Source: http://tcdb.org/tcfamilybrowse.php?tc=2.A.7
Timestamp: 2019-04-22 16:27:04+00:00

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The DMT Superfamily consists of 35 recognized families, each, in general, with a characteristic function, size and topology (Jack et al., 2001; Västermark et al., 2011). These phylogenetic families will be presented and described below; references, when available, will be provided, and representative well-characterized proteins, when available, will be tabulated. Lolkema et al. (2008) have presented bioinformatic analysis of prokaryotic members of the DMT (DUF606) superfamily concerning evolution of the antiparallel arrangements of the two homologous 5TMS domains. Recent advances have led to the proposal that the primordial SMR-type permeases resulted from duplication of a 2 TMS-encoding genetic element, which added one TMS to give five TMSs, and then duplicated to give 10 TMS proteins: 2 → 4 → 5 → 10 (TMSs), (Lam et al., 2011). One member of the SMR-2 family (2.A.7.22.2) is a lipid (isoprenoid) flippase (Yan et al., 2007; Contreras et al., 2010). Most nucleotide-sugar transporter in the endoplasmic reticulum and Golgi of eukaryotic cells are members of the DMT superfamily (Song 2013).
SMR family pumps are prokaryotic transport systems consisting of homodimeric or heterodimeric structures (Chung and Saier, 2001; Bay et al., 2007; Bay and Turner 2009). The subunits of these systems are of 100-120 amino acid residues in length and span the membrane as α-helices four times. Functionally characterized members of the SMR family catalyze multidrug efflux driven drug:H+ antiport where the proton motive force provides the driving force for drug efflux. The drugs transported are generally cationic, and a simple cation antiport mechanism involving the conserved Glu-14 has been proposed (Yerushalmi and Schuldiner, 2000). This mechanism suggests a requisite, mutually exclusive occupancy of Glu-14, providing a simple explanation for coupling the movement of two positively charged molecules. One system (YdgEF of E. coli; TC# 2.A.7.1.8) is reported to confer resistance to anionic detergents (Nishino and Yamaguchi, 2001).
The 3-D structure of the dimeric EmrE shows opposite orientation of the two subunits in the membrane (Chen et al., 2007). The first three transmembrane helices from each monomer surround the substrate binding chamber, whereas the fourth helices participate only in dimer formation. Selenomethionine markers clearly indicate an antiparallel orientation for the monomers, supporting a 'dual topology' model. On the basis of available structural data, a model for the proton-dependent drug efflux mechanism of EmrE was proposed. Interestingly, Nasie et al., (2010) suggest that EmrE can insert randomly in two orientations and can exhibit activity in both the parallel and antiparallel orientations. The orientation of small multidrug resistance transporter subunits in the membrane correlate with the positive-inside rule (Kolbusz et al., 2010). 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 BAT family consists of 5 TMS proteins from bacteria and archaea. None of these proteins is functionally characterized.
The DME family is a large family of integral membrane proteins with sizes ranging from 287 to 310 amino acyl residues and exhibiting 10 putative α-helical transmembrane spanners (TMSs). These proteins are derived from phylogenetically divergent bacteria and archaea, and B. subtilis, E. coli, S. coelicolor and A. fulgidus have multiple paralogues. Distant eukaryotic homologues are more closely related to DME family members than to other DM superfamily members can be found (i.e., the Riken gene product of the mouse (BAC31006)).
Proteins of the DME family evidently arose by an internal gene duplication event as the first halves of these proteins are homologous to the second halves. One of these prokaryotic proteins, YdeD, is functionally characterized and exports cysteine metabolites in E. coli. Another, RhtA of E. coli, exports threonine and homoserine. A third, Sam of Rickettsia prowazekii, takes up S-adenosylmethionine (TC #3.A.7.3.7; Tucker et al., 2003). In addition, several members of the DME family have been implicated in solute transport. Thus, the MttP protein of the archaeon, Methanosarcina barkeri, may transport methylamine (Ferguson and Krzycki, 1997); MadN is encoded within the malonate utilization operon of Malonomonas rubra and may be an acetate efflux pump, and PecM is encoded within a locus of Erwinia chrysanthemi controlling pectinase, cellulase and blue pigment production and might export the pigment indigoidine, produced by gene products encoded in the pecM operon. The PecM protein has been shown experimentally to exhibit a 10 TMS topology (Rouanet and Nasser, 2001).
The P-DME family is a large subset of the DME family. All of these proteins are derived from plants, and they cluster loosely together on a phylogenetic tree that includes all members of the DME and P-DME families. All of these proteins appear to have 10 TMSs. If this suggestion proves to be correct, then the two halves of these proteins will have opposite orientation in the membrane. Hydropathy plots suggest that families 2.A.7.3-2.A.7.14 all exhibit 10 putative TMSs. No member of the P-DME family is functionally characterized, although one of these proteins, Nodulin 21 of M. truncatula, may be involved in bacterial nodulation.
The glucose/ribose uptake (GRU) family includes two functionally characterized members, a glucose uptake permease of Staphylococcus xylosus, and a probable ribose uptake permease of Lactobacillus sakei. Both proteins probably function by H+ symport.
The RhaT family includes only 2 proteins, the rhamnose:H+ symporters of E. coli and Salmonella typhimurium, both of which have been functionally characterized. The RhaT proteins of both species are 344 aas long with 10 putative TMSs.
No member of the RarD family is functionally characterized. Members of the family are from Gram-negative bacteria, Gram-positive bacteria and possibly archaea. They vary in size from 250-300 residues. They exhibit 10 TMSs.
The CEO family is a small family of 6 paralogues encoded within the genome of C. elegans. None of these proteins is functionally characterized.
Functionally characterized members of the former TPT family are derived from the inner envelope membranes of chloroplasts and nongreen plastids of plants. However, homologues are also present in yeast. Saccharomyces cerevisiae has three functionally uncharacterized TPT paralogues encoded within its genome. Under normal physiological conditions, chloroplast TPTs mediate a strict antiport of substrates, frequently exchanging an organic three carbon compound phosphate ester for inorganic phosphate (Pi). Normally, a triose-phosphate, 3-phosphoglycerate, or another phosphorylated C3 compound made in the chloroplast during photosynthesis, exits the organelle into the cytoplasm of the plant cell in exchange for Pi. These transporters are members of a subfamily, the TPT subfamily within the TPT family. Experiments with reconstituted translocators in artificial membranes indicate that transport can also occur by a channel-like uniport mechanism with up to 10-fold higher transport rates. Channel opening may be induced by a membrane potential of large magnitude and/or by high substrate concentrations. Nongreen plastid and chloroplast carriers, such as those from maize endosperm and root membranes, mediate transport of C3 compounds phosphorylated at carbon atom 2, particularly phosphoenolpyruvate, in exchange for Pi. These are the phosphoenolpyruvate:Pi antiporters (the PPT subfamily). Glucose-6-P has also been shown to be a substrate of some plastid translocators (the GPT subfamily). These three subfamilies of proteins (TPT, PPT and GPT) are divergent in sequence as well as substrate specificity, but their substrate specificities overlap.
Each TPT family protein consists of about 400-450 amino acyl residues with 5-8 putative transmembrane α-helical spanners TMSs). The actual number has been proposed to be 6 for the plant proteins as for mitochondrial carriers (TC# 2.A.29) and members of several other transporter families. However, proteins of the TPT family do not exhibit significant sequence similarity with the latter proteins, and there is no evidence for an internal repeat sequence. TPT proteins may exist as homodimers in the membrane.
organic phosphate ester (in) + Pi (out) ⇌ organic phosphate ester (out) + Pi (in).
Nucleotide-sugar transporters (NSTs) are found in the Golgi apparatus and the endoplasmic reticulum of eukaryotic cells. Members of the family have been sequenced from yeast, protozoans and animals. Animals such as C. elegans possess many of these transporters. Humans have at least two closely related isoforms of the UDP-galactose:UMP exchange transporter.
NSTs generally appear to function by antiport mechanisms, exchanging a nucleotide-sugar for a nucleotide. Thus, CMP-sialic acid is exchanged for CMP; GDP-mannose is preferentially exchanged for GMP, and UDP-galactose and UDP-N-acetylglucosamine are exchanged for UMP (or possibly UDP). Other nucleotide sugars (e.g., GDP-fucose, UDP-xylose, UDP-glucose, UDP-N-acetylgalactosamine, etc.) may also be transported in exchange for various nucleotides, but their transporters have not been molecularly characterized. Each compound appears to be translocated by its own transport protein. Transport allows the compound, synthesized in the cytoplasm, to be exported to the lumen of the Golgi apparatus or the endoplasmic reticulum where it is used for the synthesis of glycoproteins and glycolipids. Comparable transport proteins exist for ATP which phosphorylates proteins, and phosphoadenosine phosphosulfate (PAPS) which is used as a percursor for protein sulfation. It is not known if these transport proteins are members of the DMT superfamily.
The sequenced NSTs are generally of about 320-340 amino acyl residues in length and exhibit 8-12 putative transmembrane α-helical spanners. An 8 TMS model has been presented by Kawakita et al. (1998) for the human UDP galactose transporter 1.
The yeast VRG4 protein, also called 'vanidate resistance protein', is a GDP-mannose transporter with the same size and topology as the other NSTs, but it shows very little sequence similarity with them. Only with the PSI-BLAST program with one iteration do these proteins exhibit apparent similarity. VRG4 is most similar to proteins in C. elegans, Leishmania donovani, Arabidopsis thaliana, and another S. cerevisiae protein reported to be of 249 aas (spP40027).
A single member of the POP family (AtPUP1) has been functionally characterized. It has been shown to transport adenine and cytosine with high affinity. Evidence concerning energy coupling suggested an H+ symport mechanism. Purine derivatives (e.g., hypoxanthine), phytohormones (e.g., zeatin and kinetin) and alkaloids (e.g., caffeine) proved to be competitive inhibitors suggesting that they may be transport substrates. In fact trans-zeatin (a cytokinin) has been shown to be taken up, probably by at least two systems (Cedzich et al. 2008). The order of inhibition of adenine uptake by a variety of purine derivatives, phytohormones and alkaloids was reported to be: adenine, kinetin, caffeine, cytosine, zeatin, hypoxanthine, cytidine, nicotine, kinetin riboside, adenosine, zeatin riboside and thymine (Williams and Miller, 2001). At least 15 members of this family have been sequenced from A. thaliana (Gillissen et al., 2000). Thus, AtPUP1 may be a broad specificity organocation transporter. Other family members have been reported to exhibit different affinities for nucleobases.
The ArAA/PE family is a small family of proteobacterial proteins with 10 putative TMSs and sizes and sequences that most resemble the proteins of the DME family (2.A.7.3) within the DMT superfamily. One member of this family, YddG of E. coli and Salmonella typhimurium (<95% identical), have been functionally characterized (Santiviago et al., 2002; Doroshenko et al., 2007). They are efflux pumps for paraquat (methyl viologen) which is a hydrophilic, doubly charged, quaternary ammonium compound that can participate in a redox cycle that generates oxygen free radicals in the bacterial cell under aerobic conditions. YddG cannot pump out acriflavin, showing that it is fairly specific. It also exports aromatic amino acids. Therefore, it may not be a multidrug resistance pump. Paraquat resistance is also dependent on the major Salmonella porin, OmpD. Thus, YddG and OmpD are believed to function together in exporting paraquat to the external medium, but it is not known if this occurs in one or two steps (Santiviago et al., 2002).
Paraquat (in) → Paraquat (out).
A single functionally characterized secondary transporter, LicB of Haemophilus influenzae defines the LicB-T family (Fan et al., 2003). It has 292 aas and 10 putative TMSs.
LicB is a high-affinity choline permease that takes up choline under choline-limiting conditions. It is required for the use of exogenous choline for the synthesis of phosphorylcholine which is incorporated into the bacterium's lipopolysaccharide (LPS). It does not play a role in osmoprotection. Phosphorylcholine derivatized LPS contributes to H. influenzae's pathogenesis by mimicry of host cell molecules (Fan et al., 2003).
choline (out) + H+ (out) → choline (in) + H+ (in).
The allantoin permeases of Phaseolus vulgaris (French bean) and Arabidopsis thaliana have been shown to transport uracil and fluorouracil as well as allantoin (Schmidt et al., 2004). Arabidopsis has several paralogues. Distant homologues are present in Bacteroides thetaiotamicron (AAO77915) and Entamoeba histolyticia (EAL46705). These proteins have 10 putative TMSs and comprise a distinct family in the DMT superfamily.
The Plasmodium falciparum chloroquine resistance protein (PfCRT) is a transporter as are its homologues in various species. In Plasmodium species it is localized to the intra-erythrocytic digestive vacuole. Mutations in this protein confer Verapamil-reversible chloroquine resistance to P. falciparum. The mutations in PfCRT give rise to increased compartment acidification. PfCRT-related changes in chloroquine response involve altered drug flux across the parasite degestive vacuole membrane. It has been concluded that PfCRT directly mediates efflux of chloroquine from the digrestive vacuole (Bray et al., 2005).
PfCRT is a 423 amino acyl protein with 10 putative TMSs, it probably catalyzes chloroquine quinine flux with H+ across the digestive vacuole membrane (Wellems, 2002). It is a member of the drug metabolite transporter (DMT) superfamily (TC #2.A.7) (Tran and Saier, 2004). In frog oocytes it has been reported to activate various endogenous transporters (Nessler et al., 2004). It transports a variety of qunoline drugs including quinine and quinidine. Mutations in TMSs 1, 4 and 9 alter drug specificity and determine levels of accumulation, suggesting that these TMSs play a role in substrate binding (Cooper et al., 2007). Chloroquine-resistance reversers are substrates for mutant PfCRTs (Lehane and Kirk, 2010).
The BAT2 family consists of 5 TMS proteins that resemble BAT family (2.A.7.2) proteins in size and topology, but show almost no sequence similarity with them.
The SMR2 family consists of 4 TMS proteins, most about 110-130 aas long, but some longer, that resemble the SMR family (2.A.7.1) proteins in size and topology. However, they show almost no sequence similarity. Not all of them have the conserved glutamate in TMS1. All close members of this family are from bacteria, but one distant member from Neurospora crassa has this domain N-terminal, fused to a CysT flavodoxin domain followed by a C-terminal radical SAM domain (Nicolet and Drennan, 2004). This protein (gi85104851) is reported to be 1061 aas long. Because this is the only protein in the database with this combination of fused domains, it could be artifactual. Another homologue from Frankia alni (419 aas; gi111220000) has a putative 9 TMS topology with a C-terminal 300 residue hydrophilic domain. Another protein, the TibA precursor glycoprotein adhesin/invasin of E. coli (336 aas; gi72166756) has 8 or 9 putative TMSs plus a C-terminal hydrophilic domain of nearly 100 residues. It may be distantly related to members of the DME family (2.A.7.3).
Expression of the Bacillus subtilis tryptophan biosynthetic genes trpEDCFBA and trpG, as well as a putative tryptophan transport gene (trpP), are regulated in response to tryptophan by the trp RNA-binding attenuation protein (TRAP). TRAP regulates expression of these genes by transcription attenuation and translation control mechanisms. TRAP and tryptophan also regulate translation of ycbK, a gene that encodes a protein of 312 aas and 10 TMSs, distantly related to members of the DMT superfamily (Yakhnin et al., 2006).
This family includes a diverse group of proteins from all types of eukaryotes as well as prokaryotes. The only one with an assigned probable function is the Thi74 protein of yeast. These proteins have 10 TMSs in a 2 + 8 arrangement (possibly 2 + 4 + 4). No mechanistic details of the transport process are available.
TPP (out) → TPP (in).
Mutations in the NIPA1(SPG6) gene of man, named for 'nonimprinted in Prader-Willi/Angelman' has been implicated in one form of autosomal dominant hereditary spastic paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and weakness. HSP comprises more than 30 genetic disorders whose predominant feature is a spastic gait. Mutations in at least six genes have been associated with autosomal dominant HSP including NIPA1(SPG6).
Reduced magnesium concentration enhances expression of NIPA1 suggesting a role in cellular magnesium metabolism. Indeed, NIPA1 mediates Mg2+ uptake that is electrogenic, voltage-dependent, and saturable with a Michaelis constant of 0.69 ± 0.21 mM when expressed in Xenopus oocytes (Goytain et al. 2007). Subcellular localization with immunofluorescence showed that endogenous NIPA1 protein associates with early endosomes and the cell surface in a variety of neuronal and epithelial cells. As expected of a magnesium-responsive gene, altered magnesium concentration leads to a redistribution between the endosomal compartment and the plasma membrane; high magnesium results in diminished cell surface NIPA1 whereas low magnesium leads to accumulation in early endosomes and recruitment to the plasma membrane. The mouse NIPA1 mutants, T39R and G100R, corresponding to the respective human mutants, showed a loss of function when expressed in oocytes and altered trafficking in transfected COS7 cells. NIPA1 seems to encode a Mg2+ transporter, and the loss of function of NIPA1(SPG6) due to abnormal trafficking of the mutated protein provides the basis of the HSP phenotype (Goytain et al. 2007).
NIPA has nine putative TMSs. Its mechanism of action is not known. It could be a channel or a carrier, and its energy dependency has not been studied. Homologues are found in a wide variety of animals, plants, and fungi. However, this family is clearly a member of the DMT superfamily (M. H. Saier, unpublished results).
YnfA is a 108 aa E. coli protein with 4 established TMSs and both the N- and C-termini in the periplasm (Drew et al., 2002). Its homologues are found in a broad range of Gram-negative and Gram-positive bacteria as well as archaea and eukaryotes. The sizes of bacterial homologues range from 98 aas to 132 aas, with a few exceptions. Plant proteins can be as large as 197aas. The first two TMSs are homologous to the second two in these 4 TMS proteins. A Methanosarciniae mazei homologue of 94 aas and a Geobacillus kaustophilus homologue of 104 aas have only 2 TMSs with 30 residue extensions C- and N-terminal, respectively. No functional data are available for any of its homologues. This family is the YnfA UPF0060 family.
This family belongs to the Drug/Metabolite Transporter (DMT) Superfamily.
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Small multidrug efflux pump, Smr (QacC, QacD, Ebr). Substrates: (1) aromatic dyes (e.g., ethidium bromide), (2) quaternary amines (e.g., the disinfectant benzalkonium) and (3) derivatives of tetraphenylphosphonium (TPP) (Fuentes et al. 2005).
SugE Supressor of GroEL/ES (He et al., 2011). Confers resistance to cetyltrimethylammonium bromide, cetylpyridinium chloride, tetraphenylphosphonium, benzalkonium chloride, ethidium bromide, and sodium dodecyl sulfate.
Small MDR pump, AbeS (53% identical to EmrE of E. coli; TC# 2.A.7.1.3). Exports chloramphenicol, ciprofloxacin, erythromycin, novobiocin, acridine orange, acriflavine, benzalkonium chloride, DAPI, deoxycholate, ethidium bromide, sodium dodecyl sulfate (SDS), tetraphenylphosphonium and others (Srinivasan et al., 2009; Lytvynenko et al. 2015). Purified AbeS binds tetraphenylphosphonium with nanomolar affinity and exhibits electrogenic transport of 1-methyl-4-phenylpyridinium after reconstitution into liposomes (Lytvynenko et al. 2016).
Small multidrug resistance (SMR) family member of 116 aas and 4 TMSs.
Putative quaternary amonium transporterof 124 aas and 4 TMSs.
Putative QacE family quaternary ammonium compound efflux (SMR-type) transporter of 108 aas and 4 TMSs.
Small multidrug efflux pump (substrates: isoniazid, tetraphenylphosphonium (TPP), erythromycin, ethidium bromide, acriflavine, safranin O and pyronin Y) (Rodrigues et al. 2013).
Small cationic multidrug efflux pump (substrates: cationic lipophilic drugs), EmrE. This pump confers resistance to a wide range of disinfectants and dyes known as quaternary cation compounds (QCCs). The 3-D structure of the dimeric EmrE shows opposite orientation of the two subunits in the membrane (Chen et al., 2007), and this conclusion has been confirmed (Fleishman et al. 2006; Lehner et al. 2008; Lloris-Garcerá et al. 2013). There may be a single intermediate state in which the substrate is occluded and immobile (Basting et al., 2008). Direct interaction between substrates (tetraphenylphosphonium, TPP+ and MTP+) and Glu14 in TMS1 has been demonstrated using solid state NMR (Ong et al. 2013). A Gly90X6Gly97 motif is important for dimer formation (Elbaz et al., 2008). Two models may account for the opposite (inverted) orientations of the two identical subunits. A post-translational model posits that topology remains malleable after synthesis and becomes fixed once the dimer forms. A second, co-translational model, posits that the protein inserts in both topologies in equal proportions (Woodall et al. 2015). Protonation of E14 leads to rotation and tilt of transmembrane helices 1-3 in conjunction with repacking of loops, conformational changes that alter the coordination of the bound substrate and modulate its access to the binding site from the lipid bilayer. The transport model that emerges posits a proton-bound, but occluded, resting state. Substrate binding from the inner leaflet of the bilayer releases the protons and triggers alternating access between inward- and outward-facing conformations of the substrate-loaded transporter, thus enabling antiport without dissipation of the proton gradient (Dastvan et al. 2016). TMS4 is the known dimerization domain of EmrE (Julius et al. 2017). Few conserved residues are essential for drug polyselectivity. Aromatic QCC selection involves a greater portion of conserved residues compared to other QCCs (Saleh et al. 2018).
The topologies of helical membrane proteins are generally defined during insertion of the transmembrane helices, yet topology can change after insertion. In EmrE, topology flipping occurs so that the populations in both orientations equalize. Woodall et al. 2017 demonstrated that when EmrE is forced to insert in a distorted topology, topology flipping of the first TMS can occur, and topological malleability also extends to the C-terminal helix; even complete inversion of the entire EmrE protein can occur after the full protein is translated and inserted. Thus, topological rearrangements appear to be possible during biogenesis. Subtle but significant differences in the sizes of EmrE with different QCC ligands bound has been reported (Qazi and Turner 2018).
The drug resistance efflux pump, Hsmr (Ninio and Schuldiner, 2003) (exports ethidium, acriflavin tetraphenylphosphonium (TPP) and other cationic drugs). Inhibited by a peptide with the sequence of TMS4 (Poulsen and Deber 2012). TMS4-TMS4 interactions may constitute the highest affinity locus for dimerization (Poulsen et al. 2009).
The putative heterodimeric SMR efflux pump, NepAB, encoded in a nicotine degradation plasmid, pAO1 (Baitsch et al., 2001; Brandsch, 2006); [probably exports methylamine; may also export excess nicotine, methylamine and/or the intermediate of nicotine catabolism, N-methyl-aminobutyrate] (Ganas et al. 2007). Uptake (Km=6μM) occurs by facilitated diffusion (Ganas and Brandsch, 2009).
The spermidine exporter, MdtIJ (MdtIJ = YdgEF) (Higashi et al., 2008). Catalyzes the export of spermidine and putrescine, and confers resistance to deoxycholate and SDS (Nishino and Yamaguchi 2001). It can be induced by these polyamines and bile salts. Details of the induction mechanism are known (Leuzzi et al. 2015).
The bifunctional Golgi nucleotide sugar transporter with specificity for UDP-xylose and UDP-N-acetylglucosamine, SLC35B4 (Ashikov et al., 2005).
Endoplasmic reticular multifunctional nucleotide sugar transporter, Efr. Substrates include GDP-fucose which can be used to fucosylate the luminar domain of the transmembrane NOTCH receptor (Ishikawa et al. 2010).
ER/Golgi UDP-N-acetylglucosamine transporter, Yea4 of 342 aas. Required for chitin biosynthesis (Roy et al. 2000). Extracellular UDP-sugars promote cellular responses by interacting with widely distributed P2Y(14) receptors, and the ER/Golgi lumen constitutes a source of extracellular UDP-sugars (Sesma et al. 2009). Yea4 therefore plays a critical role in nucleotide sugar-promoted cell signaling.
UDP-galactose:UMP antiporter. Residues essential or important for activity have been identified (Chan et al. 2010).
Translocates adenosine 3'-phosphate 5'-phosphosulfate, PAPS, the high-energy sulfate donor from the cytosol to the Golgi lumen for sulfation of glycoproteins, proteoglycans and glycolipids.
UDP-glucose transporter, UGT4. Does not transport UDP-galactose (Seino et al. 2010).
CMP-sialic acid:CMP antiporter. Amino acid residues important for CMP-sialic acid recognition have been identified (Takeshima-Futagami et al., 2012). Residues essential for activity have been identified (Chan et al. 2010).
Golgi CMP-sialic acid:CMP exchange transporter. Used for glycosylation within the Golgi lumen. Amino acid residues important for CMP-sialic acid recognition have been identified (Takeshima-Futagami et al., 2012). Loss of function results in ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria (Mohamed et al. 2013). SLC35A1 and SLC35C1, have been related to congenital disorder of glycosylation II (CDG II) (Song 2013).
Putative Golgi UDP-sugar transporter, SLC35A4. A modulatory role for SLC35A4 in intracellular trafficking of SLC35A2/SLC35A3 complexes has been proposed (Sosicka et al. 2017).
Pig Golgi-resident UDP-N-acetylglucosamine transporter of 325 aas and 10 TMSs with the N- and C-termini in the cytoplasm, SLC35A3. Essential TMSs and residues have been identified (Andersen et al. 2007).
Golgi UDP-galactose and UDP-N-acetylgalactosamine:UDP antiporter UGT or SLC35A2 (orthologue of 2.A.7.12.5) (Segawa et al., 2002). Transports nucleotide sugars from the cytosol into Golgi vesicles where glycosyltransferases function. Residues essential for activity, and mechanisms of transport by UGT allow greater understanding of the relationship between mutations in this protein and disease (Li and Mukhopadhyay 2019).
Golgi GDP-mannose:GMP antiporter, (vanadate resistance protein), VRG4 or VIG4 (Abe et al. 1999).
Golgi GDP-mannose:GDP antiporter, GONST1 (Baldwin et al., 2001).
Golgi GDP-mannose transporter, GONST2 of 375 aas (Handford et al. 2004).
Putative nucleotide sugar transporter GONST3 (Protein GOLGI NUCLEOTIDE SUGAR TRANSPORTER 3) (Handford et al. 2004).
Golgi GDP-mannose transporter of 397 aas and 10 TMSs, Gmt1. Necessary for capsular biosynthesis, protein gycosylation and virulence (Wang et al. 2014).
Golgi GDP-mannose transporter, Gmt2. Functions in capsular polysaccharide biosynthesis, protein glycosylation and virulence (Wang et al. 2014).
Purine/pyrimidine organocation uptake permease, AtPUP1. A thaliana has 15 paralogues, AtPUP1 to AtPUP15 (Gillissen et al. 2000). PUP1 transports adenine and cytosine with high affinity by a pmf-dependent mechanism. Purine derivatives (e.g., hypoxanthine), phytohormones (e.g., zeatin and kinetin), and alkaloids (e.g., caffeine) are potent competitive inhibitors of adenine and cytosine uptake and are probably substrates (Gillissen et al. 2000).
Tobacco nicotine uptake permease 1, NUP1, of 353 aas and 10 TMSs. NUP1 transports tobacco alkaloids such as nicotine, but also efficiently takes up pyridoxamine, pyridoxine and anatabine. The naturally occurring (S)-isomer of nicotine was preferentially transported over the (R)-isomer. NUP1, similar to PUP1 of A. thaiana, transported various compounds containing a pyridine ring, but the two transporters had distinct substrate preferences (Kato et al. 2015).
The Golgi UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose transporter, SQV-7-like protein SQV7L, homologue of Fringe connection protein 1 (involved in Notch signalling by transporting UDP-N-acetylglucosamine) HFRC1, Slc35D1. Transports UDP-N-acetylglucosamine (UDP-GlcNAc), UDP-glucose (UDP-Glc), and GDP-mannose (GDP-Man), with apparent Km values of 8, 2, and 0.14 μM, respectively (Suda et al. 2004).
The Golgi transporter, SQV-7. Transports UDP-glucuronic acid, UDP-N-acetylgalactosamine, and UDP-galactose (Gal). These nucleotide sugars are competitive, alternate, noncooperative substrates. Mutant sqv-7 missense alleles result in severe reductions of these three transport activities. SQV-7 did not transport CMP-sialic acid, GDP-fucose, UDP-N-acetylglucosamine, UDP-glucose, or GDP-mannose (Berninsone et al. 2001).
Endoplasmic reticulum (ER)/Golgi antiporter for UDP-glucuronic acid, UDP-N-acetylglucosamine and possibly UDP-xylose in exchange for UDP, Fringe connection (Frc) Essential for several signalling pathways including heparan sulfate and Fringe-dependent signalling (Selva et al. 2001). Involved in glycosylation and processing of Notch (Goto et al. 2001).
The GDP-fucose transporter (GFT) (defective in human leukocyte adhesion disease II) (SLC35C1) (Zhang et al. 2012). SLC35A1 and SLC35C1, have been related to congenital disorder of glycosylation II (CDG II) (Song 2013).
Golgi GDP-fucose-specific transporter, Gfr or CG9620 (Luhn et al., 2004). It is required for glycan fucosylation and can also fucosylate NOTCH, a transmembrane cell fate determining receptor (Ishikawa et al. 2010). Another transporter, the endoplasmic reticular Efr (TC# 2.A.7.10.4), can also fucoslyate NOTCH but not glycans.
Aromatic amino acid exporter (exports Phe, Tyr, Trp, and their toxic analogues (Doroshenko et al., 2007)). Also called the paraquat (methyl viologen) exporter, YddG (also exports benzyl viologen and possibly L-alanine; Hori et al., 2011). The topology of YddG has been shown to be 10 TMSs with N- and C- termini on the inside (Airich et al., 2010).
General amino acid exporter (probably including aromatic amino acids as well as thr, met lys, glu and others), YddG. Its topology with 10 TMSs and both the N- and C-termini inside has been established (Airich et al. 2010). This system has been used for the export of tryptophan for commercial purposes (Wang et al. 2013). The 3-d structures (PD# 5I20) of a homologue (TC# 2.A.7.3.66) has been determined at 2.4 Å resolution, showing the outward facing conformation of a basket shaped structure with a central substrate binding cavity (Tsuchiya et al. 2016).
2.A.7.18.3 The archael putative permease MttP2 (MA0929) (possibly a methyl amine uptake porter; D.J Ferguson, personal communication). (9 putative TMSs; The N-terminal TMS may be missing).
The uptake transporter for allantoin (Km = 50 μM) and other oxo derivatives of nitrogen heterocyclic compounds, UPS1 (ureide:H+ symport permease) (10 TMSs; 5 paralogues in Arabidopsis). Also transports purine degradation products such as uric acid and xanthine but not adenine (Desimone et al., 2002).
Ureide Permease 5, UPS5 of 415 aas and 10 TMSs. Proton-coupled transporter that transports a wide spectrum of oxo derivatives of heterocyclic nitrogen compounds, including allantoin, uric acid and xanthine, but not adenine. Mediates transport of uracil and 5-fluorouracil (a toxic uracil analog) (Schmidt et al. 2006). Allantoin accumulation mediated by UPS5 confers salt stress tolerance (Lescano et al. 2016).
Ureide permease 2, UPS2, of 398 aas and 10 TMSs. Proton-coupled transporter that transports a wide spectrum of oxo derivatives of heterocyclic nitrogen compounds, including allantoin, uric acid and xanthine, but not adenine. Mediates high affinity transport of uracil and 5-fluorouracil (a toxic uracil analog). Mediates transport of free pyrimidines and may function during early seedling development in salvage pathways, by the utilization of pyrimidines from seed storage tissue (Schmidt et al. 2004). Km for uracil = 6 μM; for xanthine = 24 μM; for allantoin = 26 μM.
Pyridoxamine-phosphate oxidase (PNPO; N-terminal) with a C-terminal DMT family domain of 4 - 5 TMSs (Guerin et al. 2015).
Uncharacterized protein of 138 aas and 5 TMSs.
Uncharacterized protein of 137 aas and 5 TMSs.
Uncharacterized protein of 136 aas and 5 TMSs.
Chloroquine resistance transporter, PfCRT. Martin et al. (2009) have demonstrated Chloroquine transport via the malaria parasite's chloroquine resistance transporter. PfCRT cotransports chloroquine and H+ out of the digestive vacuole (and hence away from its site of action) via a mutant form of the parasite's chloroquine resistance transporter (Lehane and Kirk, 2010). Many mutations give rise to resistance (Tan et al. 2014). The orthologue in P. vivax is 73% identical to the P. faciparum protein and has the same function (Sá et al. 2006). It is inhibited by verapamil, quinine, saquinavir and dibemethin 6a (Meier et al. 2018). Many mutations give rise to artemisinin resistance (Buppan et al. 2018). TMS1 is involved in substrate selectivity and catalyzes chroroquine efflux (Antony et al. 2018).
Chloroplastic chloroquine resistance transporter-1 of 447 aas and 10 TMSs, Clt-1. Involved in thiol transport from the plastid to the cytosol. Transports both glutathione (GSH) and its precursor, gamma-glutamylcysteine (gamma-EC). Exhibits some functional redundancy with CLT3 in maintaining the root GSH pool (Maughan et al. 2010).
The putative toxoflavin exporter, ToxF (co-transcribed with an RND-type toxoflavine exporter, ToxGHI; TC# 2.A.6.2.20) and reglated by a LysR transcription factor, ToxR coordinately with the toxoflavin biosynthetic enzymes (Kim et al. 2004).
Heterodimeric SMR-like transporter with subunits of 144 and 151 aas and 4 TMSs each. The two encoding genes map adjacent to a LysR transcription factor and on the other side, to a RhtB homologue, that possibly exports serine, threonine, homoserine and/or homoserine lactones. Could function in the uptake of a quorum sensing acylhomoserine lactone.
Uncharacterized protein of 159 aas and 5 TMSs.
Putative transporter of 339 aas and 10 TMSs, encoded within an operon with a polyketide cyclase/dehydrase. Possibly a polyketide exporter.
Transporter of unknown function of 143 aas and 5 TMSs. Its gene maps near a thioredoxin domain-containing oxidoreductase that may act on glycine, sarcosine and/or betaine. Possibly the transporter acts on one of these substrates.
Putative transporter encoded within a probable operon with a ser-tRNA synthetase, serine biosynthesis enzymes, a peptidase and a MarC transporter. May be an exporter of serine.
4-amino-4-deoxy-L-arabinose phosphoundecaprenol flippase, ArnEF [ArnE, 111aas; 4 TMSs; PmrL; YfbW] [ArnF, 128aas; 4 TMSs; PmrM; YfbJ] Functions in modification of lipid A during biosynthesis of lipopolysaccharide. Required for resistance to polymyxin and cationic antimicrobial peptides (Yan et al., 2007).
The undecaprenyl phosphate-α-aminoarabinose flippase ArnE/ArnF heterodimer from the cytoplasm to the periplasm (Yan et al., 2007).
Protein of unknown function (claimed to have extra cytoplasmic N- and C-termini (Västermark et al., 2011)). The 10 TMSs occur in a 6+4 arrangement.
The thiamin uptake transporter, SLC35F3. Involved in hypertension.
The nonimprinted in Prader-Willi/Angelman syndrom, subtype 2, NIPA2 protein (360 aas; 9TMSs, 43% identical with NIPA1) Mg2+ transport is electrogenic, voltage-dependent, and saturable, a KM of 0.31mM (very selective for Mg2+). (Goytain et al. 2008). As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018).
YnfA of 108 aas and 4 TMSs. YnfA increases the antibiotics' resistance of E. coli strains isolated from the urinary tract, and is an SMR-like drug efflux pump (Sarkar et al. 2015).
Sitka Spruce 4 TMS YnfA family homologue (144aas).
Csg2 (Cls2) Ca2+ homeostasis protein. Cells lacking Csg2p accumulate Ca2+ in a pool which is exchangeable with extracellular Ca2+ . The mutant cells are Ca2+ sensitive. The protein has 410 amino acyl residues, with 9-10 TMSs. It exhibits an EF-hand Ca2+ binding motif on the lumenal side of the endoplasmic reticular membrane. It is possible that it functions in Ca2+ sequestration. It regulates the activities of CSH1 and SUR1 during mannosyl phosphorylinositol ceramid synthesis. It forms heterodimers with CSH1 and SUR1 (Beeler et al. 1994; Takita et al. 1995). Cls2p likely functions in releasing Ca2+ from the endoplasmic reticulum, somehow cooperating with calcineurin (Tanida et al. 1996). It regulates the transport and protein leves of the inositol phosphorlyceramide mannosyltransferases Csg1 and Csh1 (Uemura et al. 2007).
Uncharacterized protein of 304 aas and 10 TMSs.
Prion-inhibition and propagation, HeLo domain of 901 aas. Contains a domain C-terminal to the transmembrane DMT domain that is homologous to that found in the family with TC# 1.C.104, the Heterokaryon Incompatibility Prion/Amyloid Protein (HET-s) Family.
Uncharacterized DUF803 protein of 814 aas and 10 TMSs.
Uncharacterized protein of 483 aas and 10 TMSs. May have magnesium transport activity.
Uncharacterized protein of 470 aas and 9 or 10 TMSs.
Probable Mg2+ transporter. May also transport other divalent cations such as Fe2+, Sr2+, Ba2+, Mn2+ and Co2+ but to a much lesser extent than Mg2+.
Putative acetate efflux pump, MadN (Berg et al. 1997).
10 TMS YicL protein of 307aas; function unknown, but may export δ-levulinate or protoporphyrin IX (Kanjo et al., 2001).
Putative transporter of 10TMSs (TMSs 5-10 are possibly homologous to TMSs 1-6 in LanG (9.A.29.1.1)). LanG shows limited sequence similarity to ABC porters.
DUF6 homologue, YhbE of 412 aas and 10 TMSs. Encoded by a gene that precedes the Obg GTPase involved in cell division and cell cycle control (Verstraeten et al. 2015). obg is expressed from an operon encoding two ribosomal proteins. The operon's expression varies with growth phase and is dependent on the transcriptional regulators, ppGpp and DksA (Maouche et al. 2016).
Possible L-alanine exporter, YtfF (Hori et al., 2011).
S-adenosylmethionine/S-adenosylhomocysteine transporter (SAM/SAH transporter) (SAMHT; CTL843). May function in SAM uptake and SAH export, perhaps by an SAM/SAH antiport mechanism (Binet et al. 2011).
YedA transporter of 306 aas and 10 TMSs. Probably exports amino acids and/or other metabolites (Zakataeva et al. 2006).
Cystine exporter, YijE, of 301 aas and 10 TMSs (Yamamoto et al. 2015).
PecM of 297 aas and 9 or 10 TMSs. Probable blue pigment (indigoidine) exporter (Rouanet and Nasser 2001).
Peptidase S8 & S53 Subtilisin/kexin/sedolisin. Has an N-terminal 10 (or 11) TMSs followed by a large hydrophilic domain that includes the protease domain.
Riboflavin uptake transporter, RibN of 302 aas and 8 - 10 putative TMSs (García Angulo et al. 2013).
Riboflavin transporter, RibN, of 284 aas and 8 putative TMSs (García Angulo et al. 2013).
Riboflavin uptake porter, RibN, of 284 aas (García Angulo et al. 2013).
Possible transporter of polar amino acids including glutamate, glutamine and aspartate, DmeA. It complements a sepJ mutation in Anabaena (TC# 2.A.7.23.2), and SepJ complements a dmeA mutation. Alternatively, and less likely, it could be an activator of an ABC transporter catalyzing uptake of these amino acids (Escudero et al. 2015).
Uncharacterized protein of 306 aas and 10 TMSs.
Putative transporter, YigM, of 299 aas and 10 TMSs.
Amino acid and toxic analogue exporter, YddG of 298 aas and 10 establsihed TMSs. The 3-d x-ray structures (PD# 5I20) of this protein and a homologue (TC# 3.A.7.17.2) have been determined at 2.4 Å resolution, showing the outward facing conformation of a basket shaped structure with a central substrate binding cavity (Tsuchiya et al. 2016).
PecM (YedA) of 294 aas and 10 TMSs. Promotes invasion and intracellular survival of enteropathogenic E. coli (EPEC) cells (Burska and Fletcher 2014).
Riboflavin uptake transporter of 299 aas and 10 TMSs, ImpX (Gutiérrez-Preciado et al. 2015).
Uncharacterized protein of 290 aas and 10 TMSs.
SepJ, a novel composite protein of 751 aas needed for cellular filament integrity, proper heterocyst development and N2 fixation. It has a C-terminal DME family domain (Flores et al., 2007). Mullineaux et al. (2008) have proposed that this protein (SepJ; FraG) may be a channel-forming protein for transfer of metabolites between cells. However, it may instead be a polar amino acid transporter since DmeA of Synecococcus (TC# 2.A.7.3.58) complements a defect in SepJ (E. Flores, unpubished observations).
Uncharacterized DMT member of 341 aas and 10 TMSs.
Uncharacterized protein of 303 aas and 10 TMSs.
10 TMS DMT superfamily member of unknown function. In an operon with glucan biosynthesis protein C and the AgnG (2.A.66.5.1) exporter. Regulated by RpiR (ribose regulator).
Co2+/Ni2+ efflux porter of 351 aas and 10 TMSs, CnrT. 74% identical to TC# 2.A.7.3.63, anonther protein of the DMT superfamily of unknown function (Nies 2003).
SepJ of 751 aas and 10 C-terminal domains with an N-terminal SMC (structural maintenance of chromosomes) domain and a central DUF4775 domain, before the 10 TMS DMT domain. It may transport asp, glu and gln, or it may activate an ABC-type transporter of this specificity (Escudero et al. 2015). It may be a part of the cyanobacterial intercellular septum together with FraC (P46078) and FraD (P46079).
10 TMS DMT superfamily member of unknown function.
Uncharacterized putative permease of 295 aas and 10 TMSs.
The transmembrane protein TMEM234 of 164 aas and 4 TMSs.
TMEM234 of 127 aas and 4 TMSs.
Uncharacterized protein of 128 aas.
Most closely related to the SMR2 Family (2.A.7.22).
Uncharacterized protein of 116 aas.
Uncharacterized protein of 123 aas.
EmaA-like transporter of 111 aas.
DUF486 transporter of 113 aas and 4 TMSs.
DUF486 transporter of 117 aas and 4 TMSs.
Uncharacterized protein of 324 aas and 8 TMSs.
Uncharacterized protein of 164 aas and 4 TMSs.
Uncharacterized protein of 132 aas and 4 TMSs.
Uncharacterized protein of 139 aas and 4 TMSs.
Uncharacterized protein of 301 aas and 10 or fewer TMSs.
Uncharacterized protein of 292 aas and 10 TMSs.
Uncharacterized protein of 150 aas and 4 TMSs.
Uncharacterized protein of 110 aas and 3 TMSs; possibly an incomplete sequence.
Uncharacterized protein of 235 aas and 4 TMSs.
Uncharacterized protein of 140 aas and 4 TMSs.
Uncharacterized protein of 143 aas and 4 TMSs.
Uncharacterized protein of 121 aas and 4 TMSs.
Uncharacterized protein of 130 aas and 4 TMSs in a 1 + 3 TMS arrangement, a characteristic of members of this family.
Glucose permease, GlcU (also called YcxE). (Fiegler et al., 1999) (similar to 2.A.7.5.1).
The glucose uptake porter of 285 aas, GlcU (Aké et al. 2011).
Rhamnose:H+ symporter, RhaT. Belongs to the TMEM144 family in GenBank.
Uncharacterized protein of 627 aas and 8 - 10 TMSs.
Protein RarD. Involved in antibiotic resistance (Carruthers et al. 2010).
TM protein 144 homologue 2 (DUF1632 homologue).
UDP-galactose, UDP-rhamnose, (and maybe UDP-glucose and UDP-fructose) transporter 2, UGAL2 (At1g76670) (Bakker et al. 2005; Rautengarten et al. 2014).
Golgi nucleotide-sugar (probable UDP-galactose) transporter (At1g21070; EamA superfamily).
Golgi UDP-galactofuranose transporter, UgtA of 399 aas and 11 TMSs (Engel et al. 2009). This and several other species have two redundant transporters that can substitute for each other, UgtA and UgtB (Park et al. 2015). Plays a role in hyphal morphogenesis, cell wall archtecture, conidiation and drug susceptibility (Afroz et al. 2011).
UDP-galactofuranose transporter of 400 aas and 11 TMSs, GlfB (Engel et al. 2009). Galactofuranose-containing glycolipids and glycoproteins are in the cell envelopes of several eukaryotes where they have been shown to contribute, for example, to the virulence of the parasite Leishmania major and the fungus Aspergillus fumigatus.
Xylulose-5-P:Pi antiporter, Xpt or Rpt of 417 aas (Knappe et al. 2003).
The triose-P:Pi antiporter, TPT or Ape2 of 410 aas and 10 TMSs. Transports inorganic phosphate, 3-phosphoglycerate (3-PGA), 2-phosphoglycerate (2PG) and phosphoenolpyruvate (PEP) as well as triose phosphates. Functions in the export of photoassimilates from chloroplasts during the day. In the light, triose phosphates are exported from the chloroplast stroma in counter exchange with inorganic phosphate (Pi), generated for sucrose biosynthesis in the cytosol. Involved in photosynthetic acclimation, a light response resulting in increased tolerance to high-intensity light (Knappe et al. 2003). The crylstal structures of TPT from Galdieria sulphuraria have been solved revealing the protein bound to two different substrates, 3-phosphoglycerate and inorganic phosphate, in occluded conformations.
The phosphoenolpyruvate/phosphate translocator, pPT, of 524 aas in the outer membranes of apicoplasts, vestigial plastids in apicomplexan parasites such as Plasmodium. Transports glucose-6 P and triose-3 Ps via an inorganic phosphate antiport mechanism. Apicomplexan parasites are dependant on their apicoplasts for synthesis of various molecules that they are unable to scavenge in sufficient quantity from their host. They import carbon, energy and reducing power to drive anabolic synthesis in the organelle. pPT is targeted into the outer apicoplast membrane via a transmembrane domain that acts as a recessed signal anchor to direct the protein into the endomembrane system. A tyrosine in the cytosolic N-terminus of the protein is essential for targeting (Lim et al. 2016).
The plastidic phosphate/triosephosphate transporter, TPT (Linka et al., 2008). TPT catalyses the strict 1:1 exchange of triose-phosphate, 3-phosphoglycerate and inorganic phosphate across the chloroplast envelope Lee et al. 2017 reported crystal structures of TPT bound to two different substrates, 3-phosphoglycerate and inorganic phosphate, in occluded conformations. The structures reveal that TPT adopts a 10-transmembrane drug/metabolite transporter fold. Both substrates are bound within the same central pocket, where conserved lysine, arginine and tyrosine residues recognize the shared phosphate group. A structural comparison with the outward-open conformation of the bacterial drug/metabolite transporter suggests a rocker-switch motion of helix bundles, and molecular dynamics simulations support a model in which this rocker-switch motion is tightly coupled to substrate binding to ensure strict 1:1 exchange. The results reveal the mechanism of sugar phosphate/phosphate exchange by TPT. TPTexports Calvin cycle intermediates from chloroplasts and plays fundamental roles in nearly all photosynthetic eukaryotes (Lee et al. 2017).

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