4.A.6 The PTS Mannose-Fructose-Sorbose (Man) Family

The Man (PTS splinter group) family is unique in several respects among PTS porter families. (1) It is the only PTS family in which members possess a IID protein; (2) It is the only PTS family in which the IIB constituent is phosphorylated on a histidyl rather than a cysteyl residue. (3) Its porter members usually exhibit broad specificity for a range of sugars, rather than being specific for just one or a few sugars. The mannose porter of E. coli, for example, can transport and phosphorylate glucose, mannose, fructose, glucosamine, N-acetylglucosamine, and N-acteylmannosamine (Plumbridge and Vimr, 1999). In addition to being a transporter and the lambda receptor for transport of its DNA across the cytoplasmic membrane it is a target receptors for class IIa, IId, and IIe bacteriocins.

The structure of the E. coli IIAMan domain has been shown to exhibit an α/β doubly wound superfold (Hu et al. 2008). The IIB domain also exhibits an α/β doubly wound superfold, but it is very dissimilar from that of the IIA domain (Orriss et al. 2003). Instead, it has the same topology as phosphoglyceromutase. Since both proteins (IIBMan and PGM) catalyze phosphoryl transfer with a phosphohistidine intermediate, both proteins show a similar distribution of active site residues, and both exhibit similar structures, they are probably homologous. 

Solution structures of complexes between the isolated IIAMan and IIBMan domains of the E. coli mannose EII complex have been solved by NMR (Hu et al. 2008). The complex of wild-type IIAMan and IIBMan is a mixture of two species comprising a productive, phosphoryl transfer competent complex and a non-productive complex with the two active site histidines, His-10 of IIAMan and His-175 of IIBMan, separated by approximately 25Å. Mutation of His-10 to a glutamate to mimic phosphorylation, results in the formation of a single productive complex. The apparent equilibrium dissociation constants for the binding of both wild-type and H10E IIAMan to IIBMan are approximately the same (KD ~0.5 mM). The productive complex can readily accommodate a transition state involving a pentacoordinate phosphoryl group with trigonal bipyramidal geometry bonded to the N-ε2 atom of His-10 and the N-δ1 atom of His-175 with negligible (<0.2 Å) local backbone conformational changes in the immediate vicinity of the active site. The non-productive complex is related to the productive one by an approximately 90 degree rotation and an approximately 37 Å translation of IIBMan relative to IIAMan, leaving the active site His-175 fully exposed to solvent in the non-productive complex (Hu et al. 2008).

The cryo EM structure of the mannose Enzyme IICD complex (ManY/ManZ, respectively) has been solved to 3.52 Å resolution (Liu et al. 2019). The structure in an inward-facing conformation,reveals a three-fold symmetry axis perpendicular to the membrane. The trimer has dimensions of ~104 Å × 104 Å × 73 Å. Each protomer is composed of a ManY and ManZ, which have similar folds and are related to each other by a pseudosymmetry axis parallel to the membrane. ManY consists of nine TMSs, 1–9Y and one horizontal periplasmic amphipathic α-helix (AH1Y), with N- and C-termini of the protein on periplasmic and cytoplasmic sides, respectively. ManZ also contains nine TMSs, but two instead of one horizontal amphipathic α-helices (AH1Z and AH2Z), with N- and C-termini of the protein on cytoplasmic and periplasmic sides, respectively. However, TMSs 1–6Z are located on the cytoplasmic side of the membrane. ManYZ oligomerization is mediated by extensive interactions between two C-terminal TMSs (TMS8Y and TMS9Y) of ManY, mostly through hydrophobic residues. ManY and ManZ can be classified as CoreY, ArmY, and VmotifY as well as CoreZ, ArmZ, and VmotifZ domains, respectively. VmotifY and VmotifZ interlock to form the Vmotif domain of the complex. CoreY and CoreZ clamp the substrate, forming the Core domain. The helices AH1Y and AH1Z are designated the ArmY and ArmZ domains. The two dissimilar subunits can be topologically superimposed, but once ManY and ManZ are aligned according to their CoreY and CoreZ domains, VmotifY and VmotifZ domains swing apart due to different orientations of ArmY and ArmZ. When ManY and ManZ are aligned according to the Vmotif, the Core domains rotate in the membrane, which is assumed to be the root of the elevator mechanism of transport. 

The structure shows a mannose molecule bound to each protomer, caged in an elipsoidal binding pocket of the core domain. The two loops, L12Y and L34Y, of ManY shape the top and left side of the cleft, whereas loops L12Z and L34Z of ManZ shape the bottom side of the pocket. The right-side wall is mainly constructed of residues from TMS5Z. The C6-hydroxyl of the substrate can be phosphorylated by IIB, and it orients to the solvent ready for this phosphorylation event (Liu et al. 2019). The structure and mechanism of mannose-type PTS Enzyme II complexes have been reviewed in detail (Jeckelmann and Erni 2020).

Transport via ManYZ may involve four sequential steps. The default state is probably an outward open state (modeled according to the pseudosymmetry between ManY and ManZ). In this state, the CoreZ domain approaches the VmotifZ domain. Then, the binding of the substrate to the pocket of the Core domain causes a switch to an inward-facing state through the movement of the Core relative to Vmotif. In this inward-facing state, CoreY is close to the VmotifY domain, and the substrate pocket is accessible from the cytoplasmic side. In the third step, IIB transfers the phosphory group from IIB~P to mannose. Mannose-6-P then leaves the binding site and enter the cytosol. Finally, using the energy coupled with the phosphate originally transferred from PEP, the Core domain returns to the default state, and the whole system restarts this cycle of transport (Liu et al. 2019). The EM DataBank # is EMD-9906 while the PDB # is 6K1H.

The generalized reaction catalyzed by members of the Man Family is:

Sugar (out) + PEP (in) → Sugar-P (in) + pyruvate (in).



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TC#NameOrganismal TypeExample

The mannose (glucose, 2-deoxyglucose, glucosamine, N-acetylglucosamine, N-acetylmannosamine, mannosamine and fructose) PTS porter/group translocator, ManXYZ (Rephaeli and Saier 1980; Plumbridge 2015). Catalyzes xylose facilitated diffusion in lactobacilli. The order of D-sugar substrate affinities is: glucose > mannose > 2-deoxyglucose > N-acetylglucosamine > glucosamine > N-acetylmannosamine > mannosamine > fructose (Rephaeli and Saier 1980).  The mechanism appears to be rapid equilibrium, random, bi-bi sequential (Rephaeli and Saier 1980). L-sugars are not transported. This system is allostericallly inhibited by a complex of DicB (62 aas, P09557) and MinC (231 aas, P18186) (Jeckelmann and Erni 2020). At the transcriptional level, the manXYZ operon is regulated by the Mlc transcriptional regulator, and at the translational level it is regulated by the DicF small RNA that is complementary to manXYZ (Jeckelmann and Erni 2020). The 3-d structure of the IIC/IID complex revealed that the N- and C-terminal halves form the transport and scaffold domains, respectively (Liu et al. 2019).  Two 3-helix bundles are mixed by an intersubunit helix swap yielding tight intersubunit contacts with a novel fold. An "elevator" mechanism has been proposed in which the transport domain moves vertically or rotates relative to a stationary scaffold domain, where both the transport and scaffold domains consist of α-helices of both the IIC aqnd IID domains. Only the IIC and IID proteins, not hte IIAB protein are required for lambda phage infectivity (Esquinas-Rychen and Erni 2001).



Mannose IIAB-IIC-IID (ManXYZ) complex of E. coli


The hexose (glucose and fructose demonstrated) PTS uptake system (Kim et al., 2011).


The hexose uptake system IIAB, IIC, IID of Oenococcus oeni 
IIABhex (C) (Q04GK1) 
IIChex (M) (Q04GK0)
IIDhex (M) (Q04GJ9)


Mannose enzyme II complex, IIAB, IIC, IID. IIC/IID serve allows entry of some bacteriocins including pediocin (class IIa), lactococcin A and lactococcin Z (class IIc) (Kjos et al., 2011; Daba et al. 2018). Transports and phosphorylates Glucose, Mannose and Glucosamine.  The IID component is the probably receptor for several bacteriocins, subclass IIa bacteriocins (pediocin-like; pediocins) and subclass IId ones - lactococcin A (LcnA), lactococcin B (LcnB), garvicin Q (GarQ), and garvicins A, B and C (GarA-C) (Tymoszewska et al. 2018). Individual amino acids localized mostly in the sugar channel-forming transmembrane parts of subunit IIC or in the extracellular parts of IID likely are involved in the interaction with each bacteriocin, and these have been specified (Tymoszewska et al. 2018).


IIAB, IIC, and IID of Lactococcus lactis 


Putative Hexose Enzyme II complex, IIABCD


IIABCD of Myxococcus xanthus






Fucosyl-α-1,3-N-acetylglucosamine PTS uptake porter, AlfEFG (next to an operon encoding a fucosidase (AlfB) and a transcriptional regulator of the GntR family, AlfR).  The fucosidase is specific for this disaccharide which is present in mammalian glycoproteins, glycolipids and milk (Rodríguez-Díaz et al. 2012).  Uptake is dependent of AlfF but not on the PTS Enzyme I, suggesting that uptake does not require phosphorylation, consistent with the activity of AlfB as a fucosidase.  Only the glucosamine moiety is utilized and the fucose moiety, after hydrolysis, is excreted (Rodríguez-Díaz et al. 2012).


AlfEFG of Lactobacillus casei.
AlfE  (IIAB)
AlfF  (IIC)
AlfG  (IID)


Probable PTS uptake porter (IIA - IID) for disaccharides of glucuronate and N-acetyglucosamine derived from degradation of hyaluronate and chondroitin by hyaluronidase (Marion et al. 2012). The cytoplasmic phosphorylated disaccharide (possibly glucuronyl-N-acetyglucosamine) may be hydrolyzed by the enzyme Ugl. 


Hyaluronate disaccharide porter of Streptococcus pneumoniae


The mannose PTS Enzymes IIABCD, ManLMN (MptACD). It is the primary inducible sugar transporting system, regulated by ManR, the activity of which is controlled by another mannose-like PTS system (see TC# 4.A.6.1.29) that transports sugars slowly but serves as a glucose sensor that inactivates the ManR activator by a phosphorylation/dephosphorylation mechanism (Aké et al. 2011; Zébré et al. 2015).

Mannose PTS of Listeria monocytogenes
MptA, IIAB, 321 aas (Q7BC72)
MptC, IIC, 268 aas (Q7BC71)
MptD, IID, 303 aas (Q7BC70)


Constitutively synthesized (at a low level) sensor, MpoABCD, controlling expression of the man operon-encoding the ManLMN (MptACD) transport system (see TC# 4.A.6.1.15). The Mpo system interacts with and phosphorylates ManR, the transcriptional regulator of the man operon (Aké et al. 2011). This system is a mannose PTS system, IIABCDMan or MpoABCD that transports its sugar substrates slowly and serves as a glucose (sugar substrate) sensor to regulate the activity of ManR by a phosphorylation/dephosphorylation mechanism. MptACD (TC# 4.A.6.1.15) is the primary inducible sugar transport system. ManR is an activator that is inactivated by a phosphorylation/dephosphorylation mechanism (Aké et al. 2011; Zébré et al. 2015).


MpoABCD of Listeria monocytogenes
MpoA (IID)
MpoB (IIC)
MpoC (IIB)
MpoD (IIA)


D-glucosaminate group translocating uptake porter, DgaABCD (IIA-141 aas, IIB-161 aas, IIC-249 aas, and IID-285 aas, respectively) (Miller et al. 2013).  Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) uses d-glucosaminate (2-amino-2-deoxy-d-gluconic acid) as a carbon and nitrogen source via DgaABCD (d-glucosaminate PTS permease components EIIA, EIIB, EIIC, and EIID). Two other genes in the dga operon (dgaE and dgaF) are required for wild-type growth with d-glucosaminate. Transcription of dgaABCDEF is dependent on RpoN (σ54) and an RpoN-dependent activator gene, dgaR. Introduction of a plasmid bearing dgaABCDEF under the control of the lac promoter into E. coli strains allowed them to grow on minimal medium containing d-glucosaminate. d-Glucosaminate is transported and phosphorylated at the C-6 position by DgaABCD. DgaE converts the resulting d-glucosaminate-6-phosphate to 2-keto-3-deoxygluconate 6-phosphate (KDGP), which is subsequently cleaved by the aldolase DgaF to form glyceraldehyde-3-phosphate and pyruvate. DgaF catalyzes the same reaction as that catalyzed by Eda, a KDGP aldolase in the Entner-Doudoroff pathway, and the two enzymes can substitute for each other in their respective pathways. Orthologs of the dga genes are largely restricted to certain enteric bacteria and a few Firmicutes (Miller et al. 2013).


DgaABCD of Samonella enterica Typhimurium


Uptake porter/group translocator of galacto N-biose (Gal-β-1,3-GalNAc: galactose linked β-1,3 to N-acetylgalactosamine), lacto N-biose (Gal-β-1,3-GlcNAc: galactose linked β-1,3 to N-acetylglucosamine), and D-N-acetylgalactosamine (Bidart et al. 2014). The system is designated the GnbABCD system where GnbA = IIA, GnbB = IIB, GnbC = IIC, and GnbD = IID of the mannose-type PTS Enzyme II complex.  These disaccaride substrates are human milk oligosaccharides and glycoconjugates (Bidart et al. 2014).


GnbABCD of Lactobacillus casei
GnbA, IIA, 126 aas
GnbB. IIB, 160 aas
GnbC, IIC, 305 aas
GnbD, IID, 273 aas


PTS uptake system for glucoselysine and fructoselysine, GfrABCD (Miller et al. 2015).  Two glycases, GfrE and GfrF, are requred for the utilization of these two compounds for growth, respectively, and GfrF was shown to hydrolyze fructoselysine-6-P to lysine and fructose-6-P.  Expression of the operon, gfrABCDEF, is regulated by a transcriptional activator, GfrR and sigma factor RpoN (Miller et al. 2015).  GfrD affects proteolytic processing, a necessary but insufficient step for CadC activation, rendering CadC able to activate target genes involved in lysine metabolism (Lee et al. 2013).

GfrABCD of Salmonella typhimurium
GfrA, IIA, 140 aas
GfrB, IIB, 153 aas
GfrC, IIC, 259 aas
GfrD, IID, 278 aas


Fructose group translocator, LevDEFG (Martin-Verstraete et al. 1995; Stülke et al. 1995; Seip et al. 1997; Charrier et al. 1997).


Fructose IIA-IIB-IIC-IID complex of Bacillus subtilis
LevD (IIA), 146 aas, P26379
LevE (IIB), 163 aas, P26380
LevF (IIC), 268 aas, 7 TMSs, P26381
LevG (IID), 275 aas, 5 - 7 putative TMSs


Putative sorbose PTS Enzyme II complex, IIA, IIB, IIC and IID.  The IIC protein is of 230 aas with 6 - 8 putative TMSs.  The genes encoding IIC and IID are in an operon with an Enzyme I (TC# 8.A.7.1.5) and an HPr (TC# 8.A.8.1.5).

IIC/D of Caldithrix abyssi


Putative Mannose Enzyme II complex including IIA, IIB, IIC and IID; IIC has 231 aas and 6 TMSs.

Mannose Enzyme II complex of Desulfuromonas acetoxidans


PTS Mannose-like Enzyme II complex.  IIC, 257 aas and 6 TMSs.  Hits 4.A.6.2.1, 3.1 and 4.1 with scores of e-6 - e-12.

PTS EII complex of Peptoclostridium difficile


Putative Enzyme II complex consisting of IIA, IIB, IIC and IID; IIC has 240 aas and 6 putative TMSs.

Putative EII complex of Gemmatimonas aurantiaca


Mannose (Man)-type PTS with IIA (129 aas), IIB (167 aas) and IICD (534 aas). The Enzyme I and HPr proteins of this system are 8.A.7.1.6 and 8.A.8.1.6, respectively.  The IICD protein appears to have 8 TMSs in the IIC domain and 5 TMSs in the IID domain.

Mannose PTS (IIA, IIB, and IICD) of Thermofilum pendens
IIA of 129 aas
IIB of 167 aas
IICD of 534 aas


D-ribitol (D-aldonitol) (a pentitol) PTS Enzyme II complex RtlABCD (Bourand et al. 2013).

RtlABCD of Lactobacillus casei


L-Sorbose PTS enzyme II complex, SorABCD (enzymes IIABCD, respectively (Yebra et al. 2000)). Two operons, encoding the strcutural genes (one homologous to D-glucitol-6-P dehydrogenase) as well as the regulatory genes, are induced by growth on L-sorbose.

SorABCD of Lactobacillus casei
SorA, 164 aas
SorB, 138 aas
SorC, 277 aas
SorD, 282 aas


The Mannose Enzyme IIA/IIB/IIC-IID proteins of the PTS in which the two domains of IIC and IID are fused in a single polypeptide chain, but the IIA and IIB domains are separate proteins (Navdaeva et al. 2011).

Mannose transport system of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)
IIA, 136 aas (Q8RD55)
IIB, 167 aas (Q8RD54)
IIC-IID, 554 aas (Q8RD53)


Mannose PTS system, IIABCDMan or MpoABCD that transports its sugar substrates slowly and serves as a glucose sensor to regulate the activity of ManR by a phosphorylation/dephosphorylation mechanism. The mannose PTS Enzymes, ManLMN (MptACD), is regulated by ManR. MptACD is the primary inducible sugar transporting system. ManR is regulated by MpoABCD which transports sugars slowly and serves as a glucose (sugar) sensor that inactivates the ManR activator by a phosphorylation/dephosphorylation mechanism (Aké et al. 2011; Zébré et al. 2015).

MpoABCD of Listeria monocytogenes


Sorbose porter (Wehmeier et al. 1995). It also supports mannose transport and phosphorylation.  In E. coli, this system does not support lambda phage infection although the Bacillus subtilis ortholog does (Martin-Verstraete et al. 1996).


Sorbose IIA-IIB-IIC-IID complex of Klebsiella pneumoniae


N-acetyl galactosamine (GalNAc or Aga) porter (used the same IIA protein (AgaF) as does 4.A.6.1.5) (Brinkkötter et al. 2000).


AgaVWEF complex (IIAga) of E. coli


Galactosamine (GalN or Gam) porter (used the same IIA protein (AgaF) as does 4.A.6.1.4) (Brinkkötter et al. 2000).


AgaBCDF complex (IIGam) of E. coli


Glucose porter, ManLMN (Yebra et al., 2006)

BacteriaManLMN of Lactobacillus casei
ManL (IIAB) (AAY63962)
ManM (IIC) (AAY63963)
ManN (IID) (AAY63964)
4.A.6.1.7The glucose/mannose/2-deoxyglucose/fructose phosphotransferase systems (phosphorylates without transport), ManLMN (Cochu et al., 2003)BacteriaManLMN of Streptococcus thermophilus
ManL (IIAB) (Q5M5W6)
ManM (IIC) (Q5M5W7)
ManN (IID) (Q5M5W8)

The gluconate PTS uptake system. IIAGnt and IIBGnt form a high affinity 2:2 heterotetrameric complex (Brockmeier et al., 2009; Reinelt et al., 2009).


The PTS gluconate uptake system of Enterococcus faecalis
IIAGnt (Q82ZC8)
IIBGnt (Q82ZC7)
IICGnt (Q82ZC5)
IIDGnt (Q82ZC6)


The fucose PTS uptake transporter, IIA/IIB/IIC/IIDFuc (FcsABCD) (Manzoor et al. 2015). Expression in response to fucose is under the control of the FcsR transcriptional activator, and its DNA binding site has been identified (Manzoor et al. 2015).


FucTA, B, C, D (also called FcsABCD) of Streptococcus pneumoniae
FucTA (IIA) (Q97N91)
FucTB (IIB) (Q97N92)
FucTC (IIC) (Q97N93)
FucTD (IID) (Q97N94)


TC#NameOrganismal TypeExample

Uncharacterized PTS Enzyme II complex with a putative IIC protein of 225 aas and 6 TMSs in a 3 + 3 arrangement.  The IIA, IIB and IIC components are encoded adjacent to each other in a single operon.

UP of Desulfovibrio hydrothermalis


Putative Mannose-type PTS Enzyme II complex. IIC has 248 aas and 6 TMSs.

EII complex of Desulfohalobium retbaense


TC#NameOrganismal TypeExample

Uncharacterized putative Enzyme II complex including IIA, IIB, IIC and IID.  The IIC protein is of 227 aas with 6 predicted TMSs.

Enzyme II complex of Mucispirillum schaedleri


TC#NameOrganismal TypeExample

Putative mannose/fructose/sorbose PTS Enzyme IIC of 304 aas with 11 predicted TMSs.  No IIA, IIB or IID domain for the mannose/sorbose PTS family was identified in the entire proteome of A. arabaticum.

Putative PTS Enzyme IIC of Acetohalobium arabaticum


Uncharacterized protein of 304 aas and 11 TMSs

UP of Halobacteroides halobius


TC#NameOrganismal TypeExample

Putative multi-domain sensor signal transduction histidine kinase of 562 aas with 6 N-terminal TMSs.

Putative sensor kinase with an N-terminal 6 TMS domain resembling PTS Mannose-like IIC proteins of Roseibium sp. TrichSKD4