacitracin-resistance efflex pump, BcrAB or BcrABC (Podlesek et al., 1995; Bernard et al., 2003) (BcrA is most similar to SpaF (3.A.1.124.2), but BcrB (5-6 TMSs) is only distantly related to other ABC2-type membrane proteins (Wang et al., 2009). BcrC is not sufficiently similar to detect similarity in BLAST searches. BcrC (5TMSs) belongs to the PAP2 phosphatase superfamily and may not be a contituent of the BcrAB transporter. Transcription is regulated by BcrR, a one-component transmembrane signal transduction system (Darnell et al. 2019).

BcrABC of Bacillus licheniformis
BcrA (C) - (P42332)
BcrB (M) - (P42333)

Lantibiotic immunity system, LanEF. Contains an essential E-loop, a variant of the Q-loop, well conserved in nucleotide binding domains of lantibiotic exporters (Okuda et al., 2010).

LanEF of Bacillus licheniformis
LanE (M) (Q65DD3)
LanF (C) (Q65DD1)

Transporter homologue, Tiet1372

Tiet1372 of Thermotoga lettingae (A8F6Z5)
3.A.1.132:  The Gliding Motility ABC Transporter (Gld) Family

The GldAFG putative ABC transporter required for ratchet-type gliding motility; may function in secretion of a macromolecule such as an exopolysaccharide. (Agarwal et al., 1997; Hunnicutt et al., 2002; McBride and Zhu 2013). Soluble GldG homologues (no TMSs) are found in eukaryotes (e.g. intraflagellar protein transporter, IPT52 of Chlamydomonas reinhardtii; XP_001692161)

GldAFG of Flavobacterium johnsoniae:
GldA (C; 298 aas) - (O30489)
GldF (M; 241 aas; 6TMSs (2+2+2) - (Q93LN1)
GldG (M-periplasm; putative auxillary subunit with 2TMSs at the N and C-termini; 561 aas)- (Q93LN0).

The NosDFY Copper ABC transporter (Chan et al., 1997)
NosDFY of Sinorhizobium meliloti
NosD (R; periplasmic copper binding receptor)(Q52899)
NosF (C; like GldA) (Q52900)
NosY (M; like GldF) (O07330)

The uncharacterized ABC transporter with GldF-GldG homologues fused.  The adjacent gene encodes the ATPase, GldA, and the next gene encodes an auxiliary protein of the MPA1-C family (TC# 8.A.3).

GldAFG homologues of Magnetococcus sp. MC-1
GldFG (M-Aux; 964 aas) (A0L4K8)
GldA (C; 399 aas) (A0L4L0)

The uncharacterized ABC transporter with GldF-GldG homologues fused
GldAFG homologues of Hahella chejuensis
GldF-G (M-Aux; 978 aas) (Q2SDB0)
GldA (C; 315 aas) (Q2SDB1)

Putative ABC2 transporter: Membrane protein of 274aas and 6 TMSs; Cytoplasmic ATPase of 302aas.

Putative ABC2 transporter of Shewanella pealeana
(M) (A8GZV3)
(C) (A8GZV2) 

Putative ABC2 transporter: Membrane protein of 274aas and 6 TMSs; Cytoplasmic ATPase of 302aas.

Putative ABC-2 transporter of Streptococcus pyogenes 
(M) (Q99ZC7)
(C) (Q99ZC8) 

Putative ABC membrane protein with 12 TMSs. (ATPase subunit unknown, and not encoded by an adjacent gene).

ABC membrane protein of Rhodopirellula baltica

ABC transporter, annotated as involved in multi copper protein maturation

ABC exporter of Methanocella conradii
permease (M) (H8I780)
ATPase (C) (H8I779)

Putative ABC exporter, Odosp_3144/Odosp_3145. Odosp_3144 is a 6 TMS ABC2 membrane protein (N-terminal 250 aas) fused to an auxiliary protein with one N- and one C-terminal TMS, homologous to GldG of Cytophaga johnsonae (3.A.1.132.1).

Putative ABC transporter of Odoribacter splanchnicus 
Odosp_3144 (M) (761 aas; 7 TMSs) (F9Z892)
Odosp_3145 (C) (306 aas) (F9Z893) 

Putative ABC exporter of unknown function, Gll1303/Gll1302, with two probable subunits of 477 and 494 aas with 6 TMSs each at their N-termini (M) and ATPase domains (C) in the C-termini.

Gll1303/Gll1304 putative ABC exporter of Gloeobacter violaceus
Gll1303, (M)
Gll1302, (M)

Putative ABC exporter with two membrane proteins of 478 and 417 aas and 6 TMSs respectively, and one ATPase.  The encoding genes are adjacent to a TonB-dependent OMR with possible specificity for a siderophore.  Thus, this ABC exporter could transport a siderophore.

Uncharacterized ABC exporter of Saccharophagus degradans
Sde_3610 (C), 249 aas (Q21EL4)
Sde_3609 (M), 478 aas and 6 TMSs (Q21EL5)
Sde_3608 (M), 417 aas and 6 TMSs (Q21EL6)

ABC exporter necessary for social motility, pilus assembly and pilus subunit (PilA) export, PilGHI. Mutants show elevated sporulation rates and abnormal development (Wu et al. 1998).

PilHI of Myxococcus xanthus
PilH (C) ABC protein (O30385)
PilT (M) 6 TMS membrane protein of 255aas (O30386) 

ABC transporter permease, membrane subunit of 736 aas and 7 N-terminal TMSs in a 2 + 3 + 2 TMS arrangement and a large hydrophilic C-terminal domain, similar to those in TC family 9.B.359, but with poor sequence similarity with these proteins.

ABC membrane subunit from Mahella australiensis

Putative ABC exporter with three components, two 6 TMS proteins and one ATPase, all encoded by genes that are adjacent to each other. The first of these (G2SET3) is a MusI homologue of 229 aas and 6 TMSs.

MusI homologue of Rhodothermus marinus
3.A.1.133:  The Peptide-6 Exporter (Pep6E) Family

The modified YydF* peptide exporter, YydIJ (Butcher et al., 2007)
YydIJ of Bacillus subtilis:
YydI (C) (Q45593)
YydJ (M) (Q45592)

A 6TMS homologue of YydJ (ORF1) of 280aas
ORF1 of Flavobacteria bacterium BBFL7 (Q26C21)
3.A.1.134:  The Peptide-7 Exporter (Pep7E) Family

The lantibiotic, salivericin A exporter, SalXY
SalXY of Streptococcus salivarius
SalX (C)
SalY (M)

The bacitracin-resistance (putative bacitracin exporter), MbrAB. Participate with BreSR to control its own gene expression (Bernard et al., 2007).
MbrAB of Streptococcus mutans
MbrA (C)
MbrB (M)

The putative bacitracin exporter, BceAB (BarAB; YtsCD) (Bernard et al., 2003; Ohki et al., 2003).  Functions in both signaling to the two component system, BceRS, and in export of the antimicrobial peptide (Dintner et al. 2014).  BceB interacts directly with BceS, and BceB binds bacitracin (Dintner et al. 2014).  Specific regions and residues are involved in signalling or transport (Kallenberg et al. 2013).  More recent studies suggest that BceAB may cause bacitracin resistance by transferring undecaprenyl pyrophosphate from the exteral to the internal leaflet of the inner membrane where it can't bind bacitracin and other lantibiotics that use Lipid II as a receptor (Draper et al. 2015). It may cause drug detoxification by targeet protection (Rismondo and Schulz 2021).

BceAB (YtsCD) of Bacillus subtilis
BceA (C) CAB15016
BceB (M) CAB15015

The bacitracin/vancoresmycin (a tetramic acid antibiotic) resistance exporter (Becker et al. 2009) (most like 3.A.1.134.2)

SPR0812/SPR0813 of Streptococcus pnenmoiae
SPR0812 (C) (Q8DQ77)
SPR0813 (M) (Q8DQ76)

The MDR exporter, YvcRS. Possibly linked to regulation by a sensor kinase/response regulator system (YvcQP) (Joseph et al., 2002; Bernard et al., 2007).

YvcRS of Bacillus subtilis
YvcR (C) (O06980)
YvcR (M) (O06981)

The cationic peptide/MDR exporter, YxdLM. Possibly linked to a sensor kinase/reponse regulator system (YxdJK) (Joseph et al., 2002; Bernard et al., 2007).

YxdLM of Bacillus subtilis
YxdL (C) (P42423)
YxdM (M) (P42424)

The VraFG ABC transporter interacts with GraXSR [GraX, Q7A2W7; GraS, A6QEW9; GraR, A6QEW8] to form a five- or six-component system required for cationic antimicrobial peptide sensing and resistance (Falord et al., 2012).  VraX has been termed a two component system connector and may not be a component of the transporter. VraFG may be a sensor rather than the transporter for the substrate peptide. The actual transporter regulated by VraFGX may have TC# 4.H.1.1.1 (MprF) (Falord et al. 2012). The extracellular loop of the membrane permease VraG interacts with GraS to sense cationic antimicrobial peptides in Staphylococcus aureus (Cho et al. 2021).

VraFG/GraXSR of Staphylococcus aureus 
VraF (A6QEX0)
VraG (A6QEX1)
VraX (Q7A2W7)

Antimicrobial peptide exporter, ABC12 or YvoST (Revilla-Guarinos et al. 2013).

YvoST of Lactobacillus casei

Two component toxic peptide exporter with a membrane subunit of 663 aas and 10 TMSs and an ATPase of 256 aas, ABC09 (Revilla-Guarinos et al. 2013).

ABC09 of Lactobacillus casei

Peptide exporter, YsaB (667 aas and 10 TMSs)/YsaC (257 aas).  Probably exports lantibiotic antibiotics (Draper et al. 2015).

YsaBC of Lactococcus lactis
YsaB (M)
YsaC (C)

Lantibiotic detoxification ABC transporter, VraD (252 aas)/VraE (626 aas; 10 TMSs)/VraH ( (Draper et al. 2015).  Upregulated in response to exposure to beta-defensin 3 (Sass et al. 2008).  Exports antimicrobial peptides such as nisin, bacitracin, daptomycin and gallidermin. Expression of vraH in the absence of vraDE is sufficient to mediate low-level resistance, but VraDEH is required to  confer high-level resistance against daptomycin and gallidermin. (Popella et al. 2016).

VraDE of Staphylococcus aureus VraD (Q9RL74)
VraE (Q9KWJ6)
VraH (T1YED1)

ABC multidrug resistance efflux pump, AnrAB.  Exports nisin, gallidermin, bacitracin and β-lactam antibiotics  (Collins et al. 2010).

AnrAB of Listeria monocytogenes
AnrA (C)
AnrB (M; 642 aas and 10 TMSs)

Putative ABC exporter with three constituent proteins, two membrane proteins with a probable 10 TMS topology in a 1 (N-terminal) + 6 (middle) + 3 (C-terminal) TMS arrangement, and one ATPase

Candidatus Heimdallarchaeota
ABC transporteer of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

Putative ABC3-type porter with a membrane protein and an ATPase encoded by adjacent genes, but next to the genes that encoded by the systems in TCDB under TC#s 3.A.1.207.7 and 8.

Candidatus Heimdallarchaeota
ABC3-type porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
3.A.1.135:  The Drug Exporter-4 (DrugE4) Family

The heterodimeric multidrug exporter, YdaG/YbdA  (Both proteins are ABC half transporters; only the heterodimer is active; ethidium, daunomycin and BCECF-AM are substrates; Lubelski et al., 2004) These proteins have been renamed LmrC and LmrD (Lubelski et al., 2006)

YdaG/YdbA of Lactococcus lactis YdaG (M-C) (AAK04408)
YdbA (M-C) (AAK04409)

The heterodimeric putative multidrug exporter, RscA/RscB; probably orthologous to YdaG/YbdA (TC #3.A.1.117.4) [Transcription is activated by stress conditions (heat, acid) and repressed by a 2-component system, CovRS (Dalton et al., 2006)]
RscAB of Streptococcus pyogenes RscA (M-C) (568 aas) (Q9A1K5)
RscB (M-C) (594 aas) (Q9A1K4)

Narrow spectrum fluoroquinolone (ciprofloxacin and norfloxacin) efflux pump, SatAB (Escudero et al. 2011).

SatAB of Streptococcus suis
SatA, 568 aas (M-C) (G9CHY8)
SatB, 594 aas, (M-C) (G9CHY9)

Multidrug resistance ABC exporter, PatAB (PatA, 564 aas; PatB, 588 aas) (Bidossi et al. 2012). Drug-dependent inhibition of nucleotide hydrolysis by PatAB has been demonstrated (Guffick et al. 2022). Ethidium-like inhibition was observed with propidium, novobiocin and coumermycin A1, which all inhibit nucleotide hydrolysis by a non-competitive mechanism. This fact casts light on potential mechanisms by which drugs can regulate nucleotide hydrolysis by PatAB, which might involve a novel drug binding site near the nucleotide-binding domains (Guffick et al. 2022).

PatAB of Streptococcus pneumoniae
PatA (M-C)
PatB (M-C)

The hetrodimeric ABC transporter, TM287/TM288.  The 2.9-Å crystal structure has been solved in the inward-facing state. The two nucleotide binding domains (NBDs) remain in contact through an interface involving conserved motifs that connect the two ATP hydrolysis sites.  AMP-PNP binds to a degenerate catalytic site which deviates from the consensus sequence in the same positions as the eukaryotic homologs, CFTR (TC# 3.A.1.202.1) and TAP1-TAP2 (TC# 3.A.1.209.1) (Hohl et al. 2012).  The structural basis for allosteric crosstalk (positive cooperativity) between the two ATP binding sites has been studied (Hohl et al. 2014).  The two NBDs exhibit unexpected differences and flexibility (Bukowska et al. 2015). It exports daunomycin and the nonfluorescent 2,7-bis(carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethylester (BCECF-AM) (Hohl et al. 2012). Timachi et al. 2017 observed hydrolysis-independent closure of the NBD dimer, further stabilized as the consensus site nucleotide is committed to hydrolysis.

TM287/TM288 of Thermatoga maritima

Two component multidrug efflux pump with the 6 TMS membrane domain preceding the ATPase domain in both proteins.  Confers resistance to erythromycin and tetracycline and catalyzes export of Hoechst 33342 (Moodley et al. 2014).  Expression is induced by the presence of erythromycin.

MDR pump of Bifidobacterium longum

Multidrug exporter, EfrAB.  Confers resistance to many structurally unrelated antimicrobial agents, such as norfloxacin, ciprofloxacin, doxycycline, acriflavine, 4,6-diamidino-2-phenylindole, tetraphenylphosphonium chloride, daunorubicin, and doxorubicin (Lee et al. 2003).  Induced by half minimal inhibitory concentrations (MIC) of gentamicin, streptomycin and chloramphenicol which are also exporter (Lavilla Lerma et al. 2014).  In some strains, this system may not be the primary drug exporter (Hürlimann et al. 2016).

EfrAB of Enterococcus faecalis
EfrA (MC), 567 aas and 6 TMSs
EfrB (MC), 589 aas and 6 TMSs

Multidrug efflux pump, EfrCD.  Exports daunorubicin, doxorubicin, ethidium and Hoechst 33342.  Mediates efflux of fluorescent substrates and confers resistance towards multiple dyes and drugs including fluoroquinolones (Hürlimann et al. 2016).

EfrCD of Enterococcus faecalis
EfrC, MC, 571 aas and 6 TMSs
EfrD, MC, 589 aas and 6 TMSs

Multidrug exporter, EfrEF.  Mediates efflux of fluorescent substrates and confers resistance towards multiple dyes and drugs including fluoroquinolones (Hürlimann et al. 2016).

EfrEF of Enterococcus faecalis
EfrE, MC, 575 aas and 6 TMSs
EfrF, MC, 592 aas and 6 TMSs

Uncharacterized two component ABC transporter, both of M-C domain order with 6 N-terminal TMSs. The genes encoding these two proteins are adjacent to  a putative ABC transporter of TC# 9.B.29.2.13.

UPs of Caldicellulosiruptor saccharolyticus

ABC transporter with two components, each with 6 N-terminal TMSs + a C-terminal ATPase

ABC exporter of Methanobrevibacter sp.

Two component ABC exporter, both subunits with 611 and 600 aas with 6 N-terminal TMSs in a 2 + 2 + 2 arrangement.  The C-terminal domain is the ATPase

Candidatus Lokiarchaeota
ABC exporter of Lokiarchaota

Two component netropsin resistance ABC netropsin exporter, NetP1/NetP2 (Stumpp et al. 2005).

Netropsin resistance efflux porter of Streptomyces netropsis (Streptoverticillium netropsis)
NetP1 of 618 aas and 6 TMSs (M-C) (Q66LJ1)
NetP2 of 635 aas and 6 TMSs (M-C) (Q66LJ0)
3.A.1.136:  The Uncharacterized ABC-3-type (U-ABC3-1) Family

Putative ABC3 permease complex U-ABC3-1a (403 aas; 4 TMSs in a 1 + 3 TMS arrangement) + an ATPase of 230 aas. The two genes encoding these two proteins are separated by a single gene encoding a putative FMN binding domain-containing protein of 149 aas.

U-ABC3-1a of Treponema denticola (M) (Q73MJ0)

ABC-type antimicrobial peptide transporter with a membrane protein of 421 aas and 4 TMSs (Q6MNW8) and an ATPase of encoded by a gene adjacent to the membrane protein (Q6MNW9). Adjacent to these two genes is one annotated as an iron-regluated protein, FrpA (Q6MNW7).

ABC transporter of Bdellovibrio bacteriovorus
3.A.1.137:  The Uncharacterized ABC-3-type (U-ABC3-2) Family

Putative ABC-3-type permease complex, ABC3-2a
ABC3-2a of Pyrobaculum calidifontis:
ABC3-2a (M) (A3MWP2)
ABC3-2a (C) (A3MWP1)

ABC-type antimicrobial peptide transporter of 786 aas and 8 TMSs

ABC transporter of Bdellovibrio bacteriovorus
3.A.1.138:  The Unknown ABC-2-type (ABC2-1) Family

Unknown ABC-2 transporter complex-1, U-ABC2-TC-1
U-ABC2-TC-1 of Picrophilus torridus:
U-ABC2-TC-1a (M) (Q6KYW9)
U-ABC2-TC-1a (C) (Q6KYW8)
3.A.1.139:  The UDP-Glucose/Iron Exporter (U-GlcE) Family (UPF0014 Family)

UDP-glucose exporter, STAR1/STAR2 (sensitive to aluminum rhizotoxicity) (Probable Type I topology) (Huang et al. 2009).

Viridiplantae, Streptophyta
STAR1/STAR2 of Oryza sativa
STAR1 (C) (Q5Z8H2)
STAR2 (M) (Q5W7C1)

The FetA (YbbL)/FetB (YbbM) iron exporter (SwissProt family UDF0014; 6 or 7 putative TMSs).  Expression enhances resistance to oxidative stress (Nicolaou et al. 2013).

FetA/B of E. coli
FetA (C) (P77279)
FetB (M) (P77307)

The uncharacterized ABC exporter, U-ABC-M/C

U-ABCC/U-ABC-M of Spirochaeta africana
U-ABC-C (C) (H9UM45)
U-ABC-M (M) (H9UM46)

Plasma membrane ABC exporter, sensitive to aluminum rhizotoxicity 1/2, STAR1/STAR2 (Larsen et al., 2005). Induced in response to aluminum exposure. 

Viridiplantae, Streptophyta
STAR1/2 of Arabidopsis thaliana 
STAR1 (C) (Q9C9W0)
STAR2 (M) (Q9ZUT3) 

Uncharacterized protein of 318 aas and 7 TMSs in a 5 + 2 TMS arrangement.  An ATPase for this putative porter has not been identified.

Fungi, Basidiomycota
UP of Tetrapyrgos nigripes
3.A.1.140:  The FtsX/FtsE Septation (FtsX/FtsE) Family

The FtsX/FtsE ABC transporter (Arends et al., 2009) (FtsX is of the type III topology). FtsEX directly recruits EnvC to the septum via an interaction between EnvC and a periplasmic loop of FtsX. FtsEX variants predicted to be ATPase defective still recruit EnvC to the septum but fail to promote cell separation. Amidase activation via EnvC in the periplasm is regulated by conformational changes in the FtsEX complex mediated by ATP hydrolysis in the cytoplasm. Since FtsE has been reported to interact with FtsZ, amidase activity may be coupled with the contraction of the FtsZ cytoskeletal ring (Yang et al., 2011).

FtsX/FtsE of E. coli
FtsX (M) (P0AC31)
FtsE (C) (P0A9R7)

The cell division ABC system, FtsX/FtsE

FstE/X of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)

Cell division ABC system, FtsXE.

FtsXE of Nostoc punctiforme
FtsX (M), 300 aas, 4 TMSs
FtsE (C), 248 aas

Cell division ABC system, FtsXE of 300 aas and 4 TMSs, and 229 aas and 0 TMSs, respectively.

FtsXE of Actinokineospora spheciospongiae
FtsX, (M), 300 aas and 4 TMSs
FtsE, (C), 229 aas and 0 TMSs

Cell division ABC system, FtsXE.

FtsXE of Candidatus Nitrosopumilus salaria
FtsX, (M), 301 aas, 4 TMSs
FtsE, (C), 222 aas, 0 TMSs

Cell division system, FtsXE.  The FtsEX:PcsB complex forms a molecular machine that carries out peptidoglycan (PG) hydrolysis during normal cell division. FtsEX transduces signals from the cell division apparatus to stimulate PG hydrolysis by PcsB, an amidase, which interacts with extracellular domains of FtsX (Bajaj et al. 2016).

FtsXE of Streptococcus pneumoniae
FtsX, (M), 308 aas and 4 TMSs
FtsE, (C), 226 aas and 0 TMSs

FtsEX, ABC transporter involved in cell division FtsE (229 aas, 0 TMSs) is the ATPase subunit while FtsX (298 aas) is the transmembrane protein with 4 TMSs in a 1 + 3 TMS arrangement.  It interacts with RipC, a periplasmic hydrolase of 381 aas and 1 N-terminal TMS (Samuels et al. 2024).

FtsEX of Mycobacterium smegmatis
3.A.1.141:  The Ethyl Viologen Exporter (EVE) Family (DUF990 Family)

The ethyl (methyl; benzyl) viologen export pump, EvrABC (EvrB and EvrC of 6 TMSs are members of the large DUF990 superfamily (Prosecka et al., 2009); They appear to be of the ABC-2 topological type).

EvrABC of Synechocystis sp. PCC6803
P73329 slr1910, ABC protein (EvrA)
P74256 slr1174, membrane protein (EvrB)
P74757 slr0610, membrane protein (EvrC)

ABC transporter of unknown specificity, AbcABC

AbcABC of Thermoanaerobacter tengcongensis
AbcA (M) (Q8R6Q6)
AbcB (M) (Q8R6Q5)
AbcC (C) (Q8R6Q4)
3.A.1.142:  The Glycolipid Flippase (G.L.Flippase) Family

Glycolipid translocase (flippase) Spr1816/Spr1817 (R.Hakenbeck, personal communication)

Glycolipid flippase, Spr1816/Spr1817, of Streptococcus pneumoniae
Spr1816 (M) (Q8DNC0)
Spr1817 (C) (Q8DNB9)

ABC exporter, YvfS/YvfR of 284 and 287 aas, respectively

YvfSR of Bdellovibrio bacteriovorus
YvfS (M)
YvfR (C)

Uncharacterized ABC2 exporter consisting of a 6 TMS membrane protein of 254 aas and an ATPase, encoded by the gene adjacent to the 6 TMS membrane protein.

ABC exporter of Mobiluncus curtisii (Falcivibrio vaginalis)
3.A.1.143:  The Exoprotein Secretion System (EcsAB(C))

The exoprotein (including α-amylase) secretion system, EcsAB(C) (Leskelä et al., 1999). Also may play roles in sporulation, competence (Leskelä et al., 1996) and transformation using purified DNA (Takeno et al., 2011). An involvement of EcsC in transport is not established, but it is similar in sequence to the C-terminus of the P-type ATPase, 3.A.3.31.2.

EcsAB(C) of Bacillus subtilis 
EcsA (C) (P55339)
EcsB (M) (P55340)
EcsC (M) (P55341) 

YthQ (386aas; 8-9 TMSs)/YthP (ATPase; 0 TMSs)

YthPQ (EscAB) of Bacillus amyloliquefaciens
EscA (YthP) (G0IP52)
EscB (YthQ) (G0IP51)

ABC exporter with two components, EcsA, a membrane protein of 430 aas and 10 TMSs in a 2 + 2 + 2 + 2 + 2 TMS arrangement (EOP55101) and EcsB, an ABC-type ATPase of 241 aas (EOP55100).

ABC exporter of Bacillus cereus

ABC-type exoprotein exporter with three componenets, a membrane constituent of 434 aas and 10 TMSs in a 2 + 2 + 2 + 2 + 2 arrangement (AGA59062), an ATPase of 278 aas (AGA59063) and a membrane protease of 289 aas and 2 or 3 N-terminal TMSs (TC# 8.A.21.2.6; AGA59064). The presence of the latter protein encoded adjacent to the transport system suggests that the substrate of the ABC exporter may be a protein that is processed by this protease.

ABC exporter of Thermobacillus composti KWC4

ABC exporter with two components, a membrane protein of 399 aas and 10 TMSs (PFJ32189) and an ATPase of 236 aas (PFJ32188). The gene adjacent to the two genes encoding this system is annotated as a FtsX cell division protein of 195 aas.

ABC exporter of Bacillus anthracis
3.A.1.144:  Functionally Uncharacterized ABC2-1 (ABC2-1) Family



Functionally uncharacterized ABC2 transporter #1.  This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.2.

ABC2 transporter #1 of Methanocella arvoryzae 
ABC2-1 (M) (Q0W8T3)
ABC2-1 (C) (Q0W8T4) 

Functionally uncharacterized ABC2 transporter #2.  This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.1.

ABC2 transporter #2 of Methanocella arvoryzae
ABC2-2 (M) (Q0W8T6)
ABC2-2 (C) (Q0W8T7) 

Functionally uncharacterized ABC2 transporter #3.

ABC2 transporter of Myxococcus xanthus
ABC2-3 (M) (Q1D0V0)
ABC2-3 (C) (Q1D0V1) 

Functionally uncharacterized ABC2 transporter #4 of 751 aas with 18 putative TMSs.  The first 6 TMSs are duplicated to give the N-terminal 12 TMSs.  The last 6 TMSs are non-homologous and are of the DUF95 family (TC #9.B.98) which may consist of ABC exporter auxiliary subunits/domains.

ABC2 transporter of Oscillochloris trichoides 
ABC2 (M) (E1IBA3)
ABC2 (C) (E1IBA4) 
3.A.1.145:  Peptidase Fused Functionally Uncharacterized ABC2-2 (ABC2-2) Family

ABC2 transporter domain fused to an aminopeptidase N domain (Peptidase M1 family) of 1200 aas with 13 putative N-terminal TMSs.

ABC2 protein of Myxococcus xanthus

Putative ABC2 permease of 529 aas and 12 TMSs, Glr0437.

Glr0437 of Gloeobacter violaceus

ABC2 fusion protein of 1194 aas and 13 putative TMSs.  Annotated as ABC transporter involved in multi-copper enzyme maturation; permease component.

ABC2 protein of Cecembia lonarensis

Putative ABC2 protein of 537 aas and 14 putative TMSs

ABC2 permease of Methanocella paludicola

Uncharacterized ABC membrane transport protein of 222 aas and 6 TMSs.

Candidatus Wolfebacteria
UP of Candidatus Wolfebacteria bacterium
3.A.1.146:  The actinorhodin (ACT) and undecylprodigiosin (RED) exporter (ARE) family

The probable actinorhodin (ACT) and undecylprodigiosin (RED) exporter (Lee et al. 2012), AreABCD (Sco3956-9).

AreABCD (Sco3956-9) of Streptomyces coelicolor
AreA (C) (Sco3956)
AreB (M) (Sco3957)
AreC (C) (Sco3958)
AreD (M) (Sco3959)

Putative ABC exporter, Isop2111-Isop2114

Isop2111-Isop2114 of Isophaera pallida
Isop2111 (C) (332 aas) (E8R490)
Isop2112 (M) (359 aas; 6 TMSs) (E8R491)
Isop2113 (C) (340 aas) (E8R492)
Isop2114 (M) (298 aas; 7 TMSs) (E8R493) 

Putative four component ABC exporter with two membrane proteins and two ABC ATPases.

Candidatus Heimdallarchaeota
Putative ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
3.A.1.147:  Functionally Uncharacterized ABC2-3 (ABC2-3) Family

Putative two component ABC exporter with a membrane protein of 573 aas and 12 TMSs and an ATPase encoded adjacent to the membrane protein and also adjacent to a gene encoding an adenine glycosylase, probably within a single operon.

ABC exporter of Gemmatimonas aurantiaca
Membrane protein (M) (C1A6K7)
ATPase (C) (C1A6K8)

Putative 2-component sporulation-related ABC exporter.  The genes encoding this system are adjacent to a spore germination receptor (TC# 2.A.3.9.5) and a putative signalling molecule transporter (2.A.86.1.11).

Putative 3-component ABC exporter of Paenibacillus mucilaginosus
Protein of 572 aas and 12 putative TMSs (M) (F8FLY8)
ATPase protein of 243 aas (C) (F8FLY7)

Putative two component ABC exporter with the membrane protein having 623 aas and 12 TMSs.

ABC exporter of Isosphaera pallida
Membrane protein (M) (E8R692)
ATPase (C) (E8R694)

Putative two component ABC exporter with a membrane protein of 537 aas and 12 TMSs.

ABC exporter of Ruminococcus torques
Membrane protein (M) (D4M3V3)
ATPase (C) (D4M3V2)

Putative 2 component ABC exporter with a membrane protein of 569 aas and 12 TMSs.

Putative exporter of Natranaerobius thermophilus
Membrane protein (M) (B2A6N2)
ATPase (C) (B2A6N1)

Putative two component ABC exporter. There are 78 ABC systems including 28 importers and 50 exporters. Based on NBD sequence similarity, ABC transporters in C. difficile were classified into 12 sub-families according to their substrates (Pipatthana et al. 2021). All ABC exporters, accounting for 64% of the total ABC systems, may be involved in antibiotic resistance.

Putative ABC exporter of Clostridium difficile
Membrane protein (M) (C9XJW9)
ATPase (C) (C9XJX0)

Putative ABC transporter with a membrane protein of 582 aas and 11 TMSs.

ABC transporter of Thermaerobacter marianensis
Membrane protein (M) (E6SIR8)
ATPase (C) (E6SIR7)

Putative ABC exporter with a membrane protein of 544 aas and 12 TMSs

ABC exporter of Streptococcus pneumoniae
Membrane protein (M) (B8ZKM8)
ATPase (C) (B8ZKM9)

Putative ABC exporter

ABC exporter of Methanocella conradii
Membrane protein (M) (H8I7G4)
ATPase (C) (H8I7G5)

Uncharacterized protein of 627 aas and 12 TMSs

UP of Desulfosporosinus meridiei
3.A.1.148:  Functionally Uncharacterized ABC2-4 (ABC2-4) Family

ABC lantibiotic NAI-107 immunity exporter, MlbYZ (Pozzi et al. 2015).

MlbYZ of Microbispora sp. ATCC PTA-5024
MlbY (258 aas, 6 TMSs; M)
MlbZ (300 aas; C)

ABC transport system, PspY (264 aas)/PspZ (301 aas)

PspYZ of Planomonospora alba
PspY (M; 264 aas)
PspZ (C; 301 aas)

Uncharacterized ABC transporter

Uncharacterized ABC transporter of Ktedonobacter racemifer

Uncharacterized ABC transporter, AbcYZ [Y (D2BBE4) = M with 6 TMSs; Z (D2BBE3)= C.]

AbcYZ of Streptosporangium roseum
3.A.1.149:  Functionally Uncharacterized ABC2-5 (ABC2-5) Family

ABC immunity system, TrnFG, protecting the bacteria from the bacteriocin, thuricin CD. TrnF is of 213 aas and 6 TMSs while TrnG is of 285 aas and 0 TMSs.  A 79 aa protein, TrnI with 2 TMSs, also provides immunity against thuricin CD, but the mechanism is unknown (Mathur et al. 2014). These proteins incoded in the thuricin operon.

TrnFG of Bacillus thuringiensis

Uncharacterized two component ABC-2 transporter.

UP of Clostridium intestinale
U2PSG5, M, 216 aas, 6 TMSs in a 2 + 4 arrangement
U2NJR5, C, ATPase of 290 aas

Putative 2 component ABC exporter.

Putative ABC exporter
S7U3S6, M, 215 aas, 6 TMSs in a 2 + 4 arrangement
S7U8X0, C, 285 aas, ATPase, ABC-2
3.A.1.150:  Functionally Uncharacterized ABC2-6 (ABC2-6) Family

Putative ABC transporter consisting of an ATPase and three membrane proteins having 4, 10 and 2 TMSs, respectively.  The structure of the ATPase is similar to those of ABC transorteers, and expression is down regulated in response to cold shock (Gerwe et al. 2007).

Putative ABC transporter of Pyrococcus furiosus

Putative ABC transporter consisting of an ATPase and 3 membrane proteins having 4, 10 and 2 TMSs.

Putative ABC transporter of Pyrococcus furiosus
3.A.1.151:  Functionally Uncharacterized ABC2-7 (ABC2-7) Family

3-component putative ABC transporter with two membrane proteins and an ATPase. These three genes are adjacent to a gene encoding a DegV domain-containing protein, a fatty acid binding domain, also found in PTS mannose EIIA proteins (TC# 4.A.6) and dihydrolyacetone kinases (Schulze-Gahmen et al. 2003; Kinch et al. 2005; Nan et al. 2009).

Putative ABC transporter of Halothermothrix orenii

Putative 3-compenent ABC transporter consisting of two membrane proteins and a cytoplasmic ATPase.  Adjacent to genes coding for a MoaJ/NirJ iron-sulfur nitrite-like oxidoreductase and an antilisterial bacteriocin biosynthetic enzyme, AlbA (B5YBB2 and 3, respectively).  The system could be a bacteriocin exporter.

ABC transporter of Dictyoglomus thermophilum
B5YBA9, M, 186 aas and 6 TMSs (may be N-terminally truncated)
B5YBB0, M, 223 aas and 6 TMSs (both in a 2 + 4 arrangement)
BSYBB1, C, 239 aas, ATPase
3.A.1.152:  The lipopolysaccharide export (LptBFG) Family

LPS export system, LptF (M), LptG (M) and LptB (C).  This system is also listed in TCDB under TC#1.B.42.1.2 as part of a multicomponent system.  The entire system is described in detail there. LptB2FG extracts LPSs from the IM and transports them to the outer membrane. Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa. It shows that LPS transport proteins LptF and LptG each contain a TM domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling helix that interacts with LptB on the cytoplasmic side. The LptF and LptG TMDs form a large outward-facing V-shaped cavity in the IM. Mutational analyses suggested that LPS may enter the central cavity laterally, via the interface of the TMD domains of LptF and LptG, and is expelled into the beta-jellyroll-like domains upon ATP binding and hydrolysis by LptB. These studies suggest a mechanism for LPS extraction by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa. It shows that LPS transport proteins LptF and LptG each contain a TM domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling helix that interacts with LptB on the cytoplasmic side. The LptF and LptG TMDs form a large outward-facing V-shaped cavity in the IM. Mutational analyses suggested that LPS may enter the central cavity laterally, via the interface of the TMD domains of LptF and LptG, and is expelled into the beta-jellyroll-like domains upon ATP binding and hydrolysis by LptB. These studies suggest a mechanism for LPS extraction by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (May et al. 2017).

LptFGB2 of Pseudomonas aeruginosa
LptF, M, Q9HXH4, 375 aas, 6 TMSs
LptG, M, Q9HXH5, 354 aas, 6 TMSs
LptB, C, Q9HVV6, 241 aas, ATPase

Putative ABC exporter of the YjgP/Q (LptFG) family.  The membrane protein has 772 aas and 12 TMSs in a (3 + 3)2 duplicated topology.  The gene adjacent to this membrane protein gene encodes an ABC1 ATPase of 583 aas and 6 N-terminal TMSs with a C-terminal ATPase domain. Most ATPases of family 3.A.1.152 are of the ABC2-type. Thus, it is unlikely that this protein serves to energized the YjgP/Q-dependent transport process. This protein is in TCDB with TC# 3.A.1.106.17.

Putative ABC transporter of Acidobacterium ailaaui

Uncharacterized ABC system of the YjgP/Q family; the two membrane proteins are encoded by adjacent genes, but the gene for the ATPase was not found.  However, a soluble OstA homologue (Q5SL97) of 824 aas is encoded adjacent to the two membrane protein-encoding genes.

UP of Thermus thermophilus

Uncharacterized YjgP/YjgQ family homologue of 441 aas and 6 TMSs. No other YjgP homologue and no ATPase is encoded adjacent to the gene encoding this protein.

UP of Chlorobium phaeovibrioides (Prosthecochloris vibrioformis)

Uncharacterized YjgP/Q homologue of 266 aas and 6 TMSs. No ATPase or another YjgP homologue is encoded by a gene adjacent to this one.

YjgP homologue of Leptonema illini

YjgP/Q homologue of 584 aas an 8 TMSs in a 2 + 3 +3 arrangement.

YjgP homologue of Bizionia argentinensis

YjgP/Q family protein of 392 aas and 6 TMSs

YjgP homologue of Gimesia maris

Uncharacterized YgjP homologue of 585 aas and 6 TMSs; the central hydrophilic domain is 350 aas long, about twice that of many of the homologues.  It might be duplicated.

YgjP homologue of Niabella soli

Lipopolysaccharide transporter that exports LPS from the external surface of the cytoplasmic membrane to the outer membrane, LptB2FG. The 134-kDa protein complex is unique among ABC transporters because it extracts lipopolysaccharide from the external leaflet of the inner membrane and propels it along a filament that extends across the periplasm to directly deliver lipopolysaccharide into the external leaflet of the outer membrane. Dong et al. 2017 reported the crystal structure of this transporter in which both LptF and LptG are composed of a beta-jellyroll-like periplasmic domain and six TMSs. LptF and LptG together form a central cavity containing highly conserved hydrophobic residues. Structural and functional studies suggest that LptB2FG uses an alternating lateral access mechanism to extract lipopolysaccharide and traffic it along the hydrophobic cavity toward the transporter's periplasmic domains. The structure has been presented by Dong et al. 2017. LPS transport involves long-ranging bi- directional coupling across cellular compartments between cytoplasmic LptB and periplasmic regions of the Lpt transporter (Lundstedt et al. 2020). LPS transport from the inner membrane (IM) to the OM is achieved by seven lipopolysaccharide transport proteins (LptA-G). LptB2FG, a type VI ABC transporter, forms a stable complex with LptC, extracts LPS from the IM and powers LPS transport to the OM. Luo et al. 2021 reported the cryo-EM structures of LptB2FG and LptB2FGC from Klebsiella pneumoniae in complex with LPS. The LptB2FG-LPS structure provides detailed interactions between LPS and the transporter, while the LptB2FGC-LPS structure may represent an intermediate state in which the transmembrane helix of LptC has not been fully inserted into the transmembrane domains of LptB2FG (Luo et al. 2021).


LptB2FG of Klebsiella pneumoniae
LptB, 241 aas; 0 TMSs, A6TEM0
LptF, 365 aas, 6 TMSs, A6THI3
LptG, 360 aas, 6 TMSs, A6THI4

Probable LptF/G or YjgP/Q membrane proteins of an ABC exporter, possibly specific for a lipopolysaccharide.  Adjacent genes code for proteases/peptidases.  An ATPase that energizes this system has not been identified. The two membrane proteins are of 360 and 380 aas with 6 TMSs in a 3 + 3 TMS arrangement, separated by a large hydrophilic loop. Members of this family often work together with outer membrane proteins of TC family 1.B.42, and some of these outer membrane proteins are fused to one of the subunites of these systems.

LptF/G of Candidatus Pelagibacter sp. (marine metagenome)
3.A.1.153:  The Functionally Uncharacterized ABC-X (ABC-X) Family

ABC transporter complex YtrBCD that may play a role in acetoin utilization during stationary phase and sporulation (Yoshida et al. 2000). Expression is induced early in the stationary phase. The six ytr genes form a single operon, transcribed from a promoter present upstream of ytrA. YtrA, which possesses a helix-turn-helix motif of the GntR family, may be a repressor that regulates its own transcription as well as the whole operon. Inactivation of the operon led to a decrease in the maximal cell yield and less-efficient sporulation. B. subtilis produces acetoin as an external carbon storage compound and then reuses it later during stationary phase and sporulation. Possibly the Ytr porter plays a role (Yoshida et al. 2000). The YtrEF system, believed to be a distinct ABC efflux system (M. Saier, unpublished results), can be found under TC# 3.A.1.122.19.

YtrBCD of Bacillus subtilis
YtrB, 292 aas (C)
YtrC, 328 aas (M)
YtrD, 325 aas (M)

Putative ABC acetoin exporter, ABC-2-like protein (M) plus ATPase (C).

ABC porter of Bacillus thuringiensis
ABC2-2-like protein of 375 aas and 8 TMSs (A0RI83)
BAC-type ATPase of 298 aas (A0RI82)

Uncharacterized protein

Uncharacterized protein of Streptomyces coelicolor (Q9K3K9)  

Uncharacterized protein of 316 aas and 6 TMSs.

UP of Hoyosella subflava (Amycolicicoccus subflavus)

Uncharacterized protein of 353 aas and 5 or 6 TMSs.

UP of Gordonia alkanivorans

Uncharacterized protein of 12 TMSs in a 1 + 5 + 1 +5 arrangement.  TMSs 5 and 6 as well as 11 and 12 are separated by about 30 - 50 residues.

UP of Mycobacterium abscessus

The phage infection protein of 901 aas, PIP (Geller et al. 1993). The PIP family (3.A.1.155) includes large proteins with 1 N-terminal hydrophobic TMS, a hydrophilic domain of variable length, and 5 C-terminal putative TMSs. The functionally characterized protein from Lactococcus lactis is of 901 aas (Geller et al., 1993). Homologues obtained with one PSI-BLAST iteration include members of the MmpL family of the RND superfamily (e.g., a Bacillus protein, gi#89208076; 1038 aas). With poorer scores, a protein annotated as an ABC-2-like sequence (gi#89200681; 392 aas with 1 TMS followed by a 150 residue hydrophilic domain followed by a C-terminal 5 putative TMSs) was retrieved. Another protein annotated as ABC-2 was smaller with 6 putative TMSs in a 2 + 3 + 1 arrangement (gi#57234453; 241 aas). The hydrophilic domain in these proteins may show sequence similarity with the large periplasmic hydrophilic domains of RND porters (2.A.6.1 - 9).

PIP of Lactococcus lactis (P49022)

The putative ABC-2-like protein of 678 aas (topology-like PIP)
ABC-2-like protein of Arthrobacter sp. (gi#116669229)

Uncharacterized protein YhgE (ORFB)

YhgE of Bacillus subtilis

X(3)LX(2)G heptad repeat protein of 779 aas

Heptad repeat protein of Lachnospiraceae bacterium 2_1_46FAA

Uncharacterized YhgE/Pip domain-containing protein of 432 aas and 6 TMSs.

UP of Streptomyces himastatinicus

Uncharacterized protein of 499 aas and 7 putative TMSs in a 1 + 5 + 1 TMS arrangement.  This protein may interrelate 9.B.74 and 2.A.6.10 (subfamily) which may NOT belong to the RND superfamily.

UP of Dietzia alimentaria

YhfE/Pip domain protein of 740 aas and 6 or 7 TMSs in a 1 + 5 or 6  arrangement.

YhfE protein of Gulosibacter molinativorax

The ABC-2-like protein of 392 aas
ABC-2-like protein of Bacillus cereus (A7GKA4)

Uncharacterized protein of 397 aas and  6 TMSs in a 1 + 5 TMS arrangement

UP of Bacillus cereus

ABC transporter permease

ABC permease of Rubeoparvulum massiliense
(M) 232 aas and 6 TMSs (WP_048600991.1)
(C) 244 aas (WP_048600992.1)

ABC transporter with a membrane protein of 219 aas and 6 TMSs and an ATP-binding protein, YxlF, of 316 aas.

Candidatus Lokiarchaeota
ABC-2 transporter of Lokiarchaeum sp.
(M), 219 aas and 6 TMSs
(C), 316 aa

ABC2 transporter of unknown substrate specificity with two membrane constituents and one ATPase.

Tricomponent ABC exporter of Bacillus licheniformis
M1, 170 aas and 5 TMSs, ARC67021
M2, 212 aas and 5 TMSs, ARC67023
C, ATPase, YxlF, 307 aas, ARC67024

Two component ABC transporter with one M subunit and one C subunit.

ABC transporter of Clostridioides difficile

Putative ABC3 porter with a 10 TMS membrane protein and an ATPase. This system is encoded by genes that are adjacent to those encoding 3.A.1.207.7 and 3.A.1.207.9. It is not known if these three systems are distinct or function somehow together.

Candidatus Heimdallarchaeota
ABC3 porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

Putative ABC3-type porter of 956 aas with 10 TMSs in a 1 + 3 + 2 + 1 + 3 TMS arrangement. Two ABC-type ATPases are encoded by genes adjacent to the membrane protein, and on the other side is encoded a membrane protein of 509 aas with two TMSs, one N-termnal, and one C-terminal. This last protein is included here because if could be an auxilliary protein of the ABC exporter.

Candidatus Heimdallarchaeota
ABC3-type exporter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

Putative ABC3 transporter of two constituents

Candidatus Heimdallarchaeota
ABC3 porter of Candidatus Heimdallarchaeota archaeon

Uncharacterized ABC-type exporter possibly with 4 protein components, all of which are encoded by genes that map adjacent to each other, YybMLKJ.  The proteins of this system are distantly related to members of ABC families 3.A.1.124, 132, 146 and 157. 

YybJKLM of Bacillus subtilis
YybJ, C, 218 and 0 TMSs
YybK, M, 251 aas and 6 TMSs
YybL, M, 236 aas and 6 TMSs
YybM, M, 251 aas and 6 TMSs

Putative ABC-type multidrug transport system with 3 protein components.

BAC porter with three components
ABC-A, M, 264 aas and 6 TMSs
ABC-B, M, 287 aas and 6 TMSs
ABC-C, C, 220 aas and 0 TMSs

ABC exporter of three protein components

ABC exporter of Clostridium beijerinckii (Clostridium acetobutylicum)
ABC-A, M, 6 TMSs, A6LQ39
ABC-B, M, 6 TMSs, A6LQ40
ABC-C, C, 0 TMSs, A6LQ41

Putative 4 component ABC system with 3 membrane proteins, all with 6 TMSs, and one ATPase, all encoded by genes that are adjacent to each other.

Putative 4 component ABC exporter of Lachnospiraceae bacterium (gut metagenome) HCO29007, M, 6 TMSs
HCO29006, M, 6 TMSs
HCO29005, M, 6 TMSs
HCO29004, C, ATPase, 0 TMSs

ABC-2 type transport system with three 6 TMS membrane proteins (M) and one ATP-binding protein (C).

ABC2 system of Murimonas intestini
PWJ78148, M
PWJ78149, M
PWJ78150, M
PWJ78151, C
3.A.1.201:  The Multidrug Resistance Exporter (MDR) Family (ABCB)

Broad specificity multidrug resistance (MDR1; MDR-1; Pgp; P-gp; ABCB1; P-glycoprotein) efflux pump. It exports organic cations and amphiphilic compounds of unrelated chemical structure.  These include: antibiotics, anti-viral agents, cancer chemotheraputic agents, hypertensives, depressants, histamines, emetics, and the protease inhibitor, lopinavir. Pgp also exports immunosuppressants, detergents, long-chain fatty acids, HIV protease inhibitors, synthetic tetramethylrosamine analogues, calcein M, etc.); it is also a peptide efflux pump, and peptide inhibitors have been designed (Tarasova et al. 2005). It is also a phospholipid (e.g., phosphatidyl serine), cholesterol and sterol flippase. It binds and probably transports inhibitors and agonists of SUR (3.A.1.208.4) (Bessadok et al., 2011). Modulatory effects of inhibitory amlodipine and tamoxifen on P-glycoprotein efflux activities have been studied (Darvari and Boroujerdi 2004). The 3-d structure has been determined (Aller et al., 2009). It can pump from the cytoplasmic leaflet to either the outer leaflet or the outer medium (Katzir et al., 2010). The inhibitor, 5''-fluorosulfonylbenzoyl 5''-adenosine, an ATP analogue, interacts with both drug-substrate- and nucleotide-binding sites (Ohnuma et al., 2011). Inhibited by sildenafil (Shi et al., 2011), verapamil, indomethacin, probenecid, cetirizine (He et al. 2010), and lapatinib derivatives (Sodani et al., 2012), several of which are also substrates. HG-829 is a potent non-competitive inhibitor (Caceres et al., 2012).  Berberine, palmatine, jateorhizine, cetirizine and coptisine are all P-gp substrates, and cyclosporin A and verapamil are potent inhibitors (He et al. 2010; Zhang et al., 2011).  Transports clarithromycin (CAM), a macrolide antibiotic used to treat lung infections, more effectively than azithromycin (AZM) or telithromycin (TEL) (Togami et al. 2012).  Nucleotides, lipids and drugs bind synergistically to the pump (Marcoux et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  The central cavity undergoes alternating access during ATP hydrolysis (van Wonderen et al. 2014).  Structural data suggest that signals are transduced through intracellular loops of the TMSs that slot into grooves on the NBDs. The Q loops at the base of these grooves are required to couple drug binding to the ATP catalytic cycle of drug export (Zolnerciks et al. 2014). Ocotillol analogues are strong competitive inhibitors (Zhang et al. 2015).  Durmus et al. 2015 have reviewed PGP transport of cancer chemotheraputic agents.  ABCB1 variants modulate therapeutic responses to modafinil and may partly explain pharmacoresistance in Narcolepse type 1 (NT1) patients (Moresco et al. 2016).  Many inhibitors have been identified (Hemmer et al. 2015).  The open-and-close motion of the protein alters the surface topology of P-gp within the drug-binding pocket, explaining its polyspecificity (Esser et al. 2016). The ATP- and substrate-coupled conformational cycle of the mouse Pgp transporter have been defined, showing that the energy released by ATP hydrolysis is harnessed in the NBDs in a two-stroke cycle (Verhalen et al. 2017).  Rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport (Reznicek et al. 2017).  It transports Huerzine A in the brain, a drug that is used for the treatment of Alzheimer's disease (Li et al. 2017). AbcB1 acts in concert with ABCA1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018).The structure has been determined with the ABCB1 inhibitor, zosuquidar, bound.  This structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all TMSs. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules (Alam et al. 2018).  Iit is also inhibited by dacomitinib (Fan et al. 2018). Moreover, Kim and Chen 2018 presented the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-Å resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and is compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release (Kim and Chen 2018). P-gp also transports opioid peptides (Ganapathy and Miyauchi 2005). MDR1 has been quantified in primary human renal cell carcinoma cells and corresponding normal tissue, and down-regulation or expression loss was documented in tumor tissues, corroborating its importance in drug resistance and efficacy (Poetz et al. 2018). Regarding the conformational transitions, first the transition is driven by the NBDs, then transmitted to the cytoplasmic parts of TMSs, and finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement (Zhang et al. 2018). Isoxanthohumol is a substrate and competitive inhibitor which reverses ABCB1-mediated doxorubicin resistance (Liu et al. 2017). Tariquidar is a potent inhibitor, even when taken orally (Matzneller et al. 2018). Combined oral administration of the ovarian hormones, ethinyl estradiol and progesterone, significantly lowered both MDR-1 mRNA and MDR-1 protein in the ovary (Brayboy et al. 2018). Its expression in immune cells plays a protective role from xenobiotics and toxins (Bossennec et al. 2018). Oxypeucedanin reverses P-gp-mediated drug transport by inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA levels (Dong et al. 2018). Alam et al. 2019 determined the 3.5-Å cryo-EM structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the ATP-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport (Alam et al. 2019). The TMS4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp (Xing et al. 2019). The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by ABCB1 (Wen et al. 2019). Substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites, but this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites (Dastvan et al. 2019). It transports temozolomide (TMZ) which is used as a treatment of glioblasomas (Malmström et al. 2019). Unconventional cholesterol translocation on the surface of Pgp provides a secondary transport model for the known flippase activity of ABC exporters of cholesterol (Thangapandian et al. 2020). An in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp has been developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds) (Mora Lagares et al. 2019).  Jervine is a natural teratogenic compound isolated from Veratrum californicumLiu et al. 2019 showed that jervine sensitizes the anti-proliferation effect of doxorubicin (DOX) and that the synergistic mechanism was related to the intracellular accumulation of DOX via modulating ABCB1 transport. Jervine did not affect the expression of ABCB1 in mRNA or protein levels. However, jervine increased the ATPase activity of ABCB1 and probably served as a substrate of ABCB1. Jervine binds to a closed ABCB1 conformation and blocks drug entrance to the central binding site at the transmembrane domain (Liu et al. 2019). 6-Triazolyl-substituted sulfocoumarins inhibit P-gp (Podolski-Renić et al. 2019). ATP binding causes the conformational change to the outward-facing state, and ATP hydrolysis and subsequent release of γ-phosphate from both NBDs allow the outward-facing state to return to the original inward-facing state (Futamata et al. 2020). Replacing the eleven native tryptophans by directed evolution produces an active P-glycoprotein with site-specific, non-conservative substitutions (Swartz et al. 2020). ABCB1 polymorphisms alter P-gp-mediated drug (sunitinib) sensitivities. Homology modeling provided insight into ligand binding through molecular docking studies (Mora Lagares et al. 2020). Sitravatinib  reverses MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR (Yang et al. 2020). Apiole from parsley blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents (Afonso de Lima et al. 2020). The mechanisms of action of synthetic, potent, small molecule P-gp inhibitors have been reviewed (Zhang et al. 2020). ATP binding to the open NBDs and ATP hydrolysis in the closed NBD dimer represent two steps of energy input, each leading to the formation of a high energy state. Relaxation from these high energy states occurs through conformational changes that push ABCB1 through the transport cycle (Szöllősi et al. 2020). 14 conserved residues (seven in both TMsSs 6 and 12) were substituted with alanine and generated a mutant termed 14A (Sajid et al. 2020). Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, it was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, uptake was ATP hydrolysis-, substrate concentration-, and time-dependent. Further mutagenesis identified residues in both TMSs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell (Sajid et al. 2020). Helix repacking may be the basis for P-glycoprotein promiscuity (Bonito et al. 2020). The use of carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein has been shown to overcome cancer drug resistance (Wang et al. 2021). A sequentially responsive Nnanosystem breaches cascaded bio-barriers and suppresses P-Glycoprotein function for reversing cancer drug resistance (Liu et al. 2020). Lys-268 and the cytoplasmic end of TMS5 may comprise a drug binding site (Demmer et al. 2021). MDR1 protein (ABC-C1) is overexpressed in Giardia intestinalis following incubation with the drugs, albendazole and nitazoxanide (Ángeles-Arvizu et al. 2021). The human P-gp is inhibited by benzophenone sulfonamide derivatives (Farman et al. 2020) and androstano-arylpyrimidines (Gopisetty et al. 2021), and possibly by tepoxalin (McQuerry et al. 2021). The inward facing state of P-glycoprotein in a lipid membrane has been confirmed (Carey Hulyer et al. 2020). For transmembrane pharmaceutical drug transport, non-specific trans-phospholipid bilayer transport may be negligible (Kell 2021). Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein (Abd-Ellatef et al. 2021). In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 are potential MDR reversal agents (Moosavi et al. 2022). Quercetin acts as a P-gp modulator via impeding signal transduction from the nucleotide-binding domain to the transmembrane domain (Singh et al. 2022). MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells and exports the antiseizure drug, levetiracetam (Behmard et al. 2022). Air pollution exposure increases ABCB1 and ASCT1 transporter levels in mouse cortex (Puris et al. 2022). MDR-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes (Nabi et al. 2022). The P-glycoprotein (ABCB1) transporter has been modelled with in silico methods (Mora Lagares and Novič 2022). A new ABCB1 inhibitor enhances the anticancer effect of doxorubicin in models of non-small cell lung cancer (NSCLC) (Adorni et al. 2023). A homologous series of amphiphiles interact with P-glycoprotein in a membrane environment, and the contributions of polar and non-polar interactions has been estimated (Moreno et al. 2023). TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. In taxane-resistant MCF-7 sublines, TRIP6 co-amplifies with the neighboring ABCB1 gene (Daniel et al. 2023). Inhibition of Cryptosporidium parvum by nitazoxanide (NTZ) and paclitaxel (PTX) has been validated (Yang et al. 2023). New inhibitors of ABCB1 have been identified (Cheema et al. 2023). Inhibitors of MDR pumps (MDR1, MRP1/2 and BCRP) have been described (Kaproń et al. 2023). A hyaluronic acid modified cuprous metal-organic complex reverses multidrug resistance via redox dyshomeostasis (Wan et al. 2023; Duan et al. 2023). The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface (Seelig and Li-Blatter 2023). ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade >/=3 infections (Ferrero et al. 2023). Wine-processed Chuanxiong Rhizoma enhances the efficacy of aumolertinib against EGFR mutant non-small cell lung cancer xenografts in nude mouse brain (Niu et al. 2023). The efflux of anti-psychotics through the blood-brain barrier (BBB) via this system has been demonstrated (Nasyrova et al. 2023). Residues from homologous TMSs 4 and 10 are critical for P-glycoprotein (ABCB1)-mediated drug transport (Rahman et al. 2023). Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse MDR (Ibrahim et al. 2023). Other substrates and inhibitors from Anemarrhenae rhizoma have been identified (Dai et al. 2022).  Peptides and their analogs can cross the BBB by transmembrane diffusion, saturable transport, and adsorptive transcytosis (Banks 2023). Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB (Banks 2023).  Second-site suppressor mutations reveal connections between the drug-binding pocket and the nucleotide-binding domain 1 of human P-glycoprotein (ABCB1) (Murakami et al. 2023).  Betulin derivatives are multidrug reversal agents targeting P-glycoprotein (Laiolo et al. 2024). Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance (Xu et al. 2024).

Metazoa, Chordata
MDR1 of Homo sapiens

Bile salt export pump, BSEP, ABCB11 or SPGP in the canalicular membrane of liver cells, is associated with progressive familial intrahepatic cholestasis-2 and benign recurrent intrahepatic cholestasis (Kagawa et al., 2008; Stindt et al. 2013; Park et al. 2016). It exports unconjugaged bile salts and glycine conjugates > taurine conjugates as well as the statin, pravastatin (Nigam 2015). BSEP mediates biliary excretion of bile acids from hepatocytes. Compounds based on GW4064 (Q96RI1), a representative farnesoid X receptor (RXR) agonist, enhance E297G BSEP transport activity (Misawa et al., 2012). Rescue of bile acid transport by ABCB11 variants by CFTR potentiators has been extensively documented as a possible treatment for progressive familial intrahepatic cholestasis-2 (Mareux et al. 2022).  BSEP is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs is frequently associated with severe cholestatic liver disease. Liu et al. 2023 reported the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. Two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEP(E1244Q)) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. These studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity (Liu et al. 2023).

Metazoa, Chordata
BSEP of Homo sapiens

Short chain fatty acid phosphatidylcholine translocase (phospholipid flippase), MDR3; AbcB4; Pgy3.  ABCB4 regulates the secretion into bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. It is associated with progressive familial intrahepatic cholestasis type 3 (PFIC3) (Degiorgio et al. 2007) and progressive intrafamilial hepatic disease (Quazi and Molday, 2011)). ABCB4 exhibits narrow drug specificity relative to MDR1 but exports digoxin, paclitaxel, vinblastin and bile acids. It regulates phosphatidylcholine secretion into bile and its translocation across the plasma membrane in hepatocytes (Voloshyna and Reiss, 2011; Kluth et al. 2014) and functions as a floppase (Sakamoto et al. 2019). The cryo-EM structure trapped in an ATP-bound state at a resolution of 3.2 Å has been described (Olsen et al. 2019). The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound, is present. This indicates a state following substrate release but prior to ATP hydrolysis. These results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters (Olsen et al. 2019). An in vitro assay to investigate ABCB4 transport function has been developed (Temesszentandrási-Ambrus et al. 2023).

Metazoa, Chordata
MDR3 of Homo sapiens

The multidrug resistance/chloroquine resistance protein, PfMdr1 (ABCB1, Pgh1).  PfMdr1 is the central system in P. falciparum artemisinin therapy regimen resistance (Gil and Krishna 2017).  PfMDR1 is inhibited by 4 nM actelion (ACT)-213615 and actelion (ACT)-451840 (Brunner et al. 2012, Brunner et al. 2013, Krause et al. 2016),

Pfmdr1 of Plasmodium falciparum (P13568)

Auxin efflux pump Pgp1 (MDR1; ABCB1) (Carraro et al. 2012). Regulated by Twd1, an FK506-binding protein immunophilin prolyl/peptidyl isomerase; 8.A.11.1.1 (Bouchard et al., 2006).  Involved in light-dependent hypocotyl elongation (Sidler et al. 1998). The combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance (Zhang et al. 2017). Pgp1 also confers herbicide tolerance to cycloheximide, toxic leves of the plant hormone N6-[2-isopentyl]adenine (2iP) and multiple herbicides (Windsor et al. 2003). It is up-regulated under salt stress conditions (Yang et al. 2018).

Viridiplantae, Streptophyta
Pgp1 of Arabidopsis thaliana (Q9ZR72)

Auxin efflux pump Pgp19 (MDR11; ABCB19; ABCB21) (regulated by Twd1, an FK506-binding protein immunophilin prolyl/peptidyl isomerase (TC# 8.A.11.1.1) (Bouchard et al., 2006).

Viridiplantae, Streptophyta
Pgp19 of Arabidopsis thaliana (Q9LJX2)

Auxin efflux pump Pgp4; AbcB4; MDR4; PGP4 (Lefèvre and Boutry 2018) of 1286 aas and 12 TMSs in a MCMC domain arrangement.  Functions in the basipetal redirection of auxin from the root tip. Strongly expressed in root cap and epidermal cells (Terasaka et al., 2005).  Contributes to the basipetal transport in hypocotyls and root tips by establishing an auxin uptake sink in the root cap. Confers sensitivity to 1-N-naphthylphthalamic acid (NPA). Regulates root elongation, the initiation of lateral roots and the development of root hairs. Can transport IAA, indole-3-propionic acid, NPA syringic acid, vanillic acid and some auxin metabolites, but not 2,4-D and 1-naphthaleneacetic acid (Terasaka et al., 2005). Pgps and PINs (TC# 2.A.69) function in coordinated but independent auxin transport but also function interactively in a tissue-specific manner (Blakeslee et al. 2007). Found in the plasma membranes of root hair cells (Cho et al. 2012).

Viridiplantae, Streptophyta
Pgp4 of Arabidopsis thaliana (MCMC) O80725

The aluminum chelate (aluminum sensitivity (ALS1)) protein; expressed in root vacuoles half-type ABC transporter (not induced by aluminum; Larsen et al., 2007).
Viridiplantae, Streptophyta
ALS1 (M-C) of Arabidopsis thaliana (Q0WML0)

Marine skate liver bile salt exporter, BSEP (1348 aas) (transports taurocholine in an ATP-dependent fashion (Cai et al., 2001)) (Most similar to 3.A.1.201.2)
Metazoa, Chordata
BSEP of Raja erinacea (MC MC) (Q90Z35)

Mdr1; resistance to Cilofungin and other drugs (Lamping et al., 2010)

Fungi, Ascomycota
Mdr1 (MCMC) of Aspergillus fumigatus (B0Y3B6)

Mdr1 azole resistance efflux pump (Lamping et al., 2010).  Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans has been studied (Peng et al. 2023).

Fungi, Basidiomycota
Mdr1 (MCMC) of Cryptococcus (Filobasidiella) neoformans (O43140)

California mussel ABCB/MDR multixenobiotic resistance efflux pump (Luckenbach and Epel, 2008).

Metazoa, Mollusca
ABCB/MDR transporter of Mytilus californianus (MCMC) (B2WTH9)

Plasma membrane AbcB5, of 812 aas and 6 TMSs, mediates resistance of tumor cells to doxorubicin and other drugs including taxanes and anthracyclines (Kawanobe et al. 2012) by catalyzing efflux of these drugs (Sakamoto et al. 2019).  Expression in metastatic melanoma cells is affected by nano-TiO2 exposure, which as a sunscreen ingredient, may play a role in metastatic melanoma progression (Zdravkovic et al. 2019).

Metazoa, Chordata
ABCB5 of Homo sapiens (Q2M3G0)

P-glycoprotein-1 MDR exporter.  Transports multiple drugs, cancer chemotherapy agents, cancer unrelated compounds and many xenobiotics including ivermectin (Ardelli 2013).  The crystal structure at 3.4 A resolution is available (Jin et al. 2012).  It has 4,000x higher affinity for actinomycin D in the membrane bilayers than in detergent.  A "ball and socket joint" and salt bridges similar to ABC importers suggested that both types of systems, importers and exporters, use the same mechanism to interconnect ATP hydrolysis with transport and achieve alternating access of the substrate binding site to the two sides of the membrane. 

Metazoa, Nematoda
P-glycoprotein-1 of Caenorhabditis elegans

MDR efflux pump, ABCB1a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Metazoa, Echinodermata
ABCB1a of Stronglycentrotus purpuratus

MDR efflux pump, ABCB4a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Metazoa, Echinodermata
ABCB4a of Stronglycentrotus purpuratus

Mitochondrial ABCB10 or ABC-me transporter. It is a mitochondrial inner membrane erythroid transporter involved in heme biosynthesis. ABCB10 possesses an unusually long 105-amino acid mitochondrial targeting presequence, the central subdomain of which (aas 36-70) is sufficient for mitochondrial import (Graf et al. 2004) and is essential for erythropoiesis and protection of mitochondria against oxidative stress.  The 3-d structures of several conformations are available (3ZDQ; Shintre et al. 2013; Sakamoto et al. 2019). Sitravatinib  reverses MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR (Yang et al. 2020).

Metazoa, Chordata
ABCB10 of Homo sapiens

Leptomycin B resistance protein 1, Pmd1, of 1362 aas and 13 predicted TMSs (Nishi et al. 1992). This protein is similar in sequence to Ste6-2b  of Pichia pastoralis the structure of which has been solved by cryoEM. It transports rodamines 6G and 123, Dvarapamil, flconazole, and itraconazole, and it's ATPase activity is inhibited by terbinafine, niftifine, ketoconazole and asmorilfine, It also appears to interact with sterols (Schleker et al. 2022).

Fungi, Ascomycota
Pmd1 of Schizosaccharomyces pombe

Mitochondrial iron/sulfur complex transporter, AbcB13 of 663 aas (Xiong et al. 2010).

AbcB13 (M-C) of Tetrahymena thermophila

12 TMS multidrug resistance transprter of 1318 aas, AbcB15 (Xiong et al. 2010) is the probable exporter of dichlorodiphenyltrichloroethane (DDT). Expression is induced by treatment with DDT, and this transporter appears to be responsible for DDT tolerance by pumping it out of the cell (Ning et al. 2014).

AbcB15 (M-C-M-C) of Tetrahymena thermophila

Half sized ABCB1 drug (verapamil; rhodamine 6G) exporter of specificity similar to that of P-glycoprotein (3.A.1.201.1).  The 3-d structures of the unbound (2.6 Å) and the allosteric inhibitor-bound (2.4 Å) forms have been determined (Kodan et al. 2014).  The outward opening motion is required for ATP hydrolysis. Kodan et al. 2019 have reported a pair of structures of this homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide, and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that can be clearly visualized include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among TMSs 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TMS1 and TMS3, a property that distinguishes multidrug transporters from floppases (Kodan et al. 2019). The crystal structure of the CmABCB1 G132V mutant, which favors the outward-facing state, reveals the mechanism of the pivotal joint between TMS1 and TMS3 (Matsuoka et al. 2021). The crystal structure of this CmABCB1 multi-drug exporter in lipidic mesophase has been revealed by LCP-SFX, suggesting flexibility of the substrate exit region of the protein (Pan et al. 2022).  Structure-based alteration of tryptophan residues of CmABCB1 allows assessment of substrate binding using fluorescence spectroscopy (Inoue et al. 2022).

ABCB1 of Cyanidioschyzon merolae

Mitochondrial ATP-binding cassette 1, ABCB8.  Mediates doxorubicin resistance in melanoma cells (Elliott and Al-Hajj 2009). It is regulated by the Sp1 transcription factor and down regulated by mthramycin A which blocks Sp1 binding to the DNA (Sachrajda and Ratajewski 2011). It is also regulated by neuropilin-1, NRP1 (TC# 8.A.47.1.5) (Issitt et al. 2018). The cryo-EM structure of ABCB8 bound to AMPPNP in the inward-facing conformation was solved with a resolution of 4.1 Å. hABCB8 shows an open-inward conformation when ATP is bound, and cholesterol molecules were identified in the transmembrane domain of hABCB8 (Li et al. 2021).

Metazoa, Chordata
ABCB8 of Homo sapiens

The cyclic AMP efflux pump of 1432 aas, ABCB3 (Miranda et al. 2015).

ABCB3 of Dictyostelium discoideum

Multidrug exporter, MDR49 or Pgp of 1302 aas and 12 TMSs.  Exports many drugs as well as pollutants such as polycyclic aromatic hydrocarbons (PAHs) which are major sources of air, water and soil pollution.  MDR49 is expressed at all developmental stages of the life cycle and in many tissues (Vache et al. 2007). It is essential for early development, probably because Drosophila germ cell migration depends on lipid-modified peptides that are secreted by MDR49 (Ricardo and Lehmann 2009).

Metazoa, Arthropoda
MDR49 of Drosophila melanogaster (Fruit fly)

MDR transporter, Crmdr1 of 1266 aas and 12 TMSs.  Crmdr1 is constitutively expressed in the root, stem and leaf with lower expression in leaf. It has two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) arranging in "TMD1-NBD1-TMD2-NBD2" direction (Jin et al. 2007).


Viridiplantae, Streptophyta
Crmdr1 of Catharanthus roseus (Madagascar periwinkle) (Vinca rosea)

ABC multidrug exporter, MDR1 of 1341 aas, 12 TMSs and two ATPase domains in an MCMC arrangement.  Miltefosine (hexadecylphosphocholine), the first orally available drug available to treat leishmaniasis, is pumped out of the parasite by MDR1, a P-glycoprotein-like transporter. Overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites and resistance (Pérez-Victoria et al. 2006).

MDR1 of Leishmania major

Multidrug resistance exporter of 1331 aas and 12 TMSs, TratrD or MDR2. Almost identical throughout must of its length to F2PRR1 from T equinum of 1235 aas and 12 TMSs (Martins et al. 2016). Displays increased levels of transcription of the TruMDR2 gene when mycelia were exposed to acriflavine, benomyl, ethidium bromide, ketoconazole, chloramphenicol, griseofulvin, fluconazole, imazalil, itraconazole, methotrexate, 4-nitroquinoline N-oxide (4NQO) or tioconazole. Disruption of the TruMDR2 gene rendered the mutant more sensitive to terbinafine, 4NQO and ethidium bromide than the control strain, suggesting that this transporter plays a role in modulating drug susceptibility in T. rubrum (Fachin et al. 2006).

Fungi, Ascomycota
TratrD or MDR2 of Trichophyton rubrum (Athlete's foot fungus) (Epidermophyton rubrum)

MDR1 alkaloid/multiple drug efflux transporter of 1292 aas and 12 TMSs (Shitan et al. 2003). 

Viridiplantae, Streptophyta
CjMDR1 of Coptis japonica (Japanese goldthread)

ABC transporter B family member 11 isoform X1 or ABCB11 of 1303 aas and 12 TMSs. Functions to export shikonin (Zhu et al. 2017). Shikonin is a naphthoquinone secondary metabolite with  medicinal value, found in Lithospermum erythrorhizon.

Viridiplantae, Streptophyta
ABCB11 of Jatropha curcas (Barbados nut) (closely related to Lithospermum erythrorhizon)

ABCB10 transporter of 655 aas and 6 TMSs.  Functions in resistance to acaricides (Koh-Tan et al. 2016).

Metazoa, Arthropoda
ABCB10 of Rhipicephalus microplus (Cattle tick) (Boophilus microplus)

Permeability glycoprotein, P-Glycoprotein 65, P-GP65, MDR65 of 1302 aas and 12 TMSs. a detoxification efflux pump transporting various lipophilic xenobiotics out of the cells. Exports Polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental contaminants (Vaché et al. 2006). When flies are exposed to benzo[a]pyrene or to ambient air polluted by higher or lower PAH concentrations, P-gp expression was induced (Vaché et al. 2006).

Metazoa, Arthropoda
PGP65 of Drosophila melanogaster (Fruit fly)

ABCB14 of 1247 aas and an MCMC domain arrangement. Transports malate and auxins (Lefèvre and Boutry 2018).

Viridiplantae, Streptophyta
ABCB14 of Arabidopsis thaliana (Mouse-ear cress)

ABCB15 of 1240 aas with a domain order of MCMC.

Viridiplantae, Streptophyta
ABCB15 of Arabidopsis thaliana (Mouse-ear cress)

P-glycoprotein, Pgp, ABCB1, of 1241 aas and 12 TMSs with a domain order MCMC.  Exports geraniol and other monoterpenes. Demissie et al. 2018 reported two structures of this homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that could be clearly visualized include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among transmembrane helices (TMSs) 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TMS1 and TMS3, a property that distinguishes multidrug transporters from floppases. These structural elements were proposed to participate in the mechanism of the transporter (Demissie et al. 2018).

Viridiplantae, Streptophyta
ABCB1 of Lavandula angustifolia

ABCB21 of 1296 aas and a domain order of MCMC. Transports auxins (Lefèvre and Boutry 2018).

Viridiplantae, Streptophyta
ABCB21 of Arabidopsis thaliana (Mouse-ear cress)

ABC protei, MDR1 of 1288 aas with 12 TMSs and a domain order of MCMC. Transports alkaloids (Lefèvre and Boutry 2018).

Viridiplantae, Streptophyta
MDR1 of Coptis japonica

Fusion protein with a complete ABC transporter (domain order MCMC) followed by a complete probable phosphate uptake transpoter, a member of the DASS family (TC# 2.A.47).  Many fusion proteins of this type are present in the NCBI protein database.

Fungi, Ascomycota
Fusion protein of Pochonia chlamydosporia

Multidrug resistance-1, Mdr1, of 1464 aas and 12 TMSs in a 6 +6 TMS arrangement (domain order: M-C-M-C).  Confers resistance to chloroquine (CQ) and primaquine (PQ), but mutations decrease resistance (Kittichai et al. 2018).

Mdr-1 of Plasmodium vivax

Serine protease/ABC transporter B family protein TagA of 1752 aas and 9 putative TMSs with one N-terminal TMS followed by a large hydrophilic region that may correspond to the protease domain, followed by 8 putative TMSs in a 2 + 2 + 2 + 2 TMS arrangement and the ATPase domain. It is required for general cell fate determination at the onset of development andis required for the specification of an initial population of prespore cells in which tagA is expressed. It is also required for normal SDF-2 signaling during spore encapsulation (Good et al. 2003; Cabral et al. 2006).

TagA of Dictyostelium discoideum (Slime mold)

ABC type B transporter of 1207 aas and 12 TMSs. ATP-dependent transporter genes are associated with cystic development (Bai et al. 2020).

Metazoa, Platyhelminthes
ABC transporter of Echinococcus granulosus (tape worm)

Multidrug resistance protein 1, MDR1, of 1475 aas and 12 TMSs in an M-C-M-C arrangement (Pimpat et al. 2020).

MDR1 of Plasmodium malariae

Probable MDR efflux pump of 1451 aas and 12 TMSs in a MCMC domain arrangement where each M domain has 6 TMSs.

Viridiplantae, Streptophyta
MDR exporter of Marchantia polymorpha (liverwort)

ATP-binding cassette transporter ABCB1, P-glycoprotein, MDR1, of 1339 aas and 12 TMSs. P-glycoprotein inhibitors differently affect Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti proliferation (Larrazabal et al. 2021). These organisms are all obligatory intracellular protozoan parasites, and of them, tariquidar treatment affected proliferation only of B. besnoiti (Larrazabal et al. 2021).

MDR1 of Besnoitia besnoiti

ABCB28 homolog of 732 aas and 6 N-terminal TMSs plus a C-terminal ATPase. It may play a role in the Cd2+ stress response, possibly by pumping Cd2+ out of the cell (Zhu et al. 2021).

Viridiplantae, Streptophyta
ABC homolog (M-C) of Digitaria exilis

Multidrug resistance protein homolog 49 of 542 aas and 6 or 7 N-terminal  TMSs (M-C). The sequence may be incomplete. Over-expression of the Mdr49-like transporter in the brown planthopper, Nilaparvata lugens, confers resistance to imidacloprid (Wang et al. 2021).

Metazoa, Arthropoda
Mdr49-like of Eumeta japonica, the brown planthopper

Active peptide/heavy metal cation exporter, MDR4 or ABCB4, of 1365 aas and 7 TMSs in a 1 + 2 + 2 + 2 TMS arrangement, followed by a large hydrophilic ATPase domain; it probably has an M-C domain order (Wunderlich 2022).

MDR4 of Plasmodium falciparum

Putative solute exporter of 925 aas and 7 TMSs in a 1 + 2 + 2 + 2 TMS arrangement.

Solute exporter of Plasmodium falciparum

MDR7, ABCB7 active peptide exporter of 1049 aas and 6 TMSs (Wunderlich 2022).

MDR7 of Plasmodium falciparum

The human ABCB5 exists in two forms (812 aas and 1257 aas). The latter full length protein confers resistance to taxanes and anthracyclines (Kawanobe et al., 2012). Resistance and transport were demonstrated for paclitaxel and docetaxel as well. It is present in a number of stem cells that acts as a regulator of cellular differentiation. It is able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug doxorubicin (Frank et al. 2005; Huang et al. 2004). It is specifically present in limbal stem cells, where it plays a key role in corneal development and repair (Frank et al. 2003).

Metazoa, Chordata
ABCB5 of Homo sapiens

Multidrug resistance protein 1, ABCB1, of 495 aas and 6 TMSs in a 2 + 2 + 2 TMS arrangement. This system confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance (Beesley et al. 2023).

Metazoa, Platyhelminthes
ABCB1 of Fasciola hepatica
3.A.1.202:  The Cystic Fibrosis Transmembrane Conductance Exporter (CFTR) Family (ABCC)

Cystic fibrosis transmembrane conductance regulator (CFTR) (also called ABCC7); cyclic AMP-dependent chloride channel; also catalyzes nucleotide (ATP-ADP)-dependent glutathione and glutathione-conjugate flux (Kogan et al., 2003) (may also activate inward rectifying K+ channels). The underlying mechanism by which ATP hydrolysis controls channel opening is described by Gadsby et al., 2006. The most common cause of cystic fibrosis (CF) is defective folding of a cystic fibrosis transmembrane conductance regulator (CFTR) mutant lacking Phe508 (DeltaF508) (Riordan, 2008). The DeltaF508 protein appears to be trapped in a prefolded state with incomplete packing of the transmembrane segments, a defect that can be repaired by direct interaction with correctors such as corr-4a, VRT-325, and VRT-532 (Wang et al., 2007). CFTR interacts directly with MRP4 (3.A.1.208.7) to control Cl- secretion (Li et al., 2007). It has intrinsic adenylate kinase activity that may be of functional importance (Randak and Welsh, 2007). The intact CFTR protein mediates ATPase rather than adenylate kinase activity (Ramjeesingh et al., 2008). Regulated by Na+/H+ exchange regulatory cofactors (NHERF; O14745; TC #8.A.24.1.1) (Seidler et al., 2009). Regulated by protein kinase A and C phosphorylation (Csanády et al., 2010). It is also activated by membrane stretch induced by negative pressures (Zhang et al., 2010). TMS6 plays roles in gating and permeation (Bai et al., 2010; 2011). The 3-D structure revealed the probable location of the channel gate (Rosenberg et al., 2011). Conformational changes opening the CFTR chloride channel pore, coupled to ATP-dependent gating, have been studied (Wang and Linsdell, 2012). Alternating access to the transmembrane domain of CFTR has been demonstrated (Wang and Linsdell, 2012). MRP4 and CFTR function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). An asymmetric hourglass, comprising a shallow outward-facing vestibule that tapers toward a narrow "bottleneck" linking the outer vestibule to a large inner cavity extending toward the cytoplasmic extent of the lipid bilayer has been proposed (Norimatsu et al., 2012). Small molecule CFTR potentiators and correctors that overcome the efects of deleterious mutations have been identified (Kym et al. 2018).  The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein-protein interactions in a complex network. Zhang et al. 2017 reviewed the macromolecular complex of CFTR, Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2; TC# 8.A.24.1.2), and lysophosphatidic acids (LPA) receptor 2 (LPA2; see TC# 9.A.14.2.5) at the apical plasma membrane of airway and gut epithelial cells.  The structure, gating and regulation of the CFTR anion channel has been reviewed (Csanády et al. 2019). Mutants impairing ion conductance giving rise to CF, are partially corrected using the drug ivacaftor, and the structure of CFTR bound to this drug, which keeps the channel open has been solved by cryoEM (Liu et al. 2019). The drug binds to a site with a hinge involved in channel gating. CFTR modulators reduce agonist-induced platelet activation and function; modulators, such as ivacaftor, present a promising therapeutic strategy for thrombocytopathies, including severe COVID-19 (Asmus et al. 2023). Chronic hypoxia reduces the activities of epithelial sodium and CFTR ion channels (Wong et al. 2023). CFTR function on ex vivo nasal epithelial cell models has been evaluated (Terlizzi et al. 2023). The therapeutic potential of phytochemicals for cystic fibrosis has been considered, and curcumin, genistein, and resveratrol have been shown to be effective.  These compounds  have beneficial effects on transporter function, transmembrane conductivity, and overall channel activity (Baharara et al. 2023). VX-661 and VX-445 exert effects on the plasma membrane expression of clinical CFTR variants (McKee et al. 2023). The Cl--transporting proteins CFTR, SLC26A9 (TC# 2.A.53.2.15), and anoctamins (ANO1; ANO6) (TC#s 1.A.17.1.1 and 1.4) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases in humans. Kunzelmann et al. 2023 reviewed electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Emphasis was placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. They summarize evidence indicating that CFTR is the only relevant secretory Cl- channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. The expressions of ANO1 and ANO6 are important for the correct expression and function of CFTR. The Cl- transporter, SLC26A9, expressed in the airways, may have a reabsorptive rather than a Cl--secretory function. In the renal collecting ducts, bicarbonate secretion occurs through the synergistic action of CFTR and the Cl-/HCO3- transporter SLC26A4 (pendrin; TC# 2.A.53.2.17), which is probably supported by ANO1. In autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease (Kunzelmann et al. 2023).  AlphaMissense pathogenicity predictions have been made against cystic fibrosis variants (McDonald et al. 2024). The selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads to a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer (Levring and Chen 2024). The structural basis for CFTR inhibition by CFTRinh-172 has been presented (Young et al. 2024). Fat malabsorption in cystic fibrosis pathophysiology of cystic fibrosis in the gastrointestinal tract may play a role in disease symptoms (McDonald et al. 2024).

Metazoa, Chordata
CFTR of Homo sapiens

CFTR, an epithelial ion channel, plays a role in the regulation of epithelial ion and water transport and fluid homeostasis (Bagnat et al. 2010; Navis et al. 2013; Navis and Bagnat 2015). It mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO3-; selectivity depends on the extracellular chloride concentration. CFTR exerts its function in part by modulating the activity of other ion channels and transporters, and it contributes to the regulation of the pH and the ion content of the epithelial fluid layer. It is required for normal fluid homeostasis in the gut (Bagnat et al. 2010) and for normal volume expansion of Kupffer's vesicle during embryonic development as well as for normal establishment of left-right body patterning (Navis et al. 2013; Roxo-Rosa et al. 2015). It is also required for normal resistance to infection by Pseudomonas aeruginosa (Phennicie et al. 2010).

Metazoa, Chordata
CFTR of Danio rerio (Zebrafish) (Brachydanio rerio)
3.A.1.203:  The Peroxysomal Fatty Acyl CoA Transporter (P-FAT) Family (ABCD)

Peroxisomal long chain fatty acyl (LCFA; especially branched chain fatty acids) transporter of 659 aas; associated with Zellweger Syndrome, ABCD3, PMP70, PXMP1.  Can form heterodimers with ABCD1/ALD and ABCD2/ALDR, but the transporter is perdominantly a homodimer (Hillebrand et al. 2007). Dimerization is necessary to form an active transporter. It interacts with PEX19.  abcd3-knockout mice accumulate bile acid precursors suggesting that Abcd3 imports these compounds as CoA derivatives into peroxisomes (Visser et al. 2007).  These mutants also accumulate pristanic acid suggesting that Abcd3 also imports branched chain substrates into peroxisomes (Sakamoto et al. 2019). The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity (Torres et al. 2019). Ceapins are aromatic compounds that specifically inhibit the UPR sensor ATF6alpha, an ER-tethered transcription factor, by retaining it at the ER. Ceapin's function is dependent on ABCD3. ABCD3 physically associates with ER-resident ATF6alpha in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6alpha to ABCD3's transmembrane regions without inhibiting or depending on ABCD3 transport activity (Torres et al. 2019).  Ceapins act through ABCD3 which binds to ATF6α. causing the ER to be tethered to the peroxysome, preventing ATF6α from carrying out its function as the unfolded protein response sensor (Torres et al. 2019).

Metazoa, Chordata
PMP70 of Homo sapiens

The peroxysomal long chain fatty acid (LCFA) half transporter, ABCD1 (ALD, ALDP, the X-linked adrenoleukodystrophy (X-ALD or ALDP) protein) (functions as a homodimer and accepts acyl-CoA esters (van Roermund et al. 2008)). It transports C24:0 and C26:0 fatty acids and their CoA-derivatives as substrates (van Roermund et al., 2011; Jia et al. 2022).  ABCD1 deficiency or mutation is associated with plasma and tissue elevation of C24:0 and C26:0 accompanied by demyelination and inflamation (Baarine et al. 2012).  X-ALD is a recessive neurodegenerative disorder that affects the brain's white matter and is associated with adrenal insufficiency. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues, especially in the cortex of the adrenal glands and the white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease or X-linked adrenoleukodystrophy (X-ALD) (Kallabi et al. 2013; Andreoletti et al. 2017) The system forms heterodimers with PMP70 (ABCD3; TC#3.A.1.203.1) (Hillebrand et al. 2007). X-ALD, the most common peroxisomal disorder, results from mutations in ABCD1 (ALDP) (Margoni et al. 2017). The structure and function of the ABCD1 variant database have been described (Mallack et al. 2022). This peroxisomal very long chain fatty acid (VLCFA) transporter is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairment including X-ALD. Le et al. 2022 presented cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP- dependent conformational spectrum. They identified features distinguishing ABCD1 from its closest homologs and showed that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. A transport mechanism was suggested in which the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations (Le et al. 2022). Three cryogenic EM structures of ABCD1: the apo-form, substrate- and ATP-bound forms have been solved (Chen et al. 2022). Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3'-phospho-ADP moiety of the CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrated snapshots of the ABCD1-mediated substrate transport cycle (Chen et al. 2022). Jia et al. 2022 reported the cryo-EM structure of human ALDP at 3.4 Å resolution. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette transporters, ALDP has two substrate binding cavities formed within the transmembrane domains. Such structural organization may be suitable for the coordination of VLCFAs. X-ALD is caused by a mutation in the ABCD1 gene, encoding a peroxisomal protein, which has various clinical manifestations and a rapid progression from initial symptoms to fatal inflammatory demyelination (Yu et al. 2022). Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter, ALDP, have appeared (Xiong et al. 2023).

Metazoa, Chordata
LCFA transporter ABCD1 of Homo sapiens

The BacA (Rv1819c) porter (selective for the uptake of bleomycin and antimicrobial peptides) (essential for maintenance of extended chronic infection) (Domenech et al., 2009).

BacA of Mycobacterium tuberculosis (M-C) (Q50614)

Peroxisomal importer, Comatose, of substrates for β-oxidation (transports fatty acids and precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) (Dietrich et al., 2009; Visser et al. 2007). The peroxisomal fatty acyl-CoA transporter, Comatose (CTS, ABCD1, ABCD1, ABCC1, PED3, Pxa1; 1337aas) (Nyathi et al., 2010) determines germination potential and fertility and is essential for acetate metabolism (Linka and Esser 2012).  It associates with long chain fatty acyl-CoA synthetases (LACS6 (Q8LPS1) and LACS7 (Q8LKS5) and has intrinsic acyl CoA thiesterase activity (De Marcos Lousa et al. 2013). It has been proposed that it transports and hydrolyzes acyl-CoA esters, releasing a non-esterified fatty acid into the peroxisomal matrix which then needs to be re-activated by peroxisomal LACS6 or LACS7 (Visser et al. 2007). Mutagenesis of three residues in TMS 9 differentially affected the ATPase and thioesterase activities (Carrier et al. 2019).

Viridiplantae, Streptophyta
Comatose of Arabidopsis thaliana (Q94FB9)

Peroxisomal long-chain fatty acid/oleic acid importer, PXA1 (Pat2)/PXA2 (Pat1) (Lamping et al., 2010; van Roermund et al., 2011).  PXA1 and PXA2 are two half-ABC transport subunits that can form a heterodimer. They are of 870 and 853 aas, respectively, both probably with 6 TMSs in a 1 + 2 + 2 + 1 TMS arrangement. Oxidation of its substrates requires the peroxysomal fatty acyl CoA ligase, suggesting that the free acids are the transported substrates.   

Fungi, Ascomycota
PXA1/PXA2 of Saccharomyces cerevisiae
PXA1 (MC) (P41909)
PXA2 (MC) (P34230)

Peroxisomal fatty acid transporter, ABCD2, ALD1, ALDL1, ALDR, or ALDRP. Transports C22:0 and different unsaturated very long-chain fatty acyl-CoA derivatives including C24:6 and especially C22:6 (van Roermund et al., 2011). The loss of AbcD2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1 (Lu et al. 2007). Based on the 2.85 Å resolution crystal structure of the mitochondrial ABC transporter, ABCB10, Andreoletti et al. 2017 proposed structural models for all three peroxisomal ABCD proteins. The model specifies the positions of the transmembrane and coupling helices and highlights functional motifs and putatively important amino acyl residues.

Metazoa, Chordata
ABCD2 (M-C) of Homo sapiens (Q9UBJ2)

Peroxisomal/chloroplast fatty acyl CoA transporter, ABCD2 (Linka and Esser 2012).

Viridiplantae, Streptophyta
ABCD2 of Arabidopsis thaliana

ABCD4, PMP70-related, P70R, PMP69 or PXMP1L of 606 aas.  Forms homo- and heterodimers.  May be involved in intracellular processing of vitamin B12 (cobalamin), possibly by playing a role in the lysosomal release of vitamin B12 into the cytoplasm.  Defects cause Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ), a disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2012).  The amino treminal region determines the subcellular localization of this and other ABC subfamily D proteins (Kashiwayama et al. 2009). Maybe involved in intracelluar processing of Vitamin D (Sakamoto et al. 2019).

Metazoa, Chordata
ABCD4 of Homo sapiens

Long chain fatty acid transporter consisting of a heterodimer of AbcD1 (719 aas) and AbcD2 (694 aas) (Xiong et al. 2010).

AbcD1/AbcD2 of Tetrahymena thermophila

Putative fatty acid exporter; homodimer (Moussatova et al. 2008).

YddA (M-C) of E. coli; 561 aas

ABC transporter, BclA, of 586 aas and 6 TMSs in a 2 + 2 + 2 arrangement in the N-terminus and the ABC domain in the C-terminus.  It is a peptide transprter required for bacteroid differentiation.  It catalyzes import of peptides called nodule-specific cysteine-rich (NCR) peptides in the symbiotic nodule cells which house the bacteroids. NCR peptides are related to antimicrobial peptides of innate immunity, but they induce the endosymbionts into a differentiated, enlarged, and polyploid state (Guefrachi et al. 2015). BclA is required for the formation of differentiated and functional bacteroids in the nodules of the NCR peptide-producing Aeschynomene legumes. BclA catalyzes import of NCR peptides and provides protection against the antimicrobial activity of these peptides. Moreover, BclA can complement the role of the related BacA transporter of Sinorhizobium meliloti, which has a similar symbiotic function in the interaction with Medicago legumes (Guefrachi et al. 2015).

BclA of Bradyrhizobium sp. ORS 285

Glycosomal ABC transporter of 683 aas and 6 N-terminal TMSs followed by the ATPase domain. Insertion into the glycosomal membrane is facilitated by the chaparone/receptor, Pex19 (Yernaux et al. 2006).

Glycosomal ABC half transporter of Trypanosoma brucei

Glycosomal ABC transporter of 641 aas and 6 N-terminal TMSs followed by the ATPase domain. Insertion into the glycosomal membrane is facilitated by the chaparone/receptor, Pex19 (Yernaux et al. 2006).

ABC half transporter of Trypanosoma brucei

ABCD1 transporter of 766 aas and 6 TMSs. Similar to human patients with X-linked adrenoleukodystrophy (ALD), zebrafish abcd1 mutants have elevated very long chain fatty acid levels, and CNS development was disrupted, with hypomyelination in the spinal cord, abnormal patterning, decreased numbers of oligodendrocytes, and impaired motor function followed by increased cell death (Strachan et al. 2017). Expression of human ABCD1 in zebrafish oligodendrocytes rescued apoptosis in the abcd1 mutant (Strachan et al. 2017).

Metazoa, Chordata
ABCD1 of Danio rerio (Zebrafish) (Brachydanio rerio)
3.A.1.204:  The Eye Pigment Precursor Transporter (EPP) Family (ABCG)

Eye pigment precursor transporter, White.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. White dimerize with Brown for the transport of guanine. The Scarlet (TC# 3.A.1.204.17) and White complex transports a metabolic intermediate (such as 3-hydroxy kynurenine) from the cytoplasm into the pigment granules (Mackenzie et al. 2000).  The White and Scarlet proteins are located in the membranes of pigment granules within pigment cells and retinula cells of the compound eye.  Somatic knockouts of white in the noctuid moth, Helicoverpa armigera block pigmentation of the egg, first instar larva and adult eye, but germ-line knockouts of white are recessive lethal in the embryo (Khan et al. 2017).

Metazoa, Arthropoda
White of Drosophila melanogaster

Drug resistance transporter, ABCG2 (MXR; ABCP; BCRP) (human breast cancer resistance protein, BCRP) (Moitra et al., 2011). It exports urate and haem in haempoietic cells (Latunde-Dada et al., 2006) as well as cytotoxic agents (mitoxantrone, flavopiridol, methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, topotecan, rosurvastatin, and resveratrol), fluorescent dyes (Hoechst 33342) and other toxic substances (PhIP and pheophorbide a) (Özvegy-Laczka et al., 2005; Nigam 2015). It also transports folate and sterols: estradiol, and probably cholesterol, progesterone, testosterone and tamoxifen (Janvilisri et al., 2003; Breedveld et al., 2007). It is a homotetramer (Xu et al., 2004). It forms a homodimer bound via a disulfide bond at Cys-603 which stabilizes the protein against ubiquitin-mediated degradation in proteosomes (Wakabayashi et al., 2007), and can for dodecamers with 12 subunits (Xu et al. 2007). It has 6 established TMSs with the N- and C- termini inside (Wang et al., 2008). The following drugs are exported from human breast cancer cell line MCF-7: miloxantrone, daunorubicin, doxorubicin and rhodamine123). Also transports reduced folates and mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). It is an active glutathione efflux pump (Brechbuhl et al., 2010). Mutations in ABCG2 cause hyperuricemia and gout , which led to the identification of urate as a physiological subsrate for ABCG2; it catalyzes elimination of urate across the renal tubular apical membrane (Prestin et al. 2014). Zafirlukast antagonizes ABCG2 multidrug resistance (Sun et al., 2012). Inhibited by Sildenafil (Shi et al., 2011) and lapatinib derivatives (Sodani et al., 2012).  Mutation of basic residues can increase or decrease drug efflux activities (Cai et al. 2010).  A substrate of ABCG2 is d-luciferin, allowing bioluminescent immaging of drug efflux across the blood-brain barrier.  Inhibitors include Ko143, gefetinib and nilotinib (Bakhsheshian et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  Telabinib reverses chemotheraputic MDR mediated by ABCG2 (Sodani et al. 2014).  Residues involved in protein trafficking and drug transport activity have been identified (Haider et al. 2015).  The 3-d structure in the inward facing conformation has been solved (Rosenberg et al. 2015). Durmus et al. 2015 and Westover and Li 2015 have reviewed BCRP-mediated transport of cancer chemotheraputic agents.  A role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux has been proposed (Macalou et al. 2015).  Functions at the blood:placenta barrier of the mouse (Kumar et al. 2016). The Q141K variant exhibits decreased functional expression and thus increased drug accumulation and decreased urate secretion, and the R482 position, which plays a role the substrate specificity, is located in one of the substrate binding pockets (László et al. 2016). Naturally occurring single nucleotide polymorphisms in humans giving rise to amino acyl residue substitutions in the transmembrane domains result in impared transport of Lucifer Yellow and estrone sulfate (Sjöstedt et al. 2017). A cryoEM structure revealed two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between TMSs. A multidrug recognition and transport mechanism was proposed, and disease-causing single nucleotide polymorphisms were rationalized. The structural basis of cholesterol recognition by G-subfamily ABC transporters was also revealed (Taylor et al. 2017). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017). Penylheteroaryl-phenylamide scaffold allows ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a highest potency (IC50=61nM)), selectivity, low intrinsic toxicity, and it reversed the ABCG2-mediated drug resistance at 0.1muM (Köhler et al. 2018). ABCG2 acts in concert with ABCA1, ABCB1 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). Inhibited by dacomitinib (Fan et al. 2018). A specific inhibitor, CCTA-1523, is a potent, selective and reversible modulator of ABCG2 (Patel et al. 2017). Exports uric acid (urate), and its loss promotes onset of hyperuricemia.  It has potential as a regulator of Gout (Fujita and Ichida 2018). High resolution cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar have been solved (Jackson et al. 2018). Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the TMSs (Jackson et al. 2018). Multiple drug binding pockets and residues involved in binding have been identified (Cox et al. 2018). The third transmembrane helix and adjacent regions of ABCG2 may interact with AT1 receptor antagonists, giving rise to drug-drug interactions in multi-drug regimens (Ripperger et al. 2018). The system is inhibitied by hetero aryl phenyl inhititors (Köhler et al. 2018). It is present in the blood-brain, blood-testis and maternal-fetal barriers, and cryoEM of a mutant shows the protein in a substrate-bound pre-translocation state and an ATP-bound post-translocation state (Manolaridis et al. 2018). A single molecule of estrone-3-sulfate (E1S) is bound in a central, hydrophobic, cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains (Manolaridis et al. 2018). This shows how the energy of ATP binding extrudes E1S and other substrates, and suggests that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors. Its structure, mechanism and inhibitory propensity have been reviewed (Kapoor et al. 2018). Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance (Zhao et al. 2018). ABCG2 confers resistance to several cancer treatments. Photodynamic therapy (PDT) is an anti-cancer method involving the use of light-activated photosensitisers to induce oxidative stress and cell death in cancers, but ABCG2 can efflux photosensitisers (Khot et al. 2019). Regorafenib sensitized MDR colon cancer cells to BCRP substrates by increasing  intracellular accumulation without changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Regorafenib stimulates BCRP ATPase activity and promotes a stable interaction between regorafenib and the transmembrane domain of BCRP (Zhang et al. 2019). Several potent inhibitors, effective in the millimicromolar range have been identified (Zou et al. 2020). Licochalcone A selectively resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs (Wu et al. 2020). The GXXXG motif promotes proper packing of the TMSs in the functional ABCG2 homodimer (Polgar et al. 2004). Molecular dynamics simulations have provided insight into the steps of the substrate transport process and its regulation by cholesterol (Nagy et al. 2020). Drug binding cavities other than the central binding site as well as a putative dynamic transport pathway for substrates with variable structures have been revealed. Membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion (Nagy et al. 2020). The first intracellular loop is essential for the catalytic cycle (Khunweeraphong and Kuchler 2020). While all other human ABCG transporters are specific for lipids, ABCG2 has a network of residues that may confer extra conformational flexibility, enabling it to transport a wider array of substrates (Mitchell-White et al. 2021). VKNG-1, an inhibitor of ABCG2, may, in combination with certain anticancer drugs, provide a treatment to overcome ABCG2-mediated MDR colon cancers (Narayanan et al. 2021). Sophoraflavanone (SFG) may be  an effective inhibitor of ABCG2 to improve the efficacy of therapeutic drugs in patients with advanced non-small-cell lung cancer (NSCLC) (Wu et al. 2021). It transports estrone 3-sulfate and many drugs (Dudas et al. 2022). ZIn both domestic and nondomestic cats (felids) have mutationally alterred ABCG2 proteins and consequently experience fluoroquinolone-induced retinal phototoxicity (Gochenauer et al. 2022). The multifunctionality of ABCG2 has been established, and details of the potential therapeutic role of ABCG2 in pan-cancer has been considered (Lyu et al. 2022). ABCB6, ABCG2, FECH and CPOX are expressed in meningioma tissue (Spille et al. 2023). ABCG2 limits the efficacy of transcriptional CDK inhibitors, and multiple kinase inhibitors disrupt ABCG2 transport function, thereby synergizing with CDK inhibitors (van der Noord et al. 2023). The efflux of anti-psychotics through the blood-brain barrier (BBB) via this system has been demonstrated (Nasyrova et al. 2023). The structural basis of the allosteric inhibition of human ABCG2 by nanobodies has been determined (Irobalieva et al. 2023).  Imperatorin restores chemosensitivity of multidrug-resistant cancer cells by antagonizing ABCG2-mediated drug transport (Wu et al. 2023).  ABCG2 may be a molecular target for acute myeloid leukemia (Damiani and Tiribelli 2024).

Metazoa, Chordata
ABCG2 (ABCP) of Homo sapiens (Q9UNQ0)

Putative ABC Transporter WHT-1

Metazoa, Nematoda
WHT-1 of Caenorhabditis elegans (Q11180)

The plant cuticular wax and/or lipid metabolite exporter, CER5; ABCG12; WBC12 (in the plasma membrane of epidermal cells; secretes wax to the plant surface) (Pighin et al., 2004; Panikashvili and Aharoni 2008Panikashvili and Aharoni 2008).

Viridiplantae, Streptophyta
CER5 (C-M) of Arabidopsis thaliana (Q9C8K2)

The ABCG5 (sterolin-1)/ABCG8 (sterolin-2) heterodimeric neutral sterol (cholesterol and plant sterols) (e.g., sitosterol and lutein) (phosphoryl donors ATP > CTP > GTP > UTP) exporter; present in the apical membranes of enterocytes and hepatocytes ((Reboul 2013). Cholesteryl oleate, phosphatidyl choline and enantiomeric cholesterol are poorly transported (mutation of either ABCG5 or ABCG8 cause sitosterolemia and coronary atherosclerosis) (Zhang et al., 2006; Wang et al., 2006; 2011). It is involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols as well as the drug, Marinobufagenin, a Na+/K+-ATPase inhibitor, in the liver and intestine (Lan et al. 2018). Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Lee et al. 2016 used crystallization in lipid bilayers to determine the X-ray structure in a nucleotide-free state at 3.9 Å resolution. The structure revealed a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter (Lee et al. 2016). High expression levels of both ABCG5 and ABCG8 were observed in liver, the digestive tract and the mammary gland. The system plays roles in lipid and sterol intestinal absorption, biliary excretion, and lipid trafficking and excretion during lactation (Viturro et al. 2006). ABCG5/G8 is active in the excretion of cholesterol and sterols into bile (vanBerge-Henegouwen et al. 2004). Disruption of the unique ABCG-family NBD:NBD interface impacts both drug transport and ATP hydrolysis (Kapoor et al. 2020). Transmembrane polar relay drives the allosteric regulation for the ABCG5/G8 sterol transporter (Xavier et al. 2020). Rare mutations can give rise to tendon xanthoma along with tendosynovitis (Wadsack et al. 2018). ABCG5/8 mediates secretion of neutral sterols into bile and the gut lumen, whereas G1 (TC# 3.A.1.204.12) transports cholesterol from macrophages to high-density lipoproteins (HDLs). Cryo-EM structures of human G5G8 in sterol-bound and human G1 in cholesterol- and ATP-bound states have been solved. Both transporters have a sterol-binding site that is accessible from the cytosolic leaflet. A second site is present midway through the transmembrane domains of ABCG5/G8. The Walker A motif of G8 adopts a unique conformation that accounts for the marked asymmetry in ATPase activities between the two nucleotide-binding sites of G5G8 (Sun et al. 2021). Residues have been mapped to the structural cores of TMSs), the NBD-TMD interface, and the interface between TMDs. They serve as sequence signatures to differentiate ABCG5/ABCG8 from other ABCG subfamily proteins, and some of them may contribute to substrate specificity of the ABCG5/ABCG8 transporter (Pei and Cong 2022). Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8 have been reported (Farhat et al. 2022). ABCG5/G8 gene region variants exert differential effects on lipid profiles, blood pressure status, and gallstone disease history (Teng et al. 2023).

Metazoa, Chordata
ABCG5/ABCG8 of Homo sapiens
ABCG5 (Q9H222)
ABCG8 (Q9H221)

The efflux porter for phosphatidylcholine and its analogues as well as toxic alkyl phospholipids, ABCG4 (Castanys-Munoz et al., 2007). Also promotes cholesterol efflux to the mature forms of HDL (HDL2 and HDL3) (Voloshyna and Reiss, 2011).

ABCG4 of Leishmania infantum (A4HWI7)

Multidrug resistance efflux pump, AbcG6, causes camptothecin-resistant parasites (Bosedasgupta et al., 2008)

AbcG6 of Leishmania donovani (A8WEV1)

The epidermal plasma membrane cuticular lipid (wax) exporters, ABCG11/ABCG11 and ABCG11/ABCG12; ABCG11 is also called Wbc11; Desperado (DSO); COF1; PEL1. ABCG12 is also called CER5, WBC12 and D3 (Panikashvili and Aharoni 2008).  Required for the cuticle and pollen coat development by controlling cutin and possibly wax transport to the extracellular matrix. Involved in developmental plasticity and stress responses (Bird et al. 2007).  ABCG11 can traffic to the plasma membrane in the absence of ABCG12 and can form flexible dimers. By contrast, ABCG12 was retained in the endoplasmic reticulum in the absence of ABCG11, indicating that ABCG12 can only form dimers with ABCG11 in the plasm membrane of epidermal cells. Some ABCG proteins may be promiscuous, having multiple partnerships, while others may form obligate heterodimers for specialized functions (McFarlane et al. 2010).

ABCG11 of Arabidopsis thaliana

The putative multidrug/pigment exporter, Adp1 (Lamping et al., 2010)

Fungi, Ascomycota
Adp1 (C-M) of Saccharomyces cerevisiae (P25371)

AbcH homologue

Metazoa, Nematoda
AbcH homologue of Caernorhabditis elegans (Q18900)

AbcG Homologue

AbcG of Physcomitrella patens (A9SCA8) 

The intracellular sterol transporter, ABCG1 (Tarling and Edwards, 2011). Involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). Promotes cholesterol efflux from macrophages and other cells to the mature forms of HDL (HDL2 and HDL3) (Voloshyna and Reiss, 2011).  Plays a role in arteriosclerosis (Münch et al. 2012).  The diverse functions in various cell types have been reviewed by Tarling (2013).  Many mammals have two isoforms, long and short, but mice have only the short isoform (Burns et al. 2013).  Residues have been identified that play roles in stability, oligomerization and trafficking (Wang et al. 2013).  Both the full-length and the short isoforms of ABCG1 can dimerize with ABCG4 (3.A.1.204.20) (Hegyi and Homolya 2016). Cholesterol-binding motifs in the membrane may allow transport of different cholesterol pools (Dergunov et al. 2018). It is required for maintenance of cellular cholesterol levels (Sun et al. 2021). It plays a role in the occurrance of some lipids and protein in HDL such as 7-ketocholesterol and some essential proteins such as alpha-1-antitrypsin, apoA-4, apoB-100, and serum amyloid A (SAA) (Wu et al. 2022). ABCG1-mediated cholesterol efflux influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis (Karpouzas et al. 2023).

Metazoa, Chordata
ABCG1 of Homo sapiens (P45844)

The ABCG1 transporter homologue 

ABCG1 of Dictyostelium discoideum (Q55DW4)

ABC transporter-like protein ECU11_1340

Fungi, Microsporidia
ECU11_1340 of Encephalitozoon cuniculi

MDR efflux pump, ABCG2a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Metazoa, Echinodermata
ABCG2a of Stronglycentrotus purpuratus

Half ABC transporter, ABCG10.  Secretes isoflavinoids including precursors of the phytoalexin, medicarpin (Banasiak et al. 2013). GmABCG5, an ATP-binding cassette G transporter, is involved in the iron deficiency response in soybean (Wang et al. 2023).

Viridiplantae, Streptophyta
ABCG10 of Medicago truncatula

Scarlet.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. The scarlet and white (TC# 3.A.1.204.1) complex probably transports a metabolic intermediate (such as 3-hydroxy kynurenine) from the cytoplasm into the pigment granules (Tearle et al. 1989). These proteins are located in the membranes of pigment granules within pigment cells and retinula cells of the compound eye (Mackenzie et al. 2000). Knockouts of scarlet in the noctuid moth, Helicoverpa armigera, are viable and produce pigmentless first instar larvae and yellow adult eyes lacking xanthommatin (Khan et al. 2017).

Metazoa, Arthropoda
Scarlet of Drosophila melanogaster

Brown.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. Brown and white (TC# 3.A.1.204.1) dimerize for the transport of guanine (Campbell and Nash 2001).  Knockouts of brown in the noctuid moth, Helicoverpa armigera, show no phenotypic effects on viability or pigmentation (Khan et al. 2017).

Metazoa, Arthropoda
Brown of Drosophila melanogaster

ABC transporter G family member 3, ABCG3; ABCG.3. Also called the white-brown complex homologue protein 3, WBC3, of 730 aas. It is a homologue of animal eye pigment precursor uptake porters.  The white, scarlet (TC# 3.A.1.204.17), and brown (3.A.1.204.18) genes of Drosophila melanogaster encode ABC transporter proteins involved with the uptake and storage of metabolic precursors to the red and brown eye colour pigments (Mackenzie et al. 2000). It may also transport sesquiterpenes, defensive agents or pheromones. (Lefèvre and Boutry 2018). Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters (Pakuła et al. 2023). See also, Salgado et al. 2023.

Viridiplantae, Streptophyta
ABCG3 of Arabidopsis thaliana

ATP-binding cassette sub-family G member 4, ABCG4, half transporter of 646 aas.  ABCG4 can form homodimers, but also heterodimers with its closest relative, ABCG1. Both the full-length and the short isoforms of ABCG1 can dimerize with ABCG4, whereas the ABCG2 multidrug transporter is unable to form a heterodimer with ABCG4 (Hegyi and Homolya 2016). ABCG4 is predominantly localized to the plasma membrane. AbcG4 acts in concert with ABCA1, ABCB1 and ABCG2 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). It is involved in macrophage lipid homeostasis (Sakamoto et al. 2019).

Metazoa, Chordata
ABCG4 of Homo sapiens

Pigment precursor transporter of 644 aas, Ok. In the noctuid moth, Helicoverpa armigera, Ok transports precursors from the cytoplasm into the pigment granules. Knockouts of Ok are viable and produce translucent larval cuticle and black eyes (Khan et al. 2017).

Metazoa, Arthropoda
Ok of Bombyx mori

Root heterodimeric half ABCG subfamily lipid  exporter, STR (817 aas)/STR2 (727 aas). Each protein has an ATPase domain followed by a 6 TMS membrane domain.  Exports lipids made from RAM2 (glycerol-3-phosphate acyltransferase)-catalyzed monoacylglycerols, allowing accumulation of extracellular lipids, possibly 2-monopalmitin (Luginbuehl et al. 2017).  Found in the peri-arbuscular membrane and required for colonization by mutualistic mycorrhizal and parasitic fungi (Jiang et al. 2017). Arbuscular mycorrhizal (AM) fungi facilitate plant uptake of mineral nutrients and obtain organic nutrients such as sugars and fatty acids, from the plant, and this ABCG transporter is required to form the symbiosis. Co-overexpressing STR and STR2 led to higher accumulation of extracelular unstaurated lipid polyesters such as cutin monomers (Jiang et al. 2017).

Viridiplantae, Streptophyta
STR/STR2 of Medicago truncatula (Barrel medic) (Medicago tribuloides)

Homo dimeric plasma membrane AbcG1 half ABC transporter of 633 aas and 6 TMSs.  Actively exports volatile organic compounds (Benzenoids and phenylpropanoids such as methylbenzoate and benzyl alcohol, major VOC constituents emitted by flowers) from the flower cell cytoplasm to the external environment (Adebesin et al. 2017).  May also export alcohol glycosides.  Up regulated 100-fold in petunia flowers within the 24 hour period between bud and flower opening stages. Regulated by the ODORANT1 transcription factor (Adebesin et al. 2017).

Viridiplantae, Streptophyta
AbcG1 of Petunia hybrida

Wax precursor (cuticular lipid) exporter of 678 aas and 6 TMSs, AbcG13 (Adebesin et al. 2017).

Viridiplantae, Streptophyta
AbcG13 of Arabidopsis thaliana

ABCG6 of 546 aas and 4 TMSs involved in phosholipid trafficing and drug export in Leishmania tarentolae (Gonzalez-Lobato et al. 2016).

ABCG6 of Trypanosoma grayi (C-M)

ABC transporter G family member 26, ABCG.26; AtABCG26 of 685 aas and 6 TMSs. Putative white-brown complex homolog protein 27.  May function in vacuolar arsenic accumulation with potential for bioremediation (Potdukhe et al. 2018).

Viridiplantae, Streptophyta
ABCG26 (C-M) of Arabidopsis thaliana (Mouse-ear cress)

Multidrug resistancd protein, ABCG19 (Wbc19), of 725 aas and 6 TMSs with a domain order C-M. Confers resistance to kanamycin (Mentewab and Stewart 2005).

Viridiplantae, Streptophyta
ABCG19 of Arabidopsis thaliana (Mouse-ear cress)

ABCG25 of 662 aas and 6 TMSs in a C-M domain arrangement.  Transports abscisic acid, ABA, a plant hormone that influences developmental processes, including seed and bud dormancy, the control of organ size and stomatal closure (Lefèvre and Boutry 2018). Strigolactones promote the localisation of the ABA exporter ABCG25 at the plasma membrane in root epidermal cells of Arabidopsis thaliana (Russo et al. 2023).  Thus, a mechanism for ABA homeostasis regulation is proposed in the context of osmotic stress acclimation: the fine tuning by strigolactones of ABCG25 localisation in root cells (Russo et al. 2023).  The cryo-EM structure and molecular mechanism used by the abscisic acid transporter, ABCG25, which regulates stomatal closure, seed germination and development, has been described (Huang et al. 2023). It was solved in an inward-facing apo conformation, an ABA-bound pre-translocation conformation and an outward-facing occluded conformation. A 'gate-flipper' translocation model was proposed (Huang et al. 2023). The structural basis for abscisic acid efflux mediated by ABCG25 in Arabidopsis thaliana has been described (Ying et al. 2023; Huang et al. 2023).

Viridiplantae, Streptophyta
ABCG25 of Arabidopsis thaliana (Mouse-ear cress)

ABCG14 of 648 aas and 6 TMSs in a C + M domain arrangement.  May transport cytokinins (Lefèvre and Boutry 2018).

Viridiplantae, Streptophyta
ABCG14 of Arabidopsis thaliana (Mouse-ear cress)

ABCG16 of 736 aas and 6 TMSs in a C-M domain arrangement.  Transports jasmonic acid (Lefèvre and Boutry 2018).

Viridiplantae, Streptophyta
ABCG16 of Arabidopsis thaliana (Mouse-ear cress)

ABCG6 of 727 aas and 6 TMSs in a CM domain arrangement. This transporter is an ABCG half-transporters that is required for synthesis of an effective suberin barrier in roots and seed coats, while ABCG2 and ABCG20 may serve the same function (Yadav et al. 2014).  Seed coats of abcg2 abcg6 abcg20 triple mutant plants had increased permeability to tetrazolium red and decreased suberin content. The root system of triple mutant plants was more permeable to water and salts in a zone complementary to that affected by the Casparian strip. Suberin of mutant roots and seed coats had distorted lamellar structure and reduced proportions of aliphatic components. Root wax from the mutant was deficient in alkylhydroxycinnamate esters (Yadav et al. 2014).

Viridiplantae, Streptophyta
ABCG6 of Arabidopsis thaliana (Mouse-ear cress)

ABC exporter, ABCG1 of 415 aas and 3 C-terminal TMSs.  This sequence may be incomplete, being C-terminally truncated. The protein is necessary of microsporidal infections in the midguts of silkworms (He et al. 2018).

Fungi, Microsporidia
ABCG1 of Nosema bombycis

Uncharacterized ABC transporter-like protein of 640 aas with a C-terminal membrane domain with 8 putative TMSs in a 2 + 5 + 1 TMS arrangement. This protein is a full length homologue of 3.A.1.204.32 which is C-terminally truncacted. Potential ABCG pigment transporter genes in the swallowtail butterfly, Papilio xuthus, and they control different aspects of body, but not wing, pigmentation (Liu et al. 2021).

Metazoa, Arthropoda
UP of Papilio xuthus (Asian swallowtail)

Uncharacterized membrane protein of 324 aas with 6 - 8 TMSs with homology to the membrane parts of the proteins listed under TC#s 3.A.1.204.32 and .33. 

Fungi, Microsporidia
UP of Nosema pernyi

Uncharacterized membrane protein of 389 aas of 7 - 8 TMSs, homologous to the membrane parts of TC#s 3.A.1.204.32, 33, and 34.

Fungi, Microsporidia
UP of Nosema bombycis

AbcG4 of 549 aas and 6 C-terminal TMSs (domain order C-M).  Insecticides, including permethrin and other pyrethroids, are exported by ABCG4, which is also up-regulated in response to insecticide treatments (Negri et al. 2019).

Metazoa, Arthropoda
AbcG4 of Anopheles stephensi (a mosquito malaria vector)

ABC transporter, White, of 685 aas and 6 C-terminal TMSs.  Loss gave rise to the white phenotype in embryonic eye pigmentation (Sumitani et al. 2005).

Metazoa, Arthropoda
White of Athalia rosae (Turnip sawfly)

ABC transporter (exporter) of 1109 aas and 7 - 9 TMSs in a 1 + 1 or 2 + 5 or 6 TMS arrangement. It is a phytohormone transporter. Reduction of its gene expression level was linked to the dwarfing phenotype in apple rootstocks. MdABCG28 overexpression promoted shoot growth of atabcg14 mutants (Feng et al. 2019). It is upregulated by low temperature in the pigeon pea (Cajanus cajan) (Niu et al. 2021).


Viridiplantae, Streptophyta
ABCG28 of Malus domestica

ABCG2/BCRP1 porter of 656 aas and 6 C-terminal TMSs in a 2 + 3 + 1 TMS arrangement. Expression and regulation by sex steroids in the Harderian gland of the Syrian hamster has been demonstrated (Mares et al. 2019). It may be involved in protoporphyrin IX transport and of other intermediates in heme biosynthesis.  This protein is 82% identical to the human otholog (TC# 3.A.1.204.2).

Metazoa, Chordata
ABCG2 of Mesocricetus auratus

ABC type G exporter of 961 aas and 8 TMSs in a 1 + 6 + 1 TMS arrangement.  Expression of ATP-dependent transporter genes is induced during larval cyst development in protoscoleces (Bai et al. 2020).

Metazoa, Platyhelminthes
ABCG transporter of Echinococcus granulosus.

ABCG7 of 725 aas and 6 C-terminal TMSs. This protein is upregulated by drought in pigeon pea (Cajanus cajan) (Niu et al. 2021).

Viridiplantae, Streptophyta
ABCG7 of Arabidopsis thaliana (Mouse-ear cress)

ABC transporter G family member 10, ABCG10, of 590 aas and 6 C-terminal TMSs.  In Medicago truncatula, the ortholog transports 4-coumarate and liquiritigenin, representing key branching points in the phenylpropanoid pathway, and possibly  other lignin-derived aromatic compounds such as the phenylpropanoid-derived phytoalexin (Biala et al. 2017).

Viridiplantae, Streptophyta
ABCG10 (C-M) of Arabidopsis thaliana (Mouse-ear cress)

ABCG! or ABCG2 of 660 aas and 6 C-terminal TMSs (C-M domain order). It may be a cell metabolite exporter (Wunderlich 2022).

ABCG1 of Plasmodium falciparum

Drug resistance ABC exporter, NpABC2, of 1092 aas and 8 - 10 TMSs in a 1 (N-terminus) + 1 + 6 - 8 TMS (C-terminus) arrangement. NpABC2 plays a role in the drug resistance of N. parvum and affects its virulence (Chen et al. 2022).

Fungi, Ascomycota
NpABC2 of Botryosphaeria parva (strain UCR-NP2) (Grapevine canker fungus) (Neofusicoccum parvum)
3.A.1.205:  The Pleiotropic Drug Resistance (PDR) Family (ABCG)

Pleiotropic drug resistance (PDR; Pdr5) exporter; steroid exporter; sporidesmin toxicity suppressor (Sts1); MDR; cyclic nucleotide exporter; amphipathic anion exporter. Its ATPase activity is inhibited by its substrate, clotrimazole; can use ATP, GTP and maybe UTP to drive efflux (Golin et al., 2007).  Molecular modeling revealed aspects of the binding pocket and mechanism of action (Rutledge et al. 2011).  Charged residues at the end of TMS2 affect transport (Dou et al. 2016). The 23-membered-ring macrolide tacrolimus, a commonly used immunosuppressant, also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate, and mutations that minimize its export have been isolated (Tanabe et al. 2018). An A666G mutation in TMS 5 of Pdr5 increases drug efflux by enhancing cooperativity between transport sites (Arya et al. 2019). Mutations in Pdr5 give rise to altered drug specificity (Tutulan-Cunita et al. 2005). Batzelladine D and norbatzelladine L reverse the fluconazole resistance phenotype mediated by Pdr5p. Both alkaloids were able to chemosensitize the Pdr5p-overexpressing strain by synergistic interaction with fluconazole, and both compounds also showed an inhibitory effect on the catalytic activity and on the intracellular accumulation of rhodamine 6G, but did not show significant in vitro mammalian cells toxicity (Domingos et al. 2020). The mechanism involves a "flippase" step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux (Raschka et al. 2022). The gating region residues of Pdr5, and possibly other ABCG transporters, play a role not only in molecular gating but also in allosteric regulation, conformational switching, and protein folding (Alhumaidi et al. 2022). Banerjee et al. 2023 reported a comprehensive overview of the structural and functional aspects of catalytically asymmetric ABC pumps such as members of the yeast PDR subfamily.

Fungi, Ascomycota
Pdr5 (Sts1; Ydr1) (C-M-C-M) of Saccharomyces cerevisiae (P33302)

Drug/Sterol/Mutagen exporter, Snq2p
Fungi, Ascomycota
Snq2p of Saccharomyces cerevisiae (P32568)

Weak acid exporter, Pdr12p (exports preservative anions including propionate, sorbate and benzoate) (Mollapour et al., 2008)
Fungi, Ascomycota
Pdr12p of Saccharomyces cerevisiae (Q02785)

Multidrug resistance protein, Cdr1 (Candida drug resistance 1) of 1501 aas and 14 TMSs in a CMCM arrangement with each M domain having 7 TMSs in a 6 + 1 TMS arrangement. It confers resistance to cycloheximide, xenobiotics and antifungal agents such as azoles and terbinafine (Holmes et al., 2006; Schuetzer-Muehlbauer et al., 2003); also, transports phospholipids (Shukla et al., 2007). It is the major fluconazole efflux system in fluconazole-resistant C. albicans (Holmes et al., 2008; Basso et al., 2010). Substitution of threonine-1351 results in hypersusceptibility to antifungal agents and threonine-1351 is essential for synergic effects of calcineurin inhibitor FK520 (Shukla et al. 2004). It is similar to Cdr2. For additional details of both systems, as well as other MDR pumps in various Candida species, see Cannon et al., 1998. Chimeras between Cdr1 and Cdr2 revealed