2.A.66 The Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily

The MOP flippase superfamily includes eight distantly related families, five for which functional data are available: One ubiquitous family (MATE) specific for drugs, one (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes, one (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes, one (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84, and one (MVI) of unknown transport function. The OLF family is found in the endoplasmic reticular membranes of eukaryotes. All functionally characterized members of the MOP superfamily catalyze efflux of their substrates, presumably by cation antiport.


2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family

The MATE family includes a functionally characterized multidrug efflux system from Vibrio parahaemolyticus NorM, and several homologues from other closely related bacteria that function by a drug:Na+ antiport mechanism, a putative ethionine resistance protein of Saccharomyces cerevisiae, a cationic drug efflux pump in A. thaliana and the functionally uncharacterized DNA damage-inducible protein F (DinF) of E. coli. The bacterial proteins are of about 450 amino acyl residues in length and exhibit 12 putative TMS. They arose by an internal gene duplication event from a primordial 6 TMS encoding genetic element. The yeast proteins are larger (up to about 700 residues) and exhibit about 12 TMSs.

Human MATE1 (hMATE1) is an electroneutral H+/organic cation (OC) exchanger responsible for the final excretion step of structurally unrelated toxic organic cations in kidney and liver. Glu273, Glu278, Glu300 and Glu389 are conserved in the transmembrane regions. Substitution with alanine or aspartate reduced export of tetraethylammonium (TEA) and cimetidine, and several had altered substrate affinities (Matsumoto et al., 2008). Thus, all of these glutamate residues are involved in binding and/or transport of TEA and cimetidine, but their roles are different.

The family includes hundreds of functionally uncharacterized but sequenced homologues from bacteria, archaea, and all eukaryotic kingdoms (Kuroda and Tsuchiya, 2009). A comprehensive review of the classes of efflux pump inhibitors from various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors has appeared (Durães et al. 2018).

The probable transport reaction catalyzed by NorM, and possibly by other proteins of the MATE family is:

Antimicrobial (in) + nNa+ (out) → Antimicrobial (out) + nNa+ (in).


2.A.66.2 The Polysaccharide Transport (PST) Family

The protein members of the PST family are generally of 400-500 amino acyl residues in size and traverse the membrane as putative α-helical spanners twelve times. Analyses conducted in 1997 showed that they formed two major clusters. One is concerned with lipopolysaccharide O-antigen (undecaprenol pyrophosphate-linked O-antigen repeat unit) export (flipping from the cytoplasmic side to the periplasmic side of the inner membranes) in Gram-negative bacteria. On the periplasmic side, polymerization occurs catalyzed by Wzy. The other is concerned with exopolysaccharide or capsular polysaccharide export in both Gram-negative and Gram-positive bacteria. However, arachaeal and eukaryotic homologues are now recognized. The mechanism of energy coupling is not established, but homology with the MATE family suggests that they are secondary carriers.  A review of Wzx undecaprenyl pyrophosphate (UndPP)-linked polysaccharide repeat units occurs by a substrate:product antiport mechanism (Islam and Lam 2012). These transporters may function together with auxiliary proteins that allow passage across just the cytoplasmic membrane or both membranes of the Gram-negative bacterial envelope.  They may also regulate transport. Thus, each Gram-negative bacterial PST system specific for an exo- or capsular polysaccharide functions in conjunction with a cytoplasmic membrane-periplasmic auxiliary (MPA) protein with a cytoplasmic ATP-binding domain (MPA1-C; TC #3.C.3) as well as an outer membrane auxiliary protein (OMA; TC #3.C.5). Each Gram-positive bacterial PST system functions in conjunction with a homologous MPA1 + C pair of proteins equivalent to an MPA1-C proteins of Gram-negative bacteria. The C-domain has been shown to possess tyrosine protein kinase activity, so it may function in a regulatory capacity. The lipopolysaccharide exporters may function specifically in the translocation of the lipid-linked O-antigen side chain precursor from the inner leaflet of the cytoplasmic membrane to the outer leaflet (Islam and Lam 2012). In this respect they correlate in function with the members of the oligosaccharidyl-lipid flippase (OLF) family of the MOP flippase superfamily.

The generalized transport reaction catalyzed by PST family proteins is:

Polysaccharide (in) + energy → Polysaccharide (out).


2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family

N-linked glycosylation in eukaryotic cells follows a conserved pathway in which a tetradecasaccharide substrate (Glc3Man9GlcNAc2) is initially assembled in the ER membrane as a dolichylpyrophosphate (Dol-PP)-linked intermediate before being transferred to an asparaginyl residue in a lumenal protein. An intermediate, Man5GlcNAc2-PP-Dol is made on the cytoplasmic side of the membrane and translocated across the membrane so that the oligosaccharide chain faces the ER lumen where biosynthesis continues to completion.

The flippase that catalyzes the translocation step is dependent on the Rft1 protein of S. cerevisiae (Helenius et al., 2002). Homologues are found in plants, animals and fungi including C. elegans, D. melanogaster, H. sapiens, A. thaliana, S. cerevisiae and S. pombe. The yeast protein, called the nuclear division Rft1 protein, is 574 aas with 12 putative TMSs. The homologue in A. thaliana is 401 aas in length with 8 or 9 putative TMSs while that in C. elegans is 522 aas long with 11 putative TMSs. These proteins are distantly related to MATE and PST family members and therefore are probably secondary carriers.


2.A.66.4 The Mouse Virulence Factor (MVF) Family

A single member of the MVF family, MviN of Salmonella typhimurium, has been shown to be an important virulence factor for this organism when infecting the mouse (Kutsukake et al., 1994). In several bacteria, mviN genes occur in operons including glnD genes that encode the uridylyl transferase that participates in the regulation of nitrogen metabolism (Rudnick et al., 2001). Nothing more is known about the function of this protein or any other member of the MVF family. However, these proteins are related to members of the PST and MATE families (>9 S.D.), and the greatest sequence similarity is found with members of the PST family. It is therefore possible that MVF family members are functionally related to PST family members and catalyze efflux by a cation antiport mechanism.


2.A.66.5 The Agrocin 84 Antibiotic Exporter (AgnG) Family

Agrocin 84 is a disubstituted adenine nucleotide antibiotic made by and specific for Agrobacteria. It is encoded by the pAgK84 plasmid of A. tumefaciens (Kim et al., 2006) and targets a tRNA synthetase (Reader et al., 2005). The agnG gene encodes a protein of 496 aas with 12-13 putative TMSs and a short hydrophilic N-terminal domain of 80 residues. AgnG is distantly related to members of the Mop superfamily, but is so distant, that it does not retrieve any such members in a TC BLAST search. Nevertheless, an NCBI BLAST search retrieves proteins of the PST and MVI families without iterations. agnG null mutants accumulate agrocin 84 intracellularly and do not export it (Kim et al., 2006).

The reaction catalyzed by AgnG is:

agrocin (in) agrocin (out)


2.A.66.6 The Putative Exopolysaccharide Exporter (EPS-E) Family


2.A.66.7 Putative O-Unit Flippase (OUF) Family


2.A.66.8 Unknown MOP-1 (U-MOP1) Family


2.A.66.9 The Progressive Ankylosis (Ank) Family

Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. An autosomal dominant form of the disorder has been linked to chromosome 5p15.2-p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene. The ANK protein spans the cell membrane and shuttles inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption (Nurnberg et al., 2001).

The ANK protein has 12 membrane-spanning helices with a central channel permitting the passage of PPi. Mutations occur at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. The PPi channel ANK is concerned with bone formation and remodeling (Nurnberg et al., 2001).


2.A.66.10 LPS Precursor Flippase (LPS-F) Family


2.A.66.11 Uncharacterized MOP-11 (U-MOP11) Family


2.A.66.12 Uncharacterized MOP-12 (U-MOP12) Family




This family belongs to the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily.

 

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Rodríguez-Beltrán, J., A. Rodríguez-Rojas, J.R. Guelfo, A. Couce, and J. Blázquez. (2012). The Escherichia coli SOS gene dinF protects against oxidative stress and bile salts. PLoS One 7: e34791.

Roschzttardtz, H., M. Séguéla-Arnaud, J.F. Briat, G. Vert, and C. Curie. (2011). The FRD3 citrate effluxer promotes iron nutrition between symplastically disconnected tissues throughout Arabidopsis development. Plant Cell 23: 2725-2737.

Rouquette-Loughlin, C., S.A. Dunham, M. Kuhn, J.T. Balthazar, and W.M. Shafer. (2003). The NorM efflux pump of Neisseria gonorrhoeae and Neisseria meningitidis recognizes antimicrobial cationic compounds. J. Bacteriol. 185: 1101-1106.

Rudnick, P.A., T. Arcondéguy, C.K. Kennedy, and D. Kahn. (2001). glnD and mviN are genes of an essential operon in Sinorhizobium meliloti. J. Bacteriol. 183: 2682-2685.

Ruiz, N. (2008). Bioinformatics identification of MurJ (MviN) as the peptidoglycan lipid II flippase in Escherichia coli. Proc. Natl. Acad. Sci. USA 105: 15553-15557.

Schlunk I., Krause K., Wirth S. and Kothe E. (2015). A transporter for abiotic stress and plant metabolite resistance in the ectomycorrhizal fungus Tricholoma vaccinum. Environ Sci Pollut Res Int. 22(24):19384-93.

Seo, P.J., J. Park, M.J. Park, Y.S. Kim, S.G. Kim, J.H. Jung, and C.M. Park. (2012). A Golgi-localized MATE transporter mediates iron homoeostasis under osmotic stress in Arabidopsis. Biochem. J. 442: 551-561.

Sham, L.T., E.K. Butler, M.D. Lebar, D. Kahne, T.G. Bernhardt, and N. Ruiz. (2014). Bacterial cell wall. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. Science 345: 220-222.

Shitan, N., S. Minami, M. Morita, M. Hayashida, S. Ito, K. Takanashi, H. Omote, Y. Moriyama, A. Sugiyama, A. Goossens, M. Moriyasu, and K. Yazaki. (2014). Involvement of the leaf-specific multidrug and toxic compound extrusion (MATE) transporter Nt-JAT2 in vacuolar sequestration of nicotine in Nicotiana tabacum. PLoS One 9: e108789.

Soldo, B., V. Lazarevic, M. Pagni, and D. Karamata. (1999). Teichuronic acid operon of Bacillus subtilis 168. Molec. Microbiol. 31: 795-805.

Song, H.X., A.M. Ping, M.X. Sun, X.H. Qi, M.Y. Gao, X.Y. Xu, Z.J. Zhu, M.L. Li, and L.P. Hou. (2017). Identification of genes related to floral organ development in pak choi by expression profiling. Genet Mol Res 16:.

Soto-Liebe, K., M.A. Méndez, L. Fuenzalida, B. Krock, A. Cembella, and M. Vásquez. (2012). PSP toxin release from the cyanobacterium Raphidiopsis brookii D9 (Nostocales) can be induced by sodium and potassium ions. Toxicon 60: 1324-1334.

Soto-Liebe, K., X.A. López-Cortés, J.J. Fuentes-Valdes, K. Stucken, F. Gonzalez-Nilo, and M. Vásquez. (2013). In silico analysis of putative paralytic shellfish poisoning toxins export proteins in cyanobacteria. PLoS One 8: e55664.

Su, X.Z., J. Chen, T. Mizushima, T. Kuroda, and T. Tsuchiya. (2005). AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob. Agents Chemother. 49: 4362-4364.

Takanashi, K., K. Yokosho, K. Saeki, A. Sugiyama, S. Sato, S. Tabata, J.F. Ma, and K. Yazaki. (2013). LjMATE1: a citrate transporter responsible for iron supply to the nodule infection zone of Lotus japonicus. Plant Cell Physiol. 54: 585-594.

Tanaka, Y., C.J. Hipolito, A.D. Maturana, K. Ito, T. Kuroda, T. Higuchi, T. Katoh, H.E. Kato, M. Hattori, K. Kumazaki, T. Tsukazaki, R. Ishitani, H. Suga, and O. Nureki. (2013). Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature 496: 247-251.

Tanaka, Y., S. Iwaki, and T. Tsukazaki. (2017). Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein. Structure 25: 1455-1460.e2.

Tanihara, Y., S. Masuda, T. Sato, T. Katsura, O. Ogawa, and K. Inui. (2007). Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters. Biochem Pharmacol 74: 359-371.

Thompson, E.P., C. Wilkins, V. Demidchik, J.M. Davies, and B.J. Glover. (2010). An Arabidopsis flavonoid transporter is required for anther dehiscence and pollen development. J Exp Bot 61: 439-451.

Tocci, N., F. Iannelli, A. Bidossi, M.L. Ciusa, F. Decorosi, C. Viti, G. Pozzi, S. Ricci, and M.R. Oggioni. (2013). Functional analysis of pneumococcal drug efflux pumps associates the MATE DinF transporter with quinolone susceptibility. Antimicrob. Agents Chemother. 57: 248-253.

Vanni, S., P. Campomanes, M. Marcia, and U. Rothlisberger. (2012). Ion binding and internal hydration in the multidrug resistance secondary active transporter NorM investigated by molecular dynamics simulations. Biochemistry 51: 1281-1287.

Vasseur P., C. Soscia, R. Voulhoux, and A. Filloux. (2007). PelC is a Pseudomonas aeruginosa outer membrane lipoprotein of the OMA family of proteins involved in exopolysaccharide transport. Biochimie. 89(8): 903-915.

Vasudevan, P., J. McElligott, C. Attkisson, M. Betteken, and D.L. Popham. (2009). Homologues of the Bacillus subtilis SpoVB protein are involved in cell wall metabolism. J. Bacteriol. 191: 6012-6019.

Vincent, C., P. Doublet, C. Grangeasse, E. Vaganay, A.J. Cozzone, and B. Duclos. (1999). Cells of Escherichia coli contain a protein-tyrosine kinase, Wzc, and a phosphotyrosine-protein phosphatase, Wzb. J. Bacteriol. 181: 3472-3477.

Wang, R., X. Liu, S. Liang, Q. Ge, Y. Li, J. Shao, Y. Qi, L. An, and F. Yu. (2015). A subgroup of MATE transporter genes regulates hypocotyl cell elongation in Arabidopsis. J Exp Bot 66: 6327-6343.

Whitfield, C. and I.S. Roberts. (1999). Structure, assembly and regulation of expression of capsules in Escherichia coli. Mol. Microbiol. 31: 1307-1319.

Yang, S., C.R. Lopez, and E.L. Zechiedrich. (2006). Quorum sensing and multidrug transporters in Escherichia coli. Proc. Natl. Acad. Sci. USA 103: 2386-2391.

Yonezawa, A., S. Masuda, S. Yokoo, T. Katsura, and K. Inui. (2006). Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 319: 879-886.

Young, K.D. (2014). Microbiology. A flipping cell wall ferry. Science 345: 139-140.

Zakrzewska, S., A.R. Mehdipour, V.N. Malviya, T. Nonaka, J. Koepke, C. Muenke, W. Hausner, G. Hummer, S. Safarian, and H. Michel. (2019). Inward-facing conformation of a multidrug resistance MATE family transporter. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Zhang X., He X., Baker J., Tama F., Chang G. and Wright SH. (2012). Twelve transmembrane helices form the functional core of mammalian MATE1 (multidrug and toxin extruder 1) protein. J Biol Chem. 287(33):27971-82.

Zhang, H., F.G. Zhao, R.J. Tang, Y. Yu, J. Song, Y. Wang, L. Li, and S. Luan. (2017). Two tonoplast MATE proteins function as turgor-regulating chloride channels in Arabidopsis. Proc. Natl. Acad. Sci. USA 114: E2036-E2045.

Zhao, J. and R.A. Dixon. (2009). MATE transporters facilitate vacuolar uptake of epicatechin 3''-O-glucoside for proanthocyanidin biosynthesis in Medicago truncatula and Arabidopsis. Plant Cell 21: 2323-2340.

Zhou, G., E. Delhaize, M. Zhou, and P.R. Ryan. (2013). The barley MATE gene, HvAACT1, increases citrate efflux and Al3+ tolerance when expressed in wheat and barley. Ann Bot 112: 603-612.



2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.1.1

Drug:Na+ antiporter (norfloxacin, ethidium, kanamycin, ciprofloxin, streptomycin efflux pump), NorM. Transport is dependent on Na+, and several essential residiues have been identified. Specifically, Asp32, Glu251, and Asp367 are involved in the Na+-dependent drug transport process. (Otsuka et al. 2005).

Bacteria

NorM of Vibrio parahaemolyticus (O82855)

 
2.A.66.1.10

Na -dependent cationic drug (ethidium, acriflavine, 2-N-methyl ellipticinium, berberine, norfloxacin, ciprofloxacin, rhodamine 6G, crystal violet, doxorubicin, novobiocin, enoxacin, and tetraphenylphosphonium chloride) efflux pump, NorM (Long et al. 2008).  3-d structures of the N. gonorrheae NorM transporter (96% identical to the N. miningitidis protein) have been solved complexed with three different substrates in a multidrug cavity and Cs (4HUN; Lu et al. 2013).  Lu et al. an identified an uncommon cation-π interaction in the Na+-binding site located outside the drug-binding cavity and validated the biological relevance of both the substrate- and cation-binding sites by conducting drug resistance and transport assays. Additionally, they observed a potential rearrangement of at least two transmembrane helices upon Na+-induced drug export. They suggested that Na+ triggers multidrug extrusion by inducing protein conformational changes rather than by directly competing for the substrate-binding amino acids.  However, see 2.A.66.1.32 where the opposite was concluded for a homologue that functions by drug:H+ antiport.

Bacteria

NorM of Neisseria meningitidis

 
2.A.66.1.11The Enhanced Disease Susceptibility Protein (EDS5), also called the Salicylate Induction Deficient (Sid1) protein; a possible chloroplast salicylate transporter (S. Heck, personal communication)PlantsEDS5 of Arabidopsis thaliana chloroplasts
 
2.A.66.1.12Drug:H+ antiporter (benzalkonium chloride, fluoroquinolone, ethidium bromide, acriflavin, tetraphenylphosphonium chloride efflux pump), PmpM (He et al., 2004)BacteriaPmpM of Pseudomonas aeruginosa (Q9I3Y3)
 
2.A.66.1.13

Drug (monovalent and divalent biocides; fluoroquinolones including norfloxacin and ciprofloxacin) efflux pump, SvrA (MepA) (Kaatz et al., 2006). Also exports tigecycline (McAleese et al., 2005).

Bacteria

SvrA of Staphylococcus aureus (Q2G140)

 
2.A.66.1.14

Human MATE1 electroneutral organocation:H antiporter (transports tetraethylammonium, TEA and cimetidine as well as cisplatin and oxaliplatin) (Yonezawa et al., 2006). MATE1 also exports chloroquine across the luminal membrane (Müller et al., 2011). It has an established 13 TMS topology with the "extra" TMS in an extracellular C-terminal region that is not essential for function (Zhang et al., 2012).  Also exports 1-methyl-4-phenylpyridinium (MPP), N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes (Tanihara et al. 2007).

Animals

SLC47A1 of Homo sapiens

 
2.A.66.1.15Electroneutral Multidrug & Toxin Extrusion-1 organic cation:H+ antiporter (MATE-1). Exports tetraethylammonium (TEA) and cimetidine, and probably other organic cations, such as 1-methyl-4-phenylpyridinium, amiloride, imipramine, and quinidine (Ohta et al., 2006).

Animals

MATE-1 of Rattus norvegicus (Q5I0E9)

 
2.A.66.1.16Electroneutral organic cation:H+ antiporter MATE2 (Hiasa et al., 2007). 50% identical to MATE1; 2.A.66.1.15.

Mammals

MATE2 of Mus musculus (Q3V050)

 
2.A.66.1.17

MATE efflux pump, MatE

Ciliates

MatE of Tetrahymena thermophila

 
2.A.66.1.18MATE1b (mediates tetraethylammonium (TEA) uptake with properties similar to that of mMATE1; localized in renal brush border membranes (Kobara et al., 2008)).
Metazoa

MATE1b of Mus musculus (Q8K0H1)

 
2.A.66.1.19JAT1 (transports nicotine and anabasine, and other alkaloids, such as hyoscyamine and berberine, but not flavonoids) (Morita et al., 2009).

Plants

JAT1 of Nicotiana tabacum (B7ZGMO)

 
2.A.66.1.2

Drug:Na+ antiporter, VcmA (exports norfloxacin, ciprofloxacin, ofloxacin, daunomycin, doxorubicin, streptomycin, kanamycin, ethidium, 4',6'-diamidino-2-phenylindole, Hoechst 33342 and acriflavin). The 3-d x-ray structure (3.65Å resolution) is available (He et al., 2010). Ion binding and internal hydration have been studied by molecular dynamics simulations (Vanni et al., 2012).  NorM simultaneously couples drug export to the sodium-motive force and the proton-motive force. Residues involved and protein regions that play important roles in Na+ or H+ binding have been identified (Jin et al. 2014). Na+- and H+-driven conformational changes are facilitated by a network of polar residues in the N-terminal domain cavity, whereas conserved carboxylates buried in the C-terminal domain are critical for stabilizing the drug-bound state. These results establish the role of ion-coupled conformational dynamics in the functional cycle and implicate H+ in the doxorubicin release mechanism (Claxton et al. 2018).

Bacteria

VcmA (NorM) of Vibrio cholerae non-01

 
2.A.66.1.20

Multidrug and Toxin Extrusion Protein 2, MATE-2 (catalyzes drug:H+ antiport; broad specificity, low affinity (50-3000 μM) for organic cationic and anionic compounds (Tanihara et al., 2007)).

AnimalsSLC47A2 of Homo sapiens
 
2.A.66.1.21

H+-coupled multidrug efflux pump, AbeM (most like 2.A.66.1.2, NorM of Vibrio cholerae) (Su et al., 2005). Exports norfloxacin, ciprofloxacin, DAPI, acriflavin, Hoechst 33342, daunorubicin, doxorubicin, and ethidium (Su et al., 2005).

Bacteria

AbeM of Acinetobacter baumannii (Q5FAM9)

 
2.A.66.1.22

Quinolone:H+ antiporter, EmmdR. Substates include benzalkonium chloride, norfloxacin, ciprofloxacin, levofloxacin, ethidium bromide, acriflavine, rhodamine 6G and trimethoprim.

Bacteria

EmmdR of Enterobacter cloacae (D5CJ69)

 
2.A.66.1.23

MDR efflux pump, YeeO (NorA) (81.8% identical to 2.A.66.1.22). Transports dipeptides (see 2.A.1.2.55) (Hayashi et al., 2010).  Also exports both flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). However, significant amounts of flavins were trapped intracellularly when YeeO was produced. Wild-type E. coli secretes 3 flavins (riboflavin, FMN, and FAD), so it must have additional flavin transporters (McAnulty and Wood 2014).

Bacteria

YeeO of E. coli (P76352)

 
2.A.66.1.24

FRD3 efflux pump for citrate; involved in iron homeostasis. Localized to the pericycle and vascular cylinder of roots; loads citrate into xylem tissues facilitating iron transport from the roots to the shoots; null mutants are sterile (Green and Rogers 2004; Roschzttardtz et al., 2011; Durrett et al., 2007).

Plants

FRD3 of Arabidopsis thaliana (Q9SFB0)

 
2.A.66.1.25

Probable multidrug resistance protein YoeA

Bacilli

YoeA of Bacillus subtilis

 
2.A.66.1.26Uncharacterized transporter MJ0709ArchaeaMJ0709 of Methanocaldococcus jannaschii
 
2.A.66.1.27Probable multidrug resistance protein NorM (Multidrug-efflux transporter)Bacteria

NorM of Caulobacter crescentus

 
2.A.66.1.28Probable multidrug resistance protein NorM (Multidrug-efflux transporter)Bacteria

NorM of Thermotoga maritima

 
2.A.66.1.29

MATE exporter protein

Proteobacteria

MATE exporter protein of Myxococcus xanthus

 
2.A.66.1.3

Multidrug-resistance efflux pump, NorM (MdtK, NorE or YdhE) (Nishino and Yamaguchi 2001). Exports chloramphenicol, norfloxacin, enoxacin, phosphomycin, doxorubicin, trimethoprim, ethidium, deoxycholate, etc (Long et al., 2008). May also export signals for cell-cell communication (Yang et al., 2006).

Bacteria

NorM (YdhE) of E. coli

 
2.A.66.1.30

Ciprofloxacin export permease, AbeM2

Proteobacteria

AbeM2 of Acinetobacter baumannii

 
2.A.66.1.31

Ciprofloxacin efflux pump, AbeM4 (Eijkelkamp et al. 2011).

Proteobacteria

AbeM4 of Acinetobacter baumannii

 
2.A.66.1.32

Multidrug:proton antiporter of the DinF subfamily.  The structure has been solved to 3.2 Å resolution with and without the substrate, Rhodamine 6 G.  The 12 TMSs show asymmetry with a membrane-embedded substrate-binding chamber.  Direct competition between the H+ and the substrate during transport was suggested (Lu et al. 2013).  However, the opposite was suggested for a sodium antiporter (see TC# 2.A.66.1.10).

Proteobacteria

DinF-like MDR pump of Bacillus halodurans

 
2.A.66.1.33

MDR efflux pump for quinolones (moxifloxacin, ciprofloxacin and levofloxacin) of 456 aas, DinF (Tocci et al. 2013).

Firmicutes

DinF of Streptococcus pneumoniae

 
2.A.66.1.34

MATE MDR exporter of 411 aas, SP2065 (Tocci et al. 2013).  Exports novobiocin.

Firmicutes

SP2065 of Streptococcus pneumoniae

 
2.A.66.1.35

Citrate-specific transporter of 538 aas, MATE1.  Necessary for iron supply to the nodule infection zone (Takanashi et al. 2013).

Plants

MATE1 of Lotus japonicus

 
2.A.66.1.36

Multidrug exporter, DinF, of 457 aas.  Exports various toxic compounds, including antibiotics, phytoalexins, and detergents. Mutants are less virulent on the tomato plant than the wild-type strain (Brown et al. 2007).

Proteobacteria

DinF of Ralstonia solanacearum (Pseudomonas solanacearum)

 
2.A.66.1.37

Multidrug resistance protein, CdeA of 441 aas.  Exports ethidium bromide, fluoroquinolone and acriflavin but had no effect on susceptibility to the following antibiotics: norfloxacin, ciprofloxacin, gentamicin, erythromycin, tetracyclin, and chloramphenicol (Dridi et al. 2004).  May be a Na+ antiporter.

CdeA of Clostridium difficile

 
2.A.66.1.38

Homologue of Mte1 of Tricholomp vaccinum of 588 aas which mediates detoxification of xenobiotics and metal ions such as Cu, Li, Al, and Ni, as well as secondary plant metabolites (Schlunk et al. 2015).

Fungi

Mte1 homologue of Moniliophthora roreri (Cocoa frosty pod rot fungus) (Crinipellis roreri)

 
2.A.66.1.39

Jasmonate-inducible alkaloid transporter-2, JAT2.Transports nicotine and other alkaloids into the tonoplast vacuole for sequestration (Chen et al. 2015; Shitan et al. 2014).

Plants

JAT2 of Nicotiana tabacum

 
2.A.66.1.4

DNA damage-inducible protein F, DinF.  Protects against oxidative stress and bile salts, possibly by pumping relevant compounds out of the cytoplasm (Rodríguez-Beltrán et al. 2012).

Bacteria

DinF of E. coli

 
2.A.66.1.40

Putative MDR or polysaccharide exporter of 514 aas and 12 TMSs

Spirochaetes

Exporter of Treponema succinifaciens

 
2.A.66.1.41

Na+-coupled multidrug efflux pump, PdrM (Hashimoto et al. 2013). Confers resistance to several antibacterial agents including norfloxacin, acriflavine, and 4',6-diamidino-2-phenylindole (DAPI).

Firmicutes

PdrM of Streptococcus pneumoniae

 
2.A.66.1.42

Paralytic shellfish toxin (PST; including saxitoxin (STX)) exporter, SxtM, of 464 aas (Soto-Liebe et al. 2013). These toxins, which block Na+ channels, are produced by cyanobacteria and dinoflagellates, and >30 such natural alkaloids are known (Soto-Liebe et al. 2012).

Cyanobacteria

SxtM of Cylindrospermopsis raciborskii

 
2.A.66.1.43

MATE1 of 563 aas and 12 TMSs.  Involved in aluminum resistance (Maron et al. 2013).

MATE1 of Zea mays (Maize)

 
2.A.66.1.44
Transparent Testa 12 (TT12), also called Protein DETOXIFICATION, is a valuolar transporter of proanthocyanidins (PAs).  It transports these compounds from the cytoplasm into the vacuolar lumen (Gao et al. 2015).

TT12 of Gossypium hirsutum (Upland cotton) (Gossypium mexicanum)

 
2.A.66.1.45

Damage inducible multidrug resistance protein F, DinF of 455 aas and 12 TMSs. An x-ray structure is available (Radchenko et al. 2015).

DinF of Pyrococcus furiosus

 
2.A.66.1.46

Saxitoxin, STX, exporter, SxtF; also exports fluoroquinolone, suggesting it is an MDR pump (Ongley et al. 2016).

SxtF of Cylindrospermopsis raciborskii

 
2.A.66.1.47

Saxitoxin, STX, exporter, SxtM; also exports fluoroquinolone, suggesting it is an MDR pump (Ongley et al. 2016).

SxtM of Aphanizomenon sp. NH-5 (Anabaena circinalis)

 
2.A.66.1.48

MATE transporter. ClbM, of 479 aas and 12 TMSs, ClbM.  Exports precolibactin, a genotoxin made by a polyketide complex in E. coli, that generates double strand breaks in the DNA (Mousa et al. 2016). The 3-d structure is available (PDB# 4Z3N).

ClbM of E. coli

 
2.A.66.1.49

MATE family transporter of 475 aas and 12 TMSs in a 6 + 6 TMS pseudosymmetic arrangement.  The 3-d structure has been determined at 2.9 Å resolution (Tanaka et al. 2017). The protein possesses a negatively charged internal pocket with an outward-facing shape. This structure was determined for the C. sativa orthologue of the C. rubella protein, the sequence of which is 94% identical to the one provided here.

CasMATE of Capsella rubella

 
2.A.66.1.5Ethionine resistance protein, ERC1YeastERC1 (YHR032w) of Saccharomyces cerevisiae
 
2.A.66.1.50

Detoxification protein, DTX35, of 614 aas and 12 TMSs, also called FLOWER FLAVONOID TRANSPORTER (FFT), encodes a MATE family transporter in Arabidopsis thaliana. FFT (AtDTX35) is highly transcribed in floral tissues, the transcript being localized to epidermal guard cells, including those of the anthers, stigma, siliques and nectaries (Thompson et al. 2010). The absence of FFT affects flavonoid levels in the plant. Moreover, root growth, seed development and germination, and pollen development, release and viability are all affected (Thompson et al. 2010). Also functions as a chloride channel, which, together with DTX33, is essential for turgor regulation (Zhang et al. 2017). Involved in floral development (Song et al. 2017).

DTX35 of Arabidopsis thaliana

 
2.A.66.1.51

Multidrug resistance efflux pump, Detoxification 48, DTX48. Functions as a multidrug and toxin extrusion transporter. Contributes to iron homeostasis during stress responses and senescence (Seo et al. 2012). Overexpression of DTX48 alters shoot developmental programs leading to a loss of apical dominance phenotype (Wang et al. 2015).

DTX48 of Arabidopsis thaliana (Mouse-ear cress)

 
2.A.66.1.52

Detoxification protein 14, DTX14, of 485 aas and 12 TMSs.  This MATE family (MOP superfamily) proter extrduces xenobiotics from the cell.  It's 3-d structure is known to 2.6 Å resolution (Miyauchi et al. 2017). Its carboxy-terminal lobe (C-lobe) contains an extensive hydrogen-bonding network with well-conserved acidic residues, as demonstrated by structure-based mutational analyses. The analyses suggest that the transport mechanism involves a structural change of transmembrane helix 7, induced by the formation of a hydrogen-bonding network upon the protonation of the conserved acidic residue in the C-lobe (Miyauchi et al. 2017).

DTX14 of Arabidopsis thaliana

 
2.A.66.1.53

Citrate exporter, MATE1 or DETOXIFICATION, of 553 aas and 12 probable TMSs.  It's activity gives rise to aluminum (Al3+) tolerance (Garcia-Oliveira et al. 2014). 98% identical to the rye and barley orthologs (Zhou et al. 2013).

MATE1 of Tritium aestivum (Wheat)

 
2.A.66.1.54

MATE2 or Detoxification 47 (DTX47) of 543 aas and 12 TMSs.  The orthologs from several plants have been sequenced and characterized (i.e., wheat; potato) (Li et al. 2018).  This protein may be a citrate and salicylate exporter and promote resistance to aluminum (Al3+) (Garcia-Oliveira et al. 2018).

MATE2 of Arabidopsis thaliana

 
2.A.66.1.55

MATE drug:sodium symporter of 461 aas and 12 TMSs.  Several crystal structures are known (3VVO, 3VVP, 3VVR, 3VVS, 6FHZ, 6GWH) in several distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 1.8 - 3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the N-terminal lobe induces the bending of TMS1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities (Tanaka et al. 2013). The  Na+-binding site, in the N-lobe of this transporter, is selective against K+, weakly specific against H+, and broadly conserved among prokaryotic MATEs (Ficici et al. 2018). The inward-facing state was obtained after crystallization in the presence of native lipids (Zakrzewska et al. 2019). The transition from the outward-facing state to the inward-facing state involves rigid body movements of TMSs 2-6 and 8-12 to form an inverted V, facilitated by a loose binding of TMS1 and TMS7 to their respective bundles and their conformational flexibility. The inward-facing structure of PfMATE in combination with the outward-facing one supports an alternating access mechanism for MATE family transporters ()Zakrzewska et al. 2019.

MOP superfamily transporter of Pyrococcus furiosus

 
2.A.66.1.56

MATE transporter,DETOXIFICATION 4, DTX4 or At2g04070, of 476 aas and 12 TMSs. May transport alkaloids, heavy metals, bile salts, organic acids amd organic amines (Li et al. 2018).

DTX4 of Arabidopsis thaliana (Mouse-ear cress)

 
2.A.66.1.57

DETOXIFICATION 41, DTX41, TDS3, TT12 of 507 aas and 12 TMSs. Acts as a flavonoid/H+-antiporter that controls the vacuolar sequestration of flavonoids in the seed coat endothelium (Debeaujon et al. 2001; Marinova et al. 2007).  May also transport the anthocyanin cyanidin-3-O-glucoside (Marinova et al. 2007) and epicatechin 3'-O-glucoside (Zhao and Dixon 2009).

DTX41 of Arabidopsis thaliana (Mouse-ear cress)

 
2.A.66.1.6

Drug (norfloxacin, ciprofoxacin, ethidium, tetramethylammonium, pyrrolidinone, polyvinylpyrrolidone) resistance pump, Alf5 or DTOXIFICATION 19, DTX19.  Note:  A. thaliana has 56 MATE transporters (Takanashi et al. 2013).

Plants

Alf5 of Arabidopsis thaliana

 
2.A.66.1.7Cationic drug (4',6'-diamidino-2-phenylindole (DAPI), tetraphenylphosphonium (TPP), acriflavin, ethidium):Na+ antiporter, VmrABacteriaVmrA of Vibrio parahaemolyticus
 
2.A.66.1.8

Plasma membrane efflux pump, AtDTX1, for plant alkaloids, drugs (e.g., norfloxacin), antibiotics and Cd2+ (Li et al. 2002). 

Plants

AtDTX1 of Arabidopsis thaliana

 
2.A.66.1.9Drug (norfloxacin, polymyxin B) resistance efflux pump, NorMBacteriaNorM of Burkholderia vietnamiensis
 


2.A.66.10 LPS Precursor Flippase (LPS-F) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.10.1

Wzx isoprenoid-linked O-antigen precursor glycan translocase.  A 12 TMS topology with N- and C-termini in the cytoplasm has been established, and functionally important residues have been identified (Marolda et al. 2010).  A substrate:proton antiport mechanism has been established (Islam et al. 2013).

Proteobacteria

 

Wzx of E. coli O157:H7 str 1125

 


2.A.66.11 Uncharacterized MOP-11 (U-MOP11) Family

 


Examples:

TC#NameOrganismal TypeExample
2.A.66.11.1

Uncharacterized protein

Actinobacteria

Uncharacterized protein of Streptomyces coelicolor

 
2.A.66.11.2

Uncharacterized protein

Proteobacteria

Uncharacterized protein of Beggiatoa alba

 


2.A.66.12 Uncharacterized MOP-12 (U-MOP12) Family

 


Examples:

TC#NameOrganismal TypeExample
2.A.66.12.1

Uncharacterized MOP superfamily member of 506 aas and 14 TMSs. Subfamily 2.A.66.12 may be most closely related to 2.A.66.2, suggesting that these proteins are glycolipid flippases.

δ-Proteobacteria

U-MOP family 12 member-1

 
2.A.66.12.10

Uncharacterized protein of 452 aas and 12 TMSs.

UP of Parvularcula oceani

 
2.A.66.12.11

Uncharacterized putative flippase of 496 aas and 14 TMSs.

UP of Cyclobacterium lianum

 
2.A.66.12.2

Uncharacterized MOP superfamily member of 1049 aas and 14 or 15 TMSs

Bacteroidetes

U-MOP family 12 member-2

 
2.A.66.12.3

Uncharacterized MOP superfamily member of 489 aas and 14 TMSs

Archaea

U-MOP family 12 member-3

 
2.A.66.12.4

Uncharacterized MOP superfamily member of 487 aas and 14 TMSs

Archaea

U-MOP superfamily protein

 
2.A.66.12.5

Uncharacterized MOP superfamily of 488 aas and 14 TMSs

Archaea

U-MOP superfamily member

 
2.A.66.12.6

Putative polysaccharide exporter of 449 aas, YghQ.

Proteobacteria

YghQ of E. coli

 
2.A.66.12.7

The succinoglycan biosynthesis transporter homologue, Mth342

Archaea

Mth342 of Methanobacterium thermoautotrophicum (O26442)

 
2.A.66.12.8

Putative Wzx flippase of 499 aas and 14 TMSs (Hug et al. 2016).

Wzx of Candidatus Peribacter riflensis

 
2.A.66.12.9

Uncharacterized flippase of 516 aas and 14 TMSs

UP of Cuniculiplasma divulgatum

 


2.A.66.2 The Polysaccharide Transport (PST) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.2.1Lipopolysaccharide (possibly the O-antigen side chain intermediate) exporterGram-negative bacteriaRfbX1 of E. coli
 
2.A.66.2.10The O-antigent transporter homologue, Mth347ArchaeaMth347 of Methanobacterium thermoautotrophicum(O26447)
 
2.A.66.2.11Exopolysaccharide exporter, EpsE (Huang and Schell, 1995)BacteriaEpsE of Ralstonia solanacearum (Q45411)
 
2.A.66.2.12

Isoprenoid lipid sugar glycan flippase, Wzx (note: Wzx forms a complex with Wzy and Wzz for assembly of periplasmic O-antigen) (Marolda et al., 2006). Wzx has a 12 TMS topology (Cunneen and Reeves, 2008). WzyE (450aas; 12 TMSs; TC#9.B.128.1.1; B614D1) is called the enterobacterial common antigen (ECA) polysaccharide chain elongation polymerase (Marolda et al., 2006). The structure of Wzz has been determined by cryoEM (Collins et al. 2017).

Bacteria

Wzx of E. coli (Q1L811)

 
2.A.66.2.13Unknown PST proteinBacteriaUnknown PST protein of Alteromonadales bacterium (A0XZ57)
 
2.A.66.2.14

The 14 TMS SpoVB protein (possibly catalyzes lipid-linked oligosaccharide transport across the cytoplasmic membrane; required for proper cell wall biosynthesis) (Vasudevan et al., 2009).

Firmicutes

The SpoVB protein of Bacillus subtilis (Q00758)

 
2.A.66.2.15

Anionic O-antigen (undecaprenyl pyrophosphate-linked anionic O-Ag) subunit flippase, Wzx. Translocates from the inner to the outer leaflets of the inner membrane.  The topology has been studied (Ormazabal et al. 2010).

Bacteria

Wzx of Pseudomonas aeruginosa (G3XD19)

 
2.A.66.2.16

Capsular polysaccharide exporter, CpsU (428aas; 12 TMSs).

Bacteria

CpsU of Streptococcus thermophilus (Q8KUK6)

 
2.A.66.2.17

Sporulation protein YkvU

Bacilli

YkvU of Bacillus subtilis

 
2.A.66.2.18

O-antigen transmembrane translocase, Wzx (Franklin et al. 2011). In S. enterica groups B, D2 and E, Wzx translocation exhibits specificity for the repeat-unit structure, as variants with single sugar differences are translocated with lower efficiency, and little long-chain O antigen is produced. It appears that Wzx translocases are specific for their O antigen for normal levels of translocation (Hong et al. 2012).

Bacteria

Wzx of Salmonella enterica subsp. enterica

 
2.A.66.2.19

O-antigen transmembrane translocase, Wzx (Franklin et al. 2011).  For S. enterica groups B, D2 and E, Wzx translocation exhibits specificity for the repeat-unit structure, as variants with single sugar differences are translocated with lower efficiency, and little long-chain O antigen is produced. It appears that Wzx translocases are specific for their O antigen for normal levels of translocation (Hong et al. 2012).

Bacteria

Wzx of Salmonella typhimurium subsp. houtenae

 
2.A.66.2.2Probable succinoglycan exporterGram-negative bacteriaExoT of Rhizobium meliloti
 
2.A.66.2.20

PST family homologue of 14 TMSs

Chlamydiae

Hypothetical protein of Parachlamydia acanthamoebae

 
2.A.66.2.21

Putative polysaccharide transporter

Spirochaetes

Putative polysaccharide transporter of Leptospira interrogans

 
2.A.66.2.22

Choline-derivatized teichoic acid exporter (flippase), TacF of495 aas.  TacF is responsible for the choline dependent growth phenotype (Damjanovic et al. 2007).

Firmicutes

TacF of Streptococcus pneumoniae

 
2.A.66.2.23

Xanthan precursor exporter of 499 aas and 14 TMSs, GumJ (Bianco et al. 2014).

Proteobacteria

GumJ of Xanthomonas campestris

 
2.A.66.2.24

Putative polysaccharide exporter of 471 aas and 14 TMSs

UP of E. coli

 
2.A.66.2.25

Polysaccharide export protein of 572 aas and 12 TMSs.

PS exporter of Candidatus Beckwithbacteria bacterium

 
2.A.66.2.26

Uncharacterized MOP superfamily member of 456 aas and 12 TMSs.

UP of Parvularcula oceani

 
2.A.66.2.27

Putative flippase of 416 aas and 12 TMSs.

Flippase of Candidatus Marithrix sp. Canyon 246

 
2.A.66.2.28

Uncharacterized protein of 435 aas and 13 TMSs.

UP of Bacillus wiedmannii

 
2.A.66.2.29

Uncharacterized polysaccharide precursor flippase of 476 aas and 14 TMSs.

UP of Clostridium botulinum

 
2.A.66.2.3

Undecaprenol-pyrophosphate O-antigen flippase WzxE

Gram-negative bacteria

WzxE of E. coli (P0AAA7)

 
2.A.66.2.30

Uncharacterized putative carbohydrate-lipid flippase of 486 aas and 14 TMSs in a 6 + 2 + 6 arrangement.

UP of Bacteroides timonensis

 
2.A.66.2.31

Uncharacterized protein of 455 aas and 14 TMSs.

UP of Exiguobacterium sp. KRL4

 
2.A.66.2.4Probable acetan exporterGram-negative bacteriaAceE of Acetobacter xylinus
 
2.A.66.2.5Capsular polysaccharide exporterGram-positive bacteriaCapF of Staphylococcus aureus
 
2.A.66.2.6Teichuronic acid exporter, TuaB (YvhB)Gram-positive bacteriaTuaB of Bacillus subtilis
 
2.A.66.2.7Lipopolysaccharide (colanic acid) exporter, WzxCGram-negative bacteriaWzxC of E. coli
 
2.A.66.2.8

Exopolysaccharide (Amylovoran) exporter, AmsL

Gram-negative bacteria

AmsL of Erwinia amylovora

 


2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.3.1

The OLF (Rft1 protein) of Saccharomyces cerevisiae.  May play a role in phospholipid flipping from the inner leaflet of the plasma membrane to the outer leaflet (Chauhan et al. 2016).

Eukaryotes

Rft1 of Saccharomyces cerevisiae

 
2.A.66.3.2Endoplasmic reticular RFT1 homologueAnimalsRFT1 homologue of Homo sapiens (Q96AA3)
 
2.A.66.3.3Nuclear division RFT1 homologuePlantsRFT1 homologue of Arabidopsis arenosa (Q6V5B3)
 
2.A.66.3.4Hypothetical protein; RFT1 homologueCiliatesRFT1 homologue of Paramecium tetraurelia (A0D5K0)
 


2.A.66.4 The Mouse Virulence Factor (MVF) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.4.1

The mouse virulence factor, MviN. (May flip the Lipid II peptidoglycan precursor from the cytoplasmic side of the inner membrane to the periplasmic surface) (Vasudevan et al., 2009). MviN, a putative lipid flippase (Fay and Dworkin, 2009).  In E. coli, MviN is an essential protein which when defective results in the accumulation of polyprenyl diphosphate-N-acetylmuramic acid-(pentapeptide)-N-acetyl-glucosamine.  This may be the peptidoglycan intermediated exported via MviN (Inoue et al. 2008).  It is essential for the growth of several bacteria.

Bacteria

MviN of Salmonella typhimurium (P37169)

 
2.A.66.4.2Putative virulence factor, MviN (21% identity with 2.A.66.4.1)BacteriaMviN of Borrelia garinii (Q65ZW3)
 
2.A.66.4.3

Peptidoglycan biosynthesis protein MurJ (Ruiz 2008). A 3-d structural model showed a solvent-exposed cavity within the plane of the membrane (Butler et al. 2013). MurJ has 14 TMSs, and specific charged residues localized in the central cavity are essential for function. This structural homology model suggests that MurJ functions as an essential transporter in PG biosynthesis (Butler et al. 2013). Based on an in vivo assay, MurJ is a flippase for the lipid-linked cell wall precursors, polyisoprenoid-linked disaccharide-peptapeptides (Sham et al. 2014).  There is controversy about the role of this porter and FtsW/RodA which on the basis of an in vitro assay, were thought to be flippases for the same intermediate (Young 2014). MurJ, the bacterial lipid II flippase, functions by an alternating-access mechanism (Kumar et al. 2019).

Bacteria

MurJ of Escherichia coli

 
2.A.66.4.4

MviN.  Essential for peptidoglycan biosynthesis (Gee et al. 2012).

Actinobacteria

MviN of Mycobacterium tuberculosis

 
2.A.66.4.5

MviN; LuxO regulated for induction during the early logarithmic and stationary phase of growth (Cao et al. 2010).

Enterobacteria

MviN of Vibrio alginolyticus

 
2.A.66.4.6

Uncharacterized protein

Proteobacteria

UP of E. coli

 
2.A.66.4.7

Probable peptidoglycan-lipid II flippase, MurJ or MviN; essential for cell wall synthesis and viability (Mohamed and Valvano 2014).

Proteobacteria

MurJ of Burkholderia cenocepacia

 
2.A.66.4.8

MurJ (MviV) of 475 aas and 14 TMSs. Kuk et al. 2016 presented a crystal structure of MurJ from Thermosipho africanus in an inward-facing conformation at 2.0-A resolution. A hydrophobic groove is formed by two C-terminal transmembrane helices, which leads into a large central cavity that is mostly cationic. Their results suggest that alternating access is important for MurJ function, which may be applicable to other MOP superfamily transporters (Kuk et al. 2016).

MurJ of Thermosipho africanus

 


2.A.66.5 The Agrocin 84 Antibiotic Exporter (AgnG) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.5.1The agrocin 84 exporter, AgnGBacteriaAgnG of Agrobacterium tumefaciens (Q676G9)
 
2.A.66.5.2AgnG homologue 1 (433aas; 12TMSs; (2)6 )BacteriaAgnG homologue 1 of Nitrococcus mobilis (A4BUA1)
 
2.A.66.5.3

AgnG homologue 2 (448aas; 12TMSs; (2)6.  Probable polysaccharide exporter.

Bacteria

AgnG homologue 2 of Lyngbya sp. PCC8106 (A0YL48)

 


2.A.66.6 The Putative Exopolysaccharide Exporter (EPS-E) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.6.1

Putative exopolysaccharide transporter with two subunits, PelFG (PelF has 507 aas and 1 N-terminal TMS, while PelG has 456 aas and 12 TMSs) (Vasseur et al., 2007)

Bacteria

PelFG of Pseudomonas aeruginosa (Q02PM3)

 
2.A.66.6.2Fusion protein (986 aas): Glycosyl transferase group 1 (residues 1-550); putative transporter (flippase) (residue 551-986; 12(6+6) TMSs)BacteriaFusion protein of Ralstonia solanacearum (EAP70965)
 


2.A.66.7 Putative O-Unit Flippase (OUF) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.7.1Putative O-unit flippase (OUF1)BacteriaOUF1 of Pseudomonas fluorescens (Q4K6F5)
 


2.A.66.8 Unknown MOP-1 (U-MOP1) Family (Most closely related to the OLF Family (2.A.66.3))


Examples:

TC#NameOrganismal TypeExample
2.A.66.8.1Hypothetical protein (598aas; 12-14TMSs)ProtozoaHypothetical protein of Trypanosoma brucei (Q383B3)
 
2.A.66.8.2Hypothetical protein (729aas; 14TMSs ?)ProtozoaHypothetical protein of Leishmania infantum (A4I3X2)
 


2.A.66.9 The Progressive Ankylosis (Ank) Family


Examples:

TC#NameOrganismal TypeExample
2.A.66.9.1

The progressive ankylosis (ANK) protein (AnkH) gives rise to craniometaphyseal bone dysplasia in man. This 12 TMS protein transports pyrophosphate and is expressed in the primary ciliary/basal body complex of kidney and bone tissues (Nürnberg et al., 2001; Carr et al. 2009). It is critical for the regulation of pyrophosphate, and gain of function ANK mutations are associated with calcium pyrophosphate deposition disease (Mitton-Fitzgerald et al. 2016).

 

Animals

AnkH of Homo sapiens (Q9HCJ1)

 
2.A.66.9.2

Hypothetical protein, Pcar_0400

Bacteria

Pcar_0400 of Pelobacter carbinolicus (Q3A7I4)

 
2.A.66.9.3Ank family memberBacteriaAnk protein of Desulfuromonas acetoxidans (Q1K211)