2.A.7 The Drug/Metabolite Transporter (DMT) Superfamily

The DMT Superfamily consists of 44 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. The primordial SMR-type permeases may have 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). Nucleotide-sugar transport into the Mammalian Golgi has been reviewed (Maszczak-Seneczko et al. 2022). DMT porters have the DMT fold (Ferrada and Superti-Furga 2022).

2.A.7.1 The 4 TMS Small Multidrug Resistance (SMR) Family

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). See 2.A.7.1.1 for substrates transporter by SMR systems (Lucero et al. 2023).

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). Drug metabolising enzymes and transporters in the paediatric duodenum have been quantitated (Goelen et al. 2023). Members of the SMRGdx subtype can export the degradation products of metformin, helping bacteria adapt to high environmental levels of the commonly prescribed diabetes medication (Short 2024).

2.A.7.2 The 5 TMS Bacterial/Archaeal Transporter (BAT) Family

The BAT family consists of 5 TMS proteins from bacteria and archaea. None of these proteins is functionally characterized.

2.A.7.3 The 10 TMS Drug/Metabolite Exporter (DME) Family

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).

2.A.7.4 The Plant Drug/Metabolite Exporter (P-DME) Family

The P-DME (UMAMIT) 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 are predicted by various methods 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. The P-DME family members have been called UMAMIT, and form large gene families in Arabidopsis (47 members) and rice (53 members). The few characterized members from Arabidopsis mediate amino acid export from the cytosol, with two of them shown to function as facilitators. They can be found in the plasma membrane (Ladwig et al 2012, Muller et al 2015, Besnard et al 2016, 2018) or the vacuolar membrane (Ranocha et al, 2010, Besnard et al 2018). They play multiple role in amino acid translocation between the organs of the plants, e.g. from leaves to seeds or to roots”.

2.A.7.5 The Glucose/Ribose Porter (GRP) Family

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.

2.A.7.6 The L-Rhamnose Transporter (RhaT) Family

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.

2.A.7.7 The Chloramphenicol-Sensitivity Protein (RarD) Family

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.

2.A.7.8 The Caenorhabditis elegans ORF (CEO) Family

The CEO family is a small family of 6 paralogues encoded within the genome of C. elegans. None of these proteins is functionally characterized.

2.A.7.9 The Triose-phosphate Transporter (TPT) Family

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 (P_i). 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 P_i. 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 P_i. These are the phosphoenolpyruvate:P_i 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.

The generalized reaction catalyzed by the proteins of the TPT family is:

organic phosphate ester (in) + P_i (out) ⇌ organic phosphate ester (out) + P_i (in).

2.A.7.10 The UDP-N-Acetylglucosamine:UMP Antiporter (UAA) Family

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 generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) ⇌ nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.11 The UDP-Galactose:UMP Antiporter (UGA) Family

The generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) ⇌ nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.12 The CMP-Sialate:CMP Antiporter (CSA) Family

The generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) ⇌ nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.13 The GDP-Mannose:GMP Antiporter (GMA) Family

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).

2.A.7.14 The Plant Organocation Permease (POP) Family

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 generalized transport reaction probably catalyzed by AtPUP1 is:

Organocation (out) + H⁺ (out) → Organocation (in) + H⁺ (in)

2.A.7.15 The UDP-glucuronate/UDP-N-acetylgalactosamine Transporter (UGnT) Family

2.A.7.16 The GDP-fucose Transporter (GFT) Family

2.A.7.17 The Aromatic Amino Acid/Paraquat Exporter (ArAA/P-E) Family

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).

The overall reaction catalyzed by YddG is:

Paraquat (in) → Paraquat (out).

2.A.7.18 The Choline Uptake Transporter (LicB-T) Family

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).

The overall reaction catalyzed by LicB is probably:

choline (out) + H⁺ (out) → choline (in) + H⁺ (in).

2.A.7.19 The Nucleobase Uptake Transporter (NBUT) Family

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.

2.A.7.20 The Chloroquine Resistance Transporter (PfCRT) Family

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).

2.A.7.21 The 5 TMS Bacterial/Archaeal Transporter-2 (BAT2) Family

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.

2.A.7.22 The 4 TMS Small Multidrug Resistance-2 (SMR2) Family

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).

2.A.7.23 The Putative Tryptophan Efflux (Trp-E) Family

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).

2.A.7.24 The Thiamine Pyrophosphate Transporter (TPPT) Family

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.

The reaction believed to be catalyzed by Thi74 is:

TPP (out) → TPP (in).

2.A.7.25 The NIPA Mg2+ Uptake Permease (NIPA) Family

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).

The transport reaction catalyzed by NIPA is:

Mg^2⁺ (out) → Mg^2⁺ (in)

2.A.7.26 The 4 TMS Small Multidrug Resistance-3 (SMR3) Family

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.

2.A.7.27 The Ca²⁺ Homeostasis Protein (Csg2) Family

2.A.7.29 The Uncharacterized DMT-1 (U-DMT1) Family

2.A.7.30 The Uncharacterized DMT-2 (U-DMT2) Family

2.A.7.31 The Uncharacterized DMT-3 (U-DMT3) Family

This family belongs to the Drug/Metabolite Transporter (DMT) Superfamily.

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2.A.7.1 The 4 TMS Small Multidrug Resistance (SMR) Family

Properties of the SMR family proteins have been reviewed (OE Burata et al., 2022; PMID 36100040).

Examples:

TC#

Name

Organismal Type

Example

2.A.7.1.1

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). Unassembled monomers of the SMR family exist in a dynamic equilibrium where the N-terminal TMS flips in and out of the membrane, with rates that depend on dimerization and the polypeptide sequence (Seurig et al. 2019). Additional substrates include guanidinium and metformin metabolites such as guanylurea (Lucero et al. 2023).

Bacteria

Smr of Staphylococcus aureus

2.A.7.1.10

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.

Bacteria

SugE of Enterobacter cloacae (D5CES3)

2.A.7.1.11

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).

Bacteria

AbeS of Acinetobacter baumannii (Q2FD83)

2.A.7.1.12

Small multidrug resistance (SMR) protein of 118 aas and 4 TMSs

SMR of Pseudomonas psychrotolerans

2.A.7.1.13

Uncharacterized small multidrug resistance protein of 118 aas and 4 TMSs

UP of Paraburkholderia phenoliruptrix

2.A.7.1.14

Uncharacterized protein of 123 aas and 4 TMSs

UP of Sorangium cellulosum (Polyangium cellulosum)

2.A.7.1.15

SMR family protein of 116 aas and 4 TMSs

SMR protein of Lyngbya aestuarii

2.A.7.1.16

Small multidrug resistance (SMR) family member of 116 aas and 4 TMSs.

Smr of Candidatus Wolfebacteria bacterium

2.A.7.1.17

Putative quaternary amonium transporterof 124 aas and 4 TMSs.

DMT transporter of Chrysochromulina ericina virus

2.A.7.1.18

Putative QacE family quaternary ammonium compound efflux (SMR-type) transporter of 108 aas and 4 TMSs.

QacE-type exporter of Lysinibacillus xylanilyticus

2.A.7.1.2

Small multidrug efflux pump (substrates: isoniazid, tetraphenylphosphonium (TPP), erythromycin, ethidium bromide, acriflavine, safranin O and pyronin Y) (Rodrigues et al. 2013).

Bacteria

Mmr of Mycobacterium tuberculosis (P69926)

2.A.7.1.3

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 two Glu14 residues in the dimer have independent pKa values and are not electrostatically coupled (Li et al. 2021). High level cell-free expression and specific labeling of EmrE has been achieved (Klammt et al. 2004). Cotranslational folding and assembly of the dimeric E. coli EmrE has been documented (Mermans et al. 2022). Harmane binding can uncoupled proton flux through EmrE. In E. coli, EmrE-mediated dissipation of the transmembrane pH gradient provides the mechanism underlying the in vivo phenotype of harmane susceptibility (Spreacker et al. 2022).

Bacteria

EmrE of E. coli

2.A.7.1.4

Quaternary ammonium compound (cetylpyridinium, cetyldimethyl ethylammonium, hexadecyltrimethyl ammonium) efflux pump, SugE, of 105 aas and 4 TMSs. High level cell-free expression and specific labeling of EmrE has been achieved (Klammt et al. 2004).

Bacteria

SugE of E. coli (P69937)

2.A.7.1.5

The heterooligomeric drug resistance efflux pump, YkkCD (substrates: ethidium bromide, proflavin, tetraphenylarsonium chloride, crystal violet, pyronin Y, methylviologen, cetylperdinium chloride, streptomycin, tetracycline, chloramphenicol, phosphonomycin)

Bacteria

YkkCD of Bacillus subtilis

2.A.7.1.6

The heterooligomeric drug resistance efflux pump, EbrAB (substrates: ethidium bromide, acriflavin, pyronin Y, and safranin O) (Zhang et al., 2007).

Bacteria

EbrAB of Bacillus subtilis

2.A.7.1.7

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).

Euryarchaea

Hsmr of Halobacterium salinarum (B0R6K7)

2.A.7.1.8

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).

Bacteria

NepAB of Arthrobacter nicotinovorans:
NepA (116 aas; Q8GAI5)
NepB (166 aas; Q8GAI6)

2.A.7.1.9

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).

Bacteria

MdtJI of E. coli
MdtJ (P69213)
MdtI (P69210)

2.A.7.10 The UDP-N-Acetylglucosamine:UMP Antiporter (UAA) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.10.1

UDP-N-acetylglucosamine:UMP antiporter

Yeast, animals

Mnn2-2 of Kluyveromyces lactis

2.A.7.10.2

The bifunctional ER-Golgi nucleotide sugar transporter with specificity for UDP-xylose and UDP-N-acetylglucosamine, SLC35B4 (Ashikov et al., 2005) for glycosylation. SLC35B4 plays a role in hepatocellular carcinoma (HCC) tumorigenesis (Jiang et al. 2022). The expression levels of SLC35B4 are higher in HCC tissues than adjacent non-tumor tissues, and SLC35B4 is important for the proliferation and tumorigenesis of HCC cells. Mechanistically, SLC35B4 is important for the O-GlcNAc modification of c-Myc and thus the stabilization of c-Myc, which is required for HCC tumorigenesis (Jiang et al. 2022).

Animals

SLC35B4 of Homo sapiens

2.A.7.10.3

Golgi UDP-N-acetylglucosamine (UDP-GlcNAc) transporter.

Animals

SLC35B4 (610923) of Homo sapiens (Q869W7)

2.A.7.10.4

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).

Animals

Efr of Drosophila melanogaster

2.A.7.10.5

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.

Fungi

Yea4 of Saccharomyces cerevisiae

2.A.7.11 The UDP-Galactose:UMP Antiporter (UGA) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.11.1

Possible UDP-galactose:UMP and documented ATP/ADP exchanger (antiporter). Residues essential or important for activity have been identified (Chan et al. 2010). The apparent affinities of SLC35B1 for ATP/ADP on the internal face were approximately 13 times higher than those on the external side (Schwarzbaum et al. 2022). ATP/ADP exchange by SLC35B1 is not strict; other di- and trinucleotides can act as counter-substrates for ATP, although mononucleotides and nucleotide sugars were not transported. Conserved residues K117 and K120 in TMS 4 and K277 in TMS 9 play critical roles in transport. The fact that SLC35B1 can promote ATP transport in exchange for ADP or UDP suggests a more direct coupling between ATP import requirements and the need for eliminating ADP and UDP, which are generated as side products of reactions taking place in the ER-lumen (Schwarzbaum et al. 2022). SLC35B1 contributes to the uptake of UDPGA into the endoplasmic reticulum for glucuronidation catalyzed by UDP-glucuronosyltransferases (Ondo et al. 2020).

Animals

SLC35B1 of Homo sapiens

2.A.7.11.10

UDP-galactose transporter, putative, UGT, of 343 aas and probably 10 TMSs.

UGT of Plasmodium falciparum

2.A.7.11.2

Golgi adenosine 3'-phosphate 5'-phosphosulfate transporter, slalom (functions by an exchange mechanism, essential for viability (Kamiyama et al., 2003)).

Animals

slalom of Drosophila melanogaster
(Q9VEI3)

2.A.7.11.3

Golgi adenosine 3'-phosphate 5'-phosphosulfate (PAPS):adenosine 3'-phosphate 5'-phosphate (PAP) antiporter, PAPST1 (Maszczak-Seneczko et al. 2022). (Mutations cause human inherited disorders (orthologue of 2.A.7.11.2) (Kamiyama et al., 2003). SLC35B2 is encoded by a gene that is a susceptibility gene for rheumatoid arthritis (Mo et al. 2020).

Animals

SLC35B2 of Homo sapiens

2.A.7.11.4

Golgi UDP-galactose/UDP-glucose:UDP antiporter, UTr1 (Norambuena et al., 2002)

Animals

UTr1 of Arabidopsis thaliana
(O64503)

2.A.7.11.5

SLC35B3 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 (Kamiyama et al. 2006). It is encoded by a gene in a signature gene set that serves as a simple proxy as a promising biomarker to predict chemoresponsiveness of muscle-invasive bladder cancer (MIBC) patients (Hepburn et al. 2021).

Animals

SLC35B3 of Homo sapiens

2.A.7.11.6

UDP-galactose transporter homologue 1 (Multicopy suppressor of leflunomide-sensitivity protein 6)

Fungi

HUT1 of Saccharomyces cerevisiae

2.A.7.11.7

UDP-galactose/UDP-glucose transporter 5 (AtUTr5)

Plants

UTR5 of Arabidopsis thaliana

2.A.7.11.8

UDP-glucose transporter, UGT4. Does not transport UDP-galactose (Seino et al. 2010).

Plants

UGT4 of Oryza sativa

2.A.7.11.9

DMT2 of 322 aas and 10 TMSs. Propsed to transport divalent metal ions or IPP (Wunderlich 2022).

DMT2 of Plasmodium falciparum

2.A.7.12 The CMP-Sialate:CMP Antiporter (CSA) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.12.1

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).

Animals

CMP-sialic acid transporter of Mus musculus (Q61420)

2.A.7.12.10

The ZK896.9 Golgi apparatus nucleotide-sugar transporter (transports UDP-glucose, UDP-galactose, UDP-N-acetylglucosamine, and UDP-N-acetylgalactosamine) (Caffaro et al., 2008)

Metazoa

ZK896.9 of Caenorhabditis elegans (O02345)

2.A.7.12.11

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). The loss of the sialic acid transporter SLC35A1/CST and the zinc transporter SLC30A1/ZnT1 (TC# 2.A.4.2.6) affected cell survival upon infection with cytolytic vesicular stomatitis virus (VSV). Both of these transporters seem to play a role in the apoptotic response induced by VSV (Moskovskich et al. 2019). Inherited thrombocytopenia can be caused by variants in crucial genes for glycosylation including that for SLC35A1 (Marín-Quílez et al. 2023).

Animals

SLC35A1 of Homo sapiens

2.A.7.12.12

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).

Animals

SLC35A4 of Homo sapiens

2.A.7.12.13

Putative nucleotide-sugar transporter, C2orf18 or SLC35F6 (371aas; 9 TMSs). It may play a role in cisplatin resistance in lung adenocarcinoma (Zhou et al. 2020).

Animals

C2orf18 of Homo sapiens (Q8N357)

2.A.7.12.14

Probable UDP-sugar transporter protein SLC35A5 (Solute carrier family 35 member A5)

Animals

SLC35A5 of Homo sapiens

2.A.7.12.15

CMP-sialic acid transporter 5 (CMP-SA-Tr 5) (CMP-Sia-Tr 5)

Plants

At5g65000 of Arabidopsis thaliana

2.A.7.12.16

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).

SLC35A3 of Sus scrofa (Pig)

2.A.7.12.17

Nucleoside diphosphate-sugar transporter, NGT, of 611 aas with 1- TMSs in a 5 + 2 + 3 TMS arrangement.

NGT of Plasmodium falciparum

2.A.7.12.2

CMP-Sialic Acid Transporter (CMP-SAT)

Insect

CMP-SAT of Aedes aegypti (Q175F9)

2.A.7.12.3

UDP-Galactose Transporter, UTR6

Plants

UTR6 of Arabidopsis thaliana (Q9C5H6)

2.A.7.12.4

Golgi UDP-galactose and UDP-N-acetylglucosamine:UDP antiporter, SRF-3 (Hoflich et al., 2004).

Animals

SRF-3 of Caenorhabditis elegans
(Q93890)

2.A.7.12.5

Golgi UDP-galactose and UDP-N-acetylgalactosamine:UDP antiporter, UGT (Segawa et al., 2002)

Animals

UGT of Drosophila melanogaster
(Q9W4W6)

2.A.7.12.6

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). May also take up cisplatin (Girardi et al. 2020).

Animals

SLC35A2 of Homo sapiens

2.A.7.12.7

Golgi UDP-N-acetylglucosamine transporter (Ishida et al., 1999a). Conserved Glu-47 and Lys-50 residues are critical for UDP-N-acetylglucosamine/UMP antiport activity of the mouse Golgi-associated transporter (Toscanini et al. 2019). Colorectal cancer with low SLC35A3 is associated with immune infiltrates and poor prognosis (Lu et al. 2024).

Animals

SLC35A3 of Homo sapiens

2.A.7.12.8

UDP-galactose transporter, UGT (Had-1) (Ishida et al., 1999b)

Animals

UGT of Mus musculus (Q9R0M8)

2.A.7.12.9

The ER/Golgi UDP-N-acetylgalactosamine (and possibly UDP-N-acetylglucosamine) transporter C03H5.2 gene product (Caffaro et al., 2006)

Round worm

C03H52 of Caenorhabditis elegans (O16658)

2.A.7.13 The GDP-Mannose:GMP Antiporter (GMA) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.13.1

Golgi GDP-mannose:GMP antiporter, (vanadate resistance protein), VRG4 or VIG4 (Abe et al. 1999). It is the target of a natural cyclic peptide of unknown function (SDZ 90-215) (Snyder et al. 2019).

Animals, plants, yeast

VRG4 of Saccharomyces cerevisiae (P40107)

2.A.7.13.2

Golgi GDP-mannose transporter, VRG4

Yeast

VRG4 of Candida albicans (Q96WN8)

2.A.7.13.3

Golgi GDP-mannose:GDP antiporter, GONST1 (Baldwin et al., 2001).

Plants

GONST1 of Arabidopsis thaliana
(Q941R4)

2.A.7.13.4

Golgi GDP-mannose transporter, GONST2 of 375 aas (Handford et al. 2004).

Plants

GONST2 of Arabidopsis thaliana

2.A.7.13.5

Putative nucleotide sugar transporter GONST3 (Protein GOLGI NUCLEOTIDE SUGAR TRANSPORTER 3) (Handford et al. 2004).

Plants

GONST3 of Arabidopsis thaliana

2.A.7.13.6

Golgi GDP-mannose transporter of 397 aas and 10 TMSs, Gmt1. Necessary for capsular biosynthesis, protein gycosylation and virulence (Wang et al. 2014).

Fungi

Gmt1 of Cryptococcus neoformans

2.A.7.13.7

Golgi GDP-mannose transporter, Gmt2. Functions in capsular polysaccharide biosynthesis, protein glycosylation and virulence (Wang et al. 2014).

Fungi

Gmt2 of Cryptococcus neoformans (Filobasidiella neoformans)

2.A.7.13.8

TMEM241 or SLC35D4 of the SLC35 family and of 296 aas with 10 TMSs (Luck et al. 2020).

TMEM241 of Homo sapiens

2.A.7.14 The Plant Organocation Permease (POP) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.14.1

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).

Plants

AtPUP1 of Arabidopsis thaliana

2.A.7.14.2

Probable purine permease 18 (AtPUP18)

Plants

Pup18 of Arabidopsis thaliana

2.A.7.14.3

Probable purine permease 11 (AtPUP11) of 379 aas and 10 TMSs. PUP11 positively regulates the rice seed setting rate by influencing seed development (Rong et al. 2024).

Plants

PUP11 of Arabidopsis thaliana

2.A.7.14.4

Purine permease 2 (AtPUP2). PUP2 transports cytokinins (trans- and cis-zeatin, kinetin, benzyladenine, isopentenyladenine, and to a lesser extent trans-zeatin riboside)

Plants

PUP2 of Arabidopsis thaliana

2.A.7.14.5

Putative purine permease 15 (AtPUP15)

Plants

PUP15 of Arabidopsis thaliana

2.A.7.14.6

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).

Nup1 of Nicotiana tabacum

2.A.7.15 The UDP-glucuronate/UDP-N-acetylgalactosamine Transporter (UGnT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.15.1

The Golgi UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose transporter, SQV-7-like protein SQV7L or SLC35D2, 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 K_mvalues of 8, 2, and 0.14 μM, respectively (Suda et al. 2004). The crystal structure of an nucleotide-sugar transporter, the SLC35D2 homolog, Vrg-4 from yeast has been described, and using this crystal structure, a new model of SLC35A1, (CMP-sialic acid transporter, CST) has been derived (Hadley et al. 2019).

Animals

SLC35D2 of Homo sapiens

2.A.7.15.2

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).

Animals

SQV-7 (yk46f1.5) of Caenorhabditis elegans (Q18779)

2.A.7.15.3

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).

Animals

Frc of Drosophila melanogaster
(Q95YI5)

2.A.7.15.4

The UDP glucuronate/UDP-N-acetylgalactosamine transporter, Slc35D1; responsible for Schneckenbecken dysplasia in humans (Hiraoka et al., 2007). Congenital disorders of glycosylation (CDGs) are a heterogeneous group of disorders with impaired glycosylation of proteins and lipids. These conditions have multisystemic clinical manifestations, resulting in gradually progressive complications including skeletal involvement and reduced bone mineral density (Lipiński et al. 2021).

Animals

SLC35D1 of Homo sapiens

2.A.7.15.5

The putative Golgi nucleotide-sugar transporter SLC35D3 (416aas, 10 TMSs) (Chintala et al. 2007). SLC35D3 regulates tissue-specific autophagy and plays an important role in the increased autophagic activity required for the survival of subsets of dopaminergic neurons (Wei et al. 2016). SLC35D3 silenced cells show increased expression of genes related to fat synthesis, and increased deposition of intramuscular fat, an abundance of lipid droplets, and an increased level of free fatty acid in the culture medium. In contrast, the siRNA decreased the expression of genes involved in fat catabolism (Li et al. 2020), suggesting a role in the transport of fatty acids or their derivatives. It may play a role during porcine intramuscular preadipocyte differentiation (Li et al. 2020).

Animals

SLC35D3 of Homo sapiens

2.A.7.16 The GDP-fucose Transporter (GFT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.16.1

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). Triclosan activates c-Jun/miR-218-1-3p/SLC35C1 signaling to regulate the cell viability, migration, invasion and inflammatory response of trophoblast cells (Huo et al. 2022). Elevated global fucosylation characterizes human intrahepatic cholangiocarcinoma, contributing to cell growth and migration via the upregulation of the NOTCH and EGFR/NF-kB pathways (Ament et al. 2023). SLC35C1 knockdown significantly inhibited the proliferation, migration and invasive ability of glioma cells, while SLC35C1 overexpression promoted proliferation, migration, invasion and colony formation of glioma cells (Xie et al. 2023).

Animals

SLC35C1 of Homo sapiens

2.A.7.16.2

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.

Animals

Gfr or CG9620 of Drosophila melanogaster
(Q9VHT4)

2.A.7.16.3

Uncharacterized transporter C22F8.04

Yeast

SPAC22F8.04 of Schizosaccharomyces pombe

2.A.7.17 The Aromatic Amino Acid/Paraquat Exporter (ArAA/P-E) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.17.1

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).

Gram-negative proteobacteria

YddG of Salmonella typhimurium

2.A.7.17.2

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). Mutants of the yddG gene can export phenylalanine (Radi et al. 2022).

Proteobacteria

YddG of Escherichia coli

2.A.7.18 The Choline Uptake Transporter (LicB-T) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.18.1

The high-affinity choline uptake transporter, LicB

Bacteria

LicB of Haemophilus influenzae (AAC23188)

2.A.7.18.2

The archaeal putative permease MttP 353 aas (lMA0530) possibly a methyl amine uptake porter; D.J. Ferguson, personal communication) (10 putative TMSs)

Archaeal

MttP of Methanosarcina acetivorans (Q8TTA7)

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).

Archaeal

MttP2 of Methanosarcina acetivorans (Q8TS76)

2.A.7.18.4

LicB-T family member

Actinobacteria

LicB-T family member of Streptomyces coelicolor

2.A.7.19 The Nucleobase Uptake Transporter (NBUT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.19.1

Allantoin permease, UPS1 (may also transport uracil and 5-fluorouracil) (10 TMSs) (Schmidt et al., 2004)

Plants

UPS1 of Phaseolus vulgaris (French bean) (AAS19930)

2.A.7.19.2

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).

Plants

UPS1 of Arabidopsis thaliana
(Q9ZPR7)

2.A.7.19.3

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. UPS5 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). AtUPS5-Long and AtUPS5-Short localization indicates that they play different roles in allantoin distribution between subcellular compartments. Thus, Lescano et al. 2019 predict that under non-stress conditions UPS5L and UPS5S may function in allantoin degradation pathway for nutrient recycling, whereas under stress conditions, both splice variants are involved in cell export via vesicles of the secretory pathway, allowing allantoin translocation from roots to shoots.

UPS5 of Arabidopsis thaliana (Mouse-ear cress)

2.A.7.19.4

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.

Ups2 of Arabidopsis thaliana

2.A.7.19.5

Ureide permease 1-like protein of 483 aas and 8 TM

Ureide permease 1 of Prosopis alba

2.A.7.2 The 5 TMS Bacterial/Archaeal Transporter (BAT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.2.1

Hypothethical protein

Bacteria

Ycb6 of Pseudomonas denitrificans

2.A.7.2.2

Hypothethical protein

Archaea

Orf of Pyrococcus abyssi

2.A.7.2.3

Uncharacterized protein of 156 aas and 5 TMSs

UP of Rhizophagus irregularis (Arbuscular mycorrhizal fungus) (Glomus intraradices)

2.A.7.2.4

Pyridoxamine-phosphate oxidase (PNPO; N-terminal) with a C-terminal DMT family domain of 4 - 5 TMSs (Guerin et al. 2015).

PNPO of Penicillium digitatum (Green mold)

2.A.7.2.5

Uncharacterized protein of 138 aas and 5 TMSs.

UP of Haloterrigena thermotolerans

2.A.7.2.6

Uncharacterized protein of 142 aas and 5 TMSs

UP of Pseudomonas aeruginosa

2.A.7.2.7

Uncharacterized protein of 137 aas and 5 TMSs.

UP of Natrinema versiforme

2.A.7.2.8

Uncharacterized protein of 136 aas and 5 TMSs.

UP of Haloarcula vallismortis

2.A.7.20 The Chloroquine Resistance Transporter (PfCRT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.20.1

Chloroquine resistance transporter, PfCRT. Martin et al. (2009) have demonstrated Chloroquine transport via PfCRT. It co-transports chloroquine (CQ) or piperaquine (PPQ) and H⁺out of the digestive vacuole (and hence away from its site of action) via a mutant form of the parasite's CRT (Lehane and Kirk, 2010). Many mutations give rise to resistance (Tan et al. 2014; Buppan et al. 2018). 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). TMS1 is involved in substrate selectivity and catalyzes chroroquine efflux (Antony et al. 2018). The vacuolar-half and membrane-spanning domains (especially TMS9) of PfCRT are more conserved, suggesting that its physiological substrate is expelled out of the parasite digestive vacuole. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain (Coppée et al. 2020). pH-dependence of the P. falciparum chloroquine resistance transporter is linked to the transport cycle (Berger et al. 2023). Several proteases are localized to the digestive vacuole and these proteases sequentially breakdown hemoglobin into small peptides, dipeptides, and amino acids. The peptides are exported into the host cytoplasm via the chloroquine-resistance transporter and an amino acid transporter has also been identified on the digestive vacuole membrane (Wiser 2024).

Protozoans

PfCRT of Plasmodium falciparum (AF495378)

2.A.7.20.2

Crt homologue 1 (Chloroquine resistance transporter paralogue 1) (DdCRTp1)

Amoeba

Crtp1 of Dictyostelium discoideum

2.A.7.20.3

Uncharacterized protein of 384 aas and 11 TMSs

UP of Chlamydomonas reinhardtii (Chlamydomonas smithii)

2.A.7.20.4

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).

Clt-1 of Arabidopsis thaliana (Mouse-ear cress)

2.A.7.20.5

Chloroquine resistance transporter, Crt, of 421 aas and 10 TMSs. It is 76% identical to 2.A.7.20.1. Genetic analyses have been performed (Pimpat et al. 2020).

Crt of Plasmodium malariae

2.A.7.21 The 5 TMS Bacterial/Archaeal Transporter-2 (BAT2) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.21.1

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).

Bacteria

ToxF of Burkholderia glumae (AAV52811)

2.A.7.21.2

Putative exporter

Bacteria

YdcZ of E. coli (P76111)

2.A.7.21.3

Putative exporter

Archaea

Putative exporter of Methanococcus maripaludis (CAF29821)

2.A.7.21.4

The orotate transporter, OroP (Defoor et al., 2007) (also, transports 5-fluoroorotate)

Bacteria

OroP of Lactococcus lactis (Q3SAW5)

2.A.7.21.5

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.

Proteobacteria

UP of Klebsiella oxytoca

2.A.7.21.6

Uncharacterized protein of 159 aas and 5 TMSs.

Deinococcus/Thermus

UP of Deinococcus maricopensis

2.A.7.21.7

Putative transporter of 339 aas and 10 TMSs, encoded within an operon with a polyketide cyclase/dehydrase. Possibly a polyketide exporter.

Actinobacteria

Transporter of Isoptericola variabilis

2.A.7.21.8

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.

Firmicutes

Transporter of Clostridium acetobutylicum

2.A.7.21.9

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.

Proteobacteria

Putative serine transporter of Deferribacter desulfuricans

2.A.7.22 The 4 TMS Small Multidrug Resistance-2 (SMR2) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.22.1

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).

Bacteria

ArnEF of E. coli
ArnE (Q47377)
ArnF (P76474)

2.A.7.22.2

The undecaprenyl phosphate-α-aminoarabinose flippase ArnE/ArnF heterodimer from the cytoplasm to the periplasm (Yan et al., 2007).

Bacteria

ArnEF flippase of Salmonella typhi
ArnE (P81891)
ArnF (125aas; Q8Z537)

2.A.7.22.3

Uncharacterized protein of 130 aas and 4 TMSs

UP of Spirochaeta smaragdina

2.A.7.24 The Thiamine Pyrophosphate Transporter (TPPT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.24.1

The mitochondrial thiamine-repressible putative thiamine pyrophosphate (TPP) transporter, Thi74 (370 aas; 10 TMSs in a 2 + 8 arrangement) (Mojzita and Hohmann, 2006)

Yeast

Thi74 of Saccharomyces cerevisiae
(Q04083)

2.A.7.24.10

SLC family 35 member F2 (SLC35F2; also called DUF914). It regulates cisplatin resistance and promotes malignant progression of pancreatic cancer by regulating RNA binding motif protein 14 (Zhang et al. 2022).

Animals

SLC35F2 of Homo sapiens

2.A.7.24.11

SLC family 35 member F2 (SLC35F2; also called DUF914)

Animals

SLC35F2 of Aspergillus fumigatus
(Q4WUA9)

2.A.7.24.12

DUF914 protein, possibly anthocyanin-related protein-1 (Anm1)

Animals

DUF914 protein of Arabidopsis thaliana (Q948Q9)

2.A.7.24.13

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.

Protozoa

Unknown protein of Trypanosoma brucei (Q57UU3)

2.A.7.24.14

Solute carrier family 35 member F4 of 521 aas and 10 TMSs. Exposure to violence and chronic stress may increase the risk of atopic asthma through DNA methylation of this gene in airway epithelia (Yan et al. 2020).

Animals

SLC35F4 of Homo sapiens

2.A.7.24.15

Uncharacterized DMT superfamily homologue

Fungi

Uncharacterized protein of Lodderomyces elongisporus

2.A.7.24.2

The DUF6-domain transporter homologue, TrH1

Slime mold

TrH1 of Dictyostelium discoideum (Q54E05)

2.A.7.24.3

The DUF6-domain transporter homologue, TrH2 (392 aas; 10 TMSs in a 2 + 4 + 4 arrangement)

Animals

TrH2 of Caenorhabditis elegans (Q95XC7)

2.A.7.24.4

The At3g07080 DUF6 domain transporter homologue

Plants

At3g07080 of Arabidopsis thaliana (Q9SFT8)

2.A.7.24.5

Uncharacterized vacuolar membrane protein YML018C

Fungi

YML018C of Saccharomyces cerevisiae

2.A.7.24.6

The DUF6-domain-containing solute carrier family 35, member F5 (523 aas; 10 TMSs, in a 2 + 4 + 4 TMS arrangement. Expression patterns in various tissues have been studied (Nishimura et al. 2009). The oncomiR effect of miR-369-3p may be mediated through disrupting the nucleotide sugar transport activity, and that SLC35F5 is a key effector of this chemoresistance-promoting activity (Hao et al. 2017).

Animals

SLC35F5 of Homo sapiens

2.A.7.24.7

DUF6 domain-containing protein with 150aa N-terminal hydrophilic extension

Fungi

DUF6 protein of Trichophyton equinum (F2PXJ5)

2.A.7.24.8

The thiamin uptake transporter, SLC35F3. Involved in hypertension (Zhang et al. 2014; Zang et al. 2016). Its gene appears to play a role in the antiepileptic mood stabilization (AED-MS) treatment response, and may facilitate precision medicine in bipolar disease (Ho et al. 2020).

Animals

SLC35F3 of Homo sapiens

2.A.7.24.9

SLC family 35 member F1 (SLC35F1; also called DUF914) of 412 aas and 10 TMSs. Expression in the mouse brain has been reported (Farenholtz et al. 2019). It is a candidate gene for neurodevelopmental disorders resembling Rett syndrome (Di Fede et al. 2021).

Animals

SLC35F1 of Homo sapiens

2.A.7.25 The NIPA Mg²⁺ Uptake Permease (NIPA) Family

The NIPA family is most closely related to the U-DMT family that includes probable Mg²⁺ transporters (TC# 2.A.7.29) in eukaryotes.

Examples:

TC#

Name

Organismal Type

Example

2.A.7.25.1

The nonimprinted in Prader-Willi/Angelman syndrome, subtype 1, NIPA1 (SLC57A1) Mg²⁺ uptake permease (Gyimesi and Hediger 2022); it also may take up Sr²⁺, Fe²⁺ and Co²⁺ (329 aas; 9 or 10 TMSs) (Quamme, 2009). A causative link between NIPA1 mutations and autosomal dominant hereditary spastic paraplegia has been demonstrated (Reed et al. 2005; Fabbro et al. 2021).

Animals

NIPA of Homo sapiens (Q7RTP0)

2.A.7.25.10

NIPA-like protein 2, NIPAL2 or SLC57A4 Mg²⁺ transporter; also takes up Sr²⁺ and Ba²⁺. It is of 383 aas with 9 TMSs (Gyimesi and Hediger 2022).

NIPAL2 of Homo sapiens

2.A.7.25.11

DUF803 domain containing protein of 935 aas and 10 TMSs, with 5 TMSs at the N-terminus and 5 TMSs at the C-terminus. It may be a Mg²⁺/H⁺ antiporter (Wunderlich 2022).

DUF803 protein of Plasmodium falciparum

2.A.7.25.2

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, with a K_Mof 0.31 mM (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).

Animals

NIPA2 of Homo sapiens (Q8N8Q9)

2.A.7.25.3

NIPA3 or NIPAL3 (SLC57A5) protein of 406 aas and 9 TMSs. Putative Mg²⁺ transporter

Animals

NIPA3 of Homo sapiens (Q6P499)

2.A.7.25.4

The ichthyin (ICHN; Nipal4; Nipa4; SLC57A6) autosomal recessive congenital ichthyosis (ARCI) disease Mg²⁺ transport protein (466 aas; 9 TMSs). It transports Mg²⁺ as well as other divalent cations such as Ba²⁺, Mn²⁺, Sr²⁺ and Co²⁺, but to a much less extent than Mg²⁺. It may be a receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway (Lefèvre et al. 2004). Disease-causing mutations near the transport channel cavity lead to changes in channel architecture and ARCI function (Laadhar et al. 2019).

Animals

ICHN of Homo sapiens (Q0D2K0)

2.A.7.25.5

The permease-related protein (PRP) (335 aas; 9TMSs)

Plants

PRP of Arabidopsis thaliana (Q9LIR9)

2.A.7.25.6

Hypothetical protein (HP)

Fungi

HP of Neurospora crassa (Q7RWT8)

2.A.7.25.7

Protein AN62992 (691 aas; 9TMSs at the N-terminus (1-300 aas)). The C-terminal region (DUF803) is very hydrophilic.

Fungi

AN62992 of Aspergillus nidulans (Q5AZI1)

2.A.7.25.9

Magnesium transporter NIPA3; NIPAL1; NPAL1; SLC57A3 (NIPA-like protein 1) (Non-imprinted in Prader-Willi/Angelman syndrome region protein 3 homologue). It is a Mg²⁺ transporter that can also transport Sr²⁺, Ba²⁺, Fe²⁺ and Cu²⁺ (Gyimesi and Hediger 2022). The human ortholog is 87% identical to the mouse protein.

Animals

Nipal1 of Mus musculus

2.A.7.26 The 2 or 4 TMS Small Multidrug Resistance-3 (SMR3) Family

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.

Examples:

TC#

Name

Organismal Type

Example

2.A.7.26.1

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).

Bacteria

YnfA of E. coli

2.A.7.26.2

MA_3936 (4 TMSs)

Archaea

MA_3936 of Methanosarcina acetivorans (gi#19918023)

2.A.7.26.3

Sitka Spruce 4 TMS YnfA family homologue (144aas).

Plants

YnfA homologue of Picea sitchensis (ADE77612)

2.A.7.26.4

Moss 4-5 TMS YnfA family homologue (197aas)

Plants

YnfA homologue of Physcomitrella patens (A9T501)

2.A.7.26.5

Hypothetical protein, GK2092 (2 TMSs)

Bacteria

GK2092 of Geobacillus kaustophilus (Q5KY59)

2.A.7.26.6

Conserved protein, MM_0735 (2 TMSs)

Archaea

MM_0735 of Methanosarcina mazei (Q8PYW4)

2.A.7.27 The Ca²⁺ Homeostasis Protein (Csg2) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.27.1

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).

Yeast

Csg2 of Saccharomyces cerevisiae (P35206)

2.A.7.28 The Solute Carrier 35G (SLC35G) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.28.1

Solute carrier family 35 member G1 of 365 aas and 10 TMSs. Kamel et al. 2017 reviewed acute disseminated encephalomyelitis (ADEM) and suggested a role of SLC35G1.

Animals

SLC35G1 of Homo sapiens (Q8BY79)

2.A.7.28.10

Uncharacterized protein of 340 aas and 10 TMSs

Rhodophyta

UP of Chondrus crispus (Carragheen moss) (Irish moss)

2.A.7.28.11

Uncharacterized protein of 304 aas and 10 TMSs.

Cyanobacteria

UP of Prochlorococcus marinus

2.A.7.28.12

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.

HeLo domain proteini of Umbilicaria pustulata

2.A.7.28.13

Pseudopaline exporter CntI (ZrmD) of 284 aas and 10 TMSs in a 5 + 5 TMS arrangement (Mégret-Cavalier et al. 2024).

CntI of Pseudomonas aeruginosa

2.A.7.28.2

Solute carrier family 35 member G2 of 412 aas and 10 TMSs in a 5 + 5 TMS arrangement. A novel DNA methylation-driver gene signature for long-term survival prediction of hepatitis-positive hepatocellular carcinoma patientshas been reported (Fu et al. 2022).

Animals

SLC35G2 of Homo sapiens

2.A.7.28.3

Solute carrier family 35 member G3

Animals

SLC35G3 of Homo sapiens (Q5F297)

2.A.7.28.4

Solute carrier family 35 member G4, SLC35G4, of 338 aas and 10 TMSs. May be a pseudogene; function unknown.

Animals

SLC35G4 of Homo sapiens

2.A.7.28.5

Solute carrier family 35 member G5, SLC35G5, of 338 aas and 10 TMSs. The gene for SLC35G5 is commonly mutated in pre-NACT. Patients treated with neoadjuvant chemotherapy (NACT) for advanced high-grade serous ovarian carcinoma have a higher rate and shorter time to platinum-resistant recurrence (Marchocki et al. 2022).

Animals

SLC35G5 of Homo sapiens

2.A.7.28.6

Solute carrier family 35 member G6 of 338 aas and 10 TMSs. Endometriosis and migraines co-occur within individuals more than expected by chance, and this appears to involve mutant forms of SLC35G6 (Adewuyi et al. 2020).

Animals

SLC35G6 of Homo sapiens

2.A.7.28.7

Solute carrier family 35 member G3 (Acyl-malonyl-condensing enzyme 1?) (Transmembrane protein 21A) of 338 aas and 10 TMSs. The gene encoding this protein appears to have arisen by SVA-mediated retrotransposition of the SLC35G6 gene in the primate lineage.

Animals

SLC35G3 of Homo sapiens

2.A.7.28.8

Solute carrier family 35 member G1 (Transmembrane protein 20)

Animals

SLC35G1 of Homo sapiens

2.A.7.28.9

Uncharacterized transporter HP_1234

Bacteria

HP_1234 of Helicobacter pylori

2.A.7.29 The Uncharacterized DMT-1 (possible Mg2+ uptake porter) (U-DMT1) Family

The U-DMT1 family is most closely related to the NIPA family (TC# 2.A.7.25) that includes probable Mg²⁺ transporters in prokaryotes.

Examples:

TC#

Name

Organismal Type

Example

2.A.7.29.1

Uncharacterized DUF803 protein of 814 aas and 10 TMSs.

UP of Toxoplasma gondii

2.A.7.29.2

Uncharacterized (possibly Mg²⁺) transport protein of 483 aas and 10 TMSs. May have magnesium transport activity (Wunderlich 2022).

UP of Plasmodium falciparum

2.A.7.29.3

Uncharacterized protein of 470 aas and 9 or 10 TMSs.

UP of Pythium ultimum

2.A.7.29.4

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 Mg²⁺ transporter of Glycine max (Soybean) (Glycine hispida)

2.A.7.3 The 10 TMS Drug/Metabolite Exporter (DME) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.3.1

Putative acetate efflux pump, MadN (Berg et al. 1997).

Bacteria

MadN of Malonomonas rubra

2.A.7.3.10

DUF6 domain protein of unknown function

Bacteria

DUF6 protein of Rhodococccus erythropolis (C3JHC4)

2.A.7.3.11

Putative porter, SACE_6693, of unknown function

Actinobacteria

SACE_6693 of Saccharopolyspora erythraea (A4FP84)

2.A.7.3.12

10 TMS YicL protein of 307aas; function unknown, but may export δ-levulinate or protoporphyrin IX (Kanjo et al., 2001).

Bacteria

YicL of E.coli (P31437)

2.A.7.3.13

Putative Drug/Metabolite Exporter

Bacteria

DME of Mannheimia haemolytica (A7JQ96)

2.A.7.3.14

Putative Drug/Metabolite Exporter

Bacteria

DME of Comamonas testeroni (D8D9B1)

2.A.7.3.15

Putative DUF6 protein

Bacteria

DUF6 protein of Xanthomonas vesicatoria (F0BFS6)

2.A.7.3.16

DMT Superfamily member

Bacteria

DMT member of Chlamydia trachomatis (D6YX63)

2.A.7.3.17

Putative transporter of 10 TMSs (TMSs 5-10 are possibly homologous to TMSs 1-6 out of 6 TMSs in LanG (9.A.29.1.1)). LanG shows limited sequence similarity to ABC porters as well.

Bacteria

Putative transporter of Chlamydophila abortus (Q5L5M5)

2.A.7.3.18

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).

Bacteria

YhbE of E. coli (E1ILD8)

2.A.7.3.19

Possible L-alanine exporter, YtfF (Hori et al., 2011).

Bacteria

YtfF of E. coli (P39314)

2.A.7.3.2

YdeD (EamA) efflux pump for O-acetylserine, cysteine, asparagine and glutamine (Dassler et al., 2000; Franke et al. 2003)

Bacteria

YdeD of E. coli

2.A.7.3.20

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).

Bacteria

SAMHT of Chlamydia trachomatis serovar L2

2.A.7.3.21

Putative permease of 295 aas and 10 TMSs

Spirochaetes

Permease of Leptospira biflexa

2.A.7.3.22

YedA transporter of 306 aas and 10 TMSs. Probably exports amino acids and/or other metabolites (Zakataeva et al. 2006). Mutation of the yedA gene protects the cells against toxic levels of methionine (Radi et al. 2022).

Bacteria

YedA of E. coli (P0AA70)

2.A.7.3.23

Uncharacterized transporter BU281

Bacteria

BU281 of Buchnera aphidicola subsp. Acyrthosiphon pisum

2.A.7.3.24

Uncharacterized transporter YdeK

Bacilli

YdeK of Bacillus subtilis

2.A.7.3.25

Protein PagO

Bacteria

PagO of Salmonella typhimurium

2.A.7.3.26

Cystine exporter, YijE, of 301 aas and 10 TMSs (Yamamoto et al. 2015).

Bacteria

YijE of Escherichia coli

2.A.7.3.27

Uncharacterized transporter BUsg_270

Bacteria

BUsg_270 of Buchnera aphidicola subsp. Schizaphis graminum

2.A.7.3.28

Uncharacterized transporter AF_0266

Archaea

AF_0266 of Archaeoglobus fulgidus

2.A.7.3.29

Uncharacterized transporter YoaV

Bacilli

YoaV of Bacillus subtilis

2.A.7.3.3

PecM of 297 aas and 9 or 10 TMSs. Probable blue pigment (indigoidine) exporter (Rouanet and Nasser 2001).

Bacteria

PecM of Erwinia chrysanthemi

2.A.7.3.30

Uncharacterized transporter HI_0976.1

Bacteria

HI_0976.1 of Haemophilus influenzae

2.A.7.3.31

Uncharacterized transporter ydeD

Bacilli

YdeD of Bacillus subtilis

2.A.7.3.32

Uncharacterized transporter YdfC

Bacilli

YdfC of Bacillus subtilis

2.A.7.3.33

DME family member

Actinobacteria

DME family member of Streptomyces coelicolor

2.A.7.3.34

DME family member

Actinobacteria

DME family member of Streptomyces coelicolor

2.A.7.3.35

Uncharacterized transporter YetK

Bacilli

YetK of Bacillus subtilis

2.A.7.3.36

Uncharacterized transporter AF_0510

Archaea

AF_0510 of Archaeoglobus fulgidus

2.A.7.3.37

The DUF6 domain transporter homologue, TrH3 (299 aas; 10 TMSs in a 2 + 8 arrangement)

Bacteria

TrH3 of Candidatus Pelagibacter ubique (Q4FKW8)

2.A.7.3.38

Uncharacterized transporter YrdR

Bacilli

YrdR of Bacillus subtilis

2.A.7.3.39

Putative transporter

Actinobacteria

Putative transporter of Streptomyces coelicolor

2.A.7.3.4

YwfM

Bacteria

YwfM of Bacillus subtilis

2.A.7.3.40

Putative transporter

Proteobacteria

Putative transporter of Myxococcus xanthus

2.A.7.3.41

Hypothetical protein, HP

Bacteria

HP of Streptomyces coelicolor (Q9AK99)

2.A.7.3.42

Putative riboflavin porter, ImpX. Regulated by FMN riboswitch (Vitreschak et al. 2002)

Bacillales

ImpX of Bacillus clausii (Q5WDG6)

2.A.7.3.43

Uncharacterized transporter

Actinobacteria

Uncharacterized protein of Streptomyces coelicolor

2.A.7.3.44

Hypothetical protein of 302 aas and 10 TMSs

Archaea

HP of Halarcula hispanica

2.A.7.3.45

Hypothetical protein of 363 aas and 10 TMSs

Planctomycetes

HP of Rhodopirellula baltica

2.A.7.3.46

Hypothetical protein

Planctomycetes

HP of Rhodopirellula baltica

2.A.7.3.47

10 TMS DME homologue of 280 aas

Archaea

DME homologue of Pyrococcus abyssi

2.A.7.3.48

Multidrug resistance pump, EmrE

Actinobacteria

EmrE of Blastococcus saxobsidens

2.A.7.3.49

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.

Actinobacteria

Peptidase with N-terminal 10 TMSs of Micromonospora aurantiaca

2.A.7.3.5

Yf33

Archaea

Yf33 of Archaeoglobus fulgidus

2.A.7.3.50

Uncharacterized protein of 13 putative TMSs

Rhodophyta

Putative porter of Galdieria sulphuraria

2.A.7.3.51

Putative permease of 494 aas

Rhodophyta

Putative permease of Cyanidioschyzon merolae

2.A.7.3.52

Putative permease of 277 aas

Thermus/Deinococcus

Putative permease of Thermus oshimai

2.A.7.3.53

Putative permease of 467 aas and 10 TM

Stramenopiles (diatoms)

Putative permease of Thalassiosira oceanica

2.A.7.3.54

Riboflavin uptake transporter, RibN of 302 aas and 10 putative TMSs (García Angulo et al. 2013).

Proteobacteria

RibN of Rhizobium legumenosarum

2.A.7.3.55

Riboflavin transporter, RibN, of 284 aas and 8 putative TMSs (García Angulo et al. 2013).

Proteobacteria

RibN of Ochrobactrum anthropi

2.A.7.3.56

Riboflavin uptake porter, RibN, of 284 aas and 10 TMSs (García Angulo et al. 2013).

Proteobacteria

RibN of Vibrio cholerae

2.A.7.3.57

Putative permease of 299 aas and 10 TMSs

Bacteroidetes

UP of Bacteroides thetaiotaomicron

2.A.7.3.58

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).

Cyanobacteria

DmeA of Synechococcus elongatus (strain PCC 7942) (Anacystis nidulans R2)

2.A.7.3.59

Uncharacterized protein of 347 aas and 10 TMSs

Spirochaetes

UP of Treponema denticola

2.A.7.3.6

RhtA (YbiF) Threonine/Homoserine Exporter (may export other amino acids including proline, serine, cysteine, histidine and several amino acid analogues, based on resistance phenotypes (Livshits et al., 2003))

Bacteria

RhtA (YbiF) of Escherichia coli (P0AA67)

2.A.7.3.60

Uncharacterized protein of 306 aas and 10 TMSs.

UP of Bradyrhizobium japonicum

2.A.7.3.61

Putative transporter, YigM, of 299 aas and 10 TMSs.

YigM of E. coli

2.A.7.3.62

Uncharacterized DMT porter of 332 aas and 10 TMSs

UP of Bdellovibrio exovorus

2.A.7.3.63

DMT family transporter of 352 aas and 10 TMSs

UP of Cupriavidus gilardii

2.A.7.3.64

Uncharacterized protein of 304 aas and 10 TMSs

UP of Bdellovibrio exovorus

2.A.7.3.65

Riboflavin (vitamin B2) uptake porter, ImpX, of 301 aas and 10 TMSs. the K_halffor riboflavin uptake was 20 µM. Transport experiments suggested that the energy source is the proton motive force (Rodionova et al. 2019).

ImpX of Bdellovibrio exovorus

2.A.7.3.66

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).

YddG of Starkeya novella, an α-proteobacterium

2.A.7.3.67

PecM (YedA) of 294 aas and 10 TMSs. Promotes invasion and intracellular survival of enteropathogenic E. coli (EPEC) cells (Burska and Fletcher 2014).

PecM of E. coli

2.A.7.3.68

Uncharacterized protein of 303 aas and 10 TMSs

UP of Methylobacterium nodulans

2.A.7.3.69

Uncharacterized protein of 279 aas and 9 TMSs

UP of Methylophaga lonarensis

2.A.7.3.7

The S-adenosylmethionine uptake transporter, Sam (Tucker et al., 2003) (may function by an exchange mechanism (i.e., S-adenosyl-
methionine/S-adenosylhomocysteine exchange))

Bacteria

Sam (RPO76) of Rickettsia prowazekii

2.A.7.3.70

10 TMS DMT superfamily member

Planctomycetes

DMT member of Rhodopirellula baltica

2.A.7.3.71

Riboflavin uptake transporter of 299 aas and 10 TMSs, ImpX (Gutiérrez-Preciado et al. 2015).

ImpX of Fusobacterium nucleatum

2.A.7.3.72

Uncharacterized DMT superfamily protein of 277 aas and 10 TMSs

UP of Candidatus Beckwithbacteria bacterium

2.A.7.3.73

Uncharacterized protein of 290 aas and 10 TMSs.

UP of Candidatus Beckwithbacteria bacterium

2.A.7.3.74

The putative tryptophan efflux protein, YcbK

Bacteria

YcbK of Bacillus subtilis (P42243)

2.A.7.3.75

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).

Bacteria

SepJ of Anabaena sp. PCC7120 (Q8YUK6)

2.A.7.3.76

Uncharacterized DMT family protein of 297 aas and 10 TMSs

UP of Pseudoalteromonas luteoviolacea

2.A.7.3.77

Uncharacterized DMT member of 341 aas and 10 TMSs.

UP of Parvularcula oceani

2.A.7.3.78

Uncharacterized protein of 303 aas and 10 TMSs.

UP of Parvularcula oceani

2.A.7.3.79

Uncharacterized putative DMT family protein of 313 aas and 10 TMSs

UP of Lactobacillus similis

2.A.7.3.8

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).

Bacteria

Permease of Agrobacterium tumefaciens (A9CFB8)

2.A.7.3.80

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).

CnrT of Cupriavidus metallidurans (Ralstonia metallidurans)

2.A.7.3.81

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).

SepJ of Anabaena sp. 90

2.A.7.3.82

Riboflavin (RF) uptake porter, ImpX, of 302 aas and 10 TMSs. Functional complementation, growth inhibition experiments, direct uptake experiments and inhibition studies, suggesting a high degree of specificity for RF uptake (Rodionova et al. 2019). The EC50 for growth with RF was estimated to be in the range 0.5-1 µM, estimated from the half-maximal RF concentration supporting the growth of a RF auxotrophic Escherichia coli strain, but the K_half for RF uptake was 20 µM. Transport experiments suggested that the energy source is the proton motive force, but that NaCl stimulates uptake (Rodionova et al. 2019).

ImpX of Bdellovibrio exovorus JSS

2.A.7.3.83

Uncharacterized protein of 318 aas and 10 TMSs

UP of Candidatus Heimdallarchaeota archaeon B3_Heim (marine sediment metagenome)

2.A.7.3.84

DMT family metabolite transporter of 311 aas and 10 TMSs.

DMT transporter of Patescibacteria group bacterium

2.A.7.3.85

Uncharacterized protein of 148 aas and 5 TMSs.

UP of Parcubacteria group bacterium GW2011_GWC2_52_8c (groundwater metagenome)

2.A.7.3.86

Uncharacterized protein of 300 aas and 10 TMSs

UP of Candidatus Beckwithbacteria bacterium

2.A.7.3.87

Triose-P (PEP; glycerate-3-P and glycerate-2-P) of 302 aas and 10 TMSs .

Triose-P transporter of Lysinibacillus xylanilyticus

.

2.A.7.3.88

DMT putative drug resistance efflux pump of 320 aas and 10 TMSs in a 2 + 3 + 2 + 3 TMS arrangement (Chanket et al. 2024).

DMT drug efflux pump of Clostridioides difficile (strain 630) (Peptoclostridium difficile)

2.A.7.3.9

10 TMS DMT superfamily member of unknown function.

Bacteria

Permease of Vibriocholerae (A2P528)

2.A.7.30 The Uncharacterized DMT-2 (U-DMT2) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.30.1

Hypothetical protein of 299 aas and 10 putative TMSs

Planctomycetes

HP of Rhodopirellula baltica

2.A.7.30.2

Uncharacterized putative permease of 295 aas and 10 TMSs.

UP of Flavobacterium frigoris

2.A.7.31 The Uncharacterized DMT-3 (U-DMT3) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.31.1

10 TMS DMT Superfamily member

δ-Proteobacteria

DMT protein of Myxococcus xanthus (Q1DCP3)

2.A.7.31.2

10 TMS DMT Superfamily member

γ-Proteobacteria

Legionella pneumophila (A5IFT5)

2.A.7.31.3

10 TMS DMT Superfamily member

α-Proteobacteria

DMT protein of Rhizobium torpici (L0LHM3)

2.A.7.32 The Uncharacterized DMT-4 (U-DMT4) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.32.1

The transmembrane protein TMEM234 of 164 aas and 4 TMSs.

Animals

TMEM234 of Homo sapiens

2.A.7.32.2

TMEM234 of 127 aas and 4 TMSs.

Animals

TMEM234 of Caenorhabditis elegans

2.A.7.32.3

Uncharacterized protein of 128 aas.

Slime molds

UP of Dictyostelium discoideum

2.A.7.32.4

Uncharcterized protein of 182 aas and 4 TMSs

Fungi

UP of Pyrenophora teres

2.A.7.32.5

Uncharacterized protein of 121 aas

Protozoa

UP of Leishmania infantum

2.A.7.32.6

TMEM234 of 234 aas and 4 TMSs in a 1 + 3 TMS arrangement. In zebrafish larvae, Tmem234 is essential for the organization and functional integrity of the pronephric glomerulus filtration barrier. Inactivation of Tmem234 expression results in foot process effacement and proteinuria. It is one of four highly podocyte-enriched proteins. Tmem234 is essential for the normal filtration barrier in the zebrafish pronephric glomerulus (Rodriguez et al. 2015).

TMEM234 of Danio rerio (Zebrafish)

2.A.7.33 The Uncharacterized DMT-5 (U-DMT5) Family

Most closely related to the SMR2 Family (2.A.7.22).

Examples:

TC#

Name

Organismal Type

Example

2.A.7.33.1

Permease of 116 aa

Acidobacteria

Permease of Solibacter usitatus

2.A.7.33.2

Uncharacterized protein of 116 aas.

Bacteroidetes

UP of Bacteroides fragilis

2.A.7.33.3

Uncharacterized protein of 123 aas.

Proteobacteria

UP of Burkholderia caribensis

2.A.7.33.4

EmaA-like transporter of 111 aas.

Cyanobacteria

UP of Dactylococcopsis salina

2.A.7.33.5

Uncharacterized protein of 116 aas

Actinobacteria

UP of Olsenilla profusa

2.A.7.33.6

Uncharacterized protein of 114 aas and 4 TMSs

UP of Thermincola potens

2.A.7.33.7

SMR protein of 127 aas and 4 TMSs

SMR protein of Nostoc punctiforme

2.A.7.34 The Uncharacterized DMT-6 (U-DMT6) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.34.1

DUF486 transporter of 113 aas and 4 TMSs.

Proteobacteria

UP of Laribacter hongknogensis

2.A.7.34.2

DUF486 transporter of 117 aas and 4 TMSs.

Proteobacteria

UP of Xanthomonas campestris

2.A.7.34.3

DUF486 homologue of 122 aas

Bacteroidetes

UP of Bacteroides fragilis

2.A.7.34.4

DUF486 homologue of 112 aas

Euryarchaeota

UP of Methanococcus maripaludis

2.A.7.34.5

DUF486 homologue of 124 aas

Bacteroidetes

UP of Cytophaga hutchinsonii

2.A.7.34.6

DUF486 homologue of 122 aas

Spirochaeta

UP of Brachyspira intermedia

2.A.7.34.7

Small multidrug resistance (SMR) protein of 116 aas

Acidobacteria

SMR protein of Terriglobus saanensis

2.A.7.34.8

Uncharacterized protein of 179 aas

Heptophyceae (Eukaryote)

UP of Emiliania huxleyi

2.A.7.34.9

Uncharacterized protein of 146 aas

Cryptophyta (Eukaryotes)

UP of Guillardia theta

2.A.7.35 The Uncharacterized DMT-7 (U-DMT7) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.35.1

Membrane protein of 280 aas and 9 TMSs.

Actinobacteria

Membrane protein of Corynebacterium matruchotii (E0DBX6)

2.A.7.35.10

Uncharacterized protein of 324 aas and 9 TMSs.

UP of Mycobacterium intracellulare

2.A.7.35.2

NIPA family member of 419 aas and 9 or 10 TMSs.

Actinobacteria

NIPA family member of Streptomyces coelicolor

2.A.7.35.3

Uncharacterized permease of 370 aas and 9 or 10 TMSs.

Actinobacteria

UP of Frankia sp.

2.A.7.35.4

Uncharacterized protein of 311 aas and 9 or 10 TMSs

Actinobacteria

UP of Kribbella flavida

2.A.7.35.5

Uncharacterized protein of 292 aas and 9 TMSs

Actinobacteria

UP of Streptomyces grisius

2.A.7.35.6

Uncharacterized protein of 299 aas and 9 TMSs

Actinobacteria

UP of Streptomyces coelicolor

2.A.7.35.7

Uncharacterized protein of 295 aas and 9 or 10 TMSs.

Actinobacteria

UP of Conexibacter woesei

2.A.7.35.8

Uncharacterized protein of 289 aas and 9 TMSs.

Actinobacteria

UP of Amycolatopsis mediterranei

2.A.7.35.9

Uncharacterized protein of 303 aas and 9 TMSs

Actinobacteria

UP of Thermobifida fusca

Examples:

TC#

Name

Organismal Type

Example

2.A.7.36.1

EamA-like transporter of 287 aas and 10 TMSs

EamA-like protein of Mycobacterium chubuense

2.A.7.36.2

Uncharacterized protein of 283 aas and 10 TMSs

UP of Acidothermus cellulolyticus

2.A.7.36.3

Uncharacterized protein of 275 aas and 10 TMSs

UP of Geodermatophilus obscurus

2.A.7.36.4

Uncharacterized protein of 291 aas and 10 TMSs

UP of Truepera radiovictrix

2.A.7.36.5

Uncharacterized protein of 281 aas and 10 TMSs

UP of Methanolobus psychrophilus

Examples:

TC#

Name

Organismal Type

Example

2.A.7.37.1

Uncharacterized protein of 164 aas and 4 TMSs.

UP of Delftia acidovorans

2.A.7.37.2

Uncharacterized protein of 132 aas and 4 TMSs.

UP of Pseudomonas chlororaphis subsp. aureofaciens

2.A.7.37.3

Uncharacterized protein of 139 aas and 4 TMSs.

UP of Rhizobium mesoamericanum

Examples:

TC#

Name

Organismal Type

Example

2.A.7.38.1

Uncharacterized protein of 301 aas and 10 or fewer TMSs.

UP of Parvibaculum lavamentivorans

2.A.7.38.2

Uncharacterized protein of 343 aas and 10 TMSs

UP of Agrobacterium radiobacter

2.A.7.38.3

Uncharacterized protein of 298 aas and 10 TMSs

UP of Maritimibacter alkaliphilus

Examples:

TC#

Name

Organismal Type

Example

2.A.7.4 The Plant Amino Acid Transporter (UMAMIT) (formerly the P-DME) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.4.1

MtN21 nodulin protein

Plants

MtN21 of Medicago truncatula

2.A.7.4.10

USUALLY MULTIPLE AMINO ACIDS MOVE IN AND OUT TRANSPORTER (UMAMIT) family proteiin, UMAMIT31 is a glucosinolate exporters with a uniport mechanism. Loss-of-function umamit29 umamit30 umamit31 triple mutants have a very low level of seed glucosinolates, demonstrating a key role for these transporters in translocating glucosinolates into seeds. The UMAMIT uniporters facilitate glucosinolate efflux from biosynthetic cells along the electrochemical gradient into the apoplast, where the high-affinity H⁺-coupled glucosinolate importers GLUCOSINOLATE TRANSPORTERS (GTRs) load them into the phloem for translocation to the seeds (Xu et al. 2023).

UMAMIT31 of Arabidopsis thaliana

2.A.7.4.2

Nodulin MfN21 or UMAMIT24 of 355 aas and 10 TMSs. UMAMIT24 and UMAMIT25 function in amino acid transfer in developing seeds. Besnard et al. 2018 showed that UMAMIT24 and UMAMIT25 promote export of a broad range of amino acids. They are expressed in distinct tissues within developing seeds; UMAMIT24 is mainly expressed in the chalazal seed coat and localized on the tonoplast, whereas the plasma membrane-localized UMAMIT25 is expressed in endosperm cells.

Plants

MfN21 of Arabidopsis thaliana (NP_173898)

2.A.7.4.3

Nodulin MtN21/EamA-like transporter

Plants

Nodulin MtN21 of Arabidopsis thaliana (Q9ZUI8)

2.A.7.4.4

WAT1 (Walls are thin 1) of 389 aas and 10 TMSs in a 5 + 5 TMS arrangement. Required for secondary wall formation in fibers, especially in short days conditions. Promotes indole metabolism and transport (e.g. tryptophan, neoglucobrassicin and auxin (indole-3-acetic acid)) (Denancé et al. 2013). May prevent salicylic-acid (SA) accumulation. It exports indolebutyric acid from vacuoles (Damodaran and Strader 2019).

WAT1 of Arabidopsis thaliana

2.A.7.4.5

UMAMIT14 amino acid efflux transporter of 374 aas and 10 TMSs, a member of the nodulin MtN21 family. It is involved in phloem unloading in Arabidopsis roots (Besnard et al. 2016). UMAMIT14 is expressed in root pericycle and phloem cells and mediates export of a broad range of amino acids. Loss-of-function of UMAMIT14 leads to a reduced shoot-to-root and root-to-medium transfer of amino acids originating from the leaves. These fluxes were further reduced in an umamti14 umamit18 double loss-of-function mutant. Thus, UMAMIT14 is involved in phloem unloading of amino acids in roots, and both UMAMIT14 and UMAMIT18 are involved in the radial transport of amino acids in roots (Besnard et al. 2016).

UMAMIT14 in Arabidopsis thaliana (Mouse-ear cress)

2.A.7.4.6

Red1; UMAMIT18; WAT1-related protein At1g44800, or SIART of 370 aas and 10 TMSs. It is an L-amino acid efflux transporter that can function bidirectionally into and out of the cell (Müller et al. 2015). In Arabidopsis, SIAR1 localizes to the plasma membrane and is expressed in the vascular tissue, in the pericycle, stamen, and the chalazal seed coat of ovules and developing seeds. Mutant alleles of SIAR1 accumulate anthocyanins as a symptom of reduced amino acid content in the early stages of silique development (Ladwig et al. 2012).

Red1 of Arabidopsis thaliana (Mouse-ear cress)

2.A.7.4.7

RTP1 of 375 aas and 10 TMSs, a nodulin‐related MtN21 family endoplasmic reticulum protein that mediates susceptibility to infection by the fungi, Phytophthora parasitica and Golovinomyces cichoracearum, as well as the bacterium, Pseudomonas syringae (Pan et al. 2016). In agreement with the functions of other members of the NODULIN21 family, it probably catalyzes uptake of amino acids from the cytoplasm into the lumen of the ER.

RTP1 of Arabidopsis thaliana

2.A.7.4.8

USUALLY MULTIPLE AMINO ACIDS MOVE IN AND OUT TRANSPORTER (UMAMIT) family proteiin, UMAMIT29 is a glucosinolate exporters with a uniport mechanism. Loss-of-function umamit29 umamit30 umamit31 triple mutants have a very low level of seed glucosinolates, demonstrating a key role for these transporters in translocating glucosinolates into seeds. The UMAMIT uniporters facilitate glucosinolate efflux from biosynthetic cells along the electrochemical gradient into the apoplast, where the high-affinity H⁺-coupled glucosinolate importers GLUCOSINOLATE TRANSPORTERS (GTRs) load them into the phloem for translocation to the seeds (Xu et al. 2023).

UMAMIT29 of Arabidopsis thaliana

2.A.7.4.9

USUALLY MULTIPLE AMINO ACIDS MOVE IN AND OUT TRANSPORTER (UMAMIT) family proteiin, UMAMIT30 is a glucosinolate exporters with a uniport mechanism. Loss-of-function umamit29 umamit30 umamit31 triple mutants have a very low level of seed glucosinolates, demonstrating a key role for these transporters in translocating glucosinolates into seeds. The UMAMIT uniporters facilitate glucosinolate efflux from biosynthetic cells along the electrochemical gradient into the apoplast, where the high-affinity H⁺-coupled glucosinolate importers GLUCOSINOLATE TRANSPORTERS (GTRs) load them into the phloem for translocation to the seeds (Xu et al. 2023).

UMAMIT30 of Arabidopsis thaliana

Examples:

TC#

Name

Organismal Type

Example

2.A.7.40.1

Uncharacterized protein of 292 aas and 10 TMSs.

UP of Desulfobacca acetoxidans

2.A.7.40.2

Uncharacterized protein of 297 aas and 10 TMSs

UP of Fibrisoma limi

2.A.7.40.3

Uncharacterized protein of 324 aas and 10 TMSs

UP of Methylotenera versatilis

2.A.7.40.4

DMT family transporter of 290 aas and 10 TMSs.

Transporter of Patescibacteria group bacterium (groundwater metagenome)

Examples:

TC#

Name

Organismal Type

Example

2.A.7.41.1

Uncharacterized protein of 178 aas and 4 TMSs

UP of Corynebacterium glutamicum

2.A.7.41.2

Uncharacterized protein of 150 aas and 4 TMSs.

UP of Mobilicoccus pelagius

2.A.7.41.3

Uncharacterized protein of 149 aas and 4 TMSs

UP of Arsenicicoccus bolidensis

2.A.7.41.4

Uncharacterized protein of 110 aas and 3 TMSs; possibly an incomplete sequence.

UP of Corynebacterium pseudogenitalium

2.A.7.41.5

Uncharacterized protein of 235 aas and 4 TMSs.

UP of Raineyella antarctica

Examples:

TC#

Name

Organismal Type

Example

2.A.7.42.1

Uncharacterized protein of 140 aas and 4 TMSs.

UP of Actinopolyspora alba

2.A.7.42.2

Uncharacterized protein of 139 aas and 4 TMSs

UP of Streptomyces rimosus

2.A.7.42.3

Uncharacterized protein of 147 aas and 4 TMSs

UP of Planobispora rosea

2.A.7.42.4

Uncharacterized protein of 141 aas and 4 TMSs

UP of Thermobispora bispora

2.A.7.42.5

Uncharacterized protein of 143 aas and 4 TMSs.

UP of Glycomyces arizonensis

2.A.7.42.6

Uncharacterized protein of 140 aas and 4 TMSs

UP of Nocardiopsis trehalosi

2.A.7.42.7

Uncharacterized protein of 149 aas and 4 TMSs

UP of Dietzia alimentaria

Examples:

TC#

Name

Organismal Type

Example

2.A.7.43.1

Uncharacterized protein of 129 aas and 4 TMSs

UP of Bauldia litoralis

2.A.7.43.10

This uncharacterized protein is annotated in the NCBI database as an NAD-dependent epimerase/dehydratase family protein of 461 aas and 4 C-terminal TMSs that are homologous to the members of TC subfamily 2.A.7.43, but the rest of the protein is hydrophilic and presumable is a fusion between the N-terminal dehydratase and the C-terminal DMT domain.

UP of an α-proteobacterium

2.A.7.43.11

Uncharacterized protein of 167 aas and 4 TMSs

UP of Leptonema illini (bioanode metagenome)

2.A.7.43.12

Uncharacterized protein of 291 aas and 8 TMSs, where the 4 TMSs of many members of this subfamily are duplicaed to give two 4 TMS domains, each with a 1 + 2 + 1 TMS arrangement.

UP of Nitrospiraceae bacterium (marine sediment metagenome)

2.A.7.43.2

Uncharacterized protein of 121 aas and 4 TMSs.

UP of Dehalococcoides mccartyi

2.A.7.43.3

Uncharacterized protein of 128 aas and 4 TMSs

UP of Lokiarchaeum sp. GC14_75 (marine sediment metagenome)

2.A.7.43.4

Uncharacterized protein of 126 aas and 4 TMSs

UP of Dehalogenimonas alkenigignens

2.A.7.43.5

Uncharacterized protein of 130 aas and 4 TMSs in a 1 + 3 TMS arrangement, a characteristic of members of this family.

UP of Haloferax denitrificans

2.A.7.43.6

Uncharacterized protein of 131 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement.

UP of Candidatus Prometheoarchaeum syntrophicum

2.A.7.43.7

Uncharacterized protein of 143 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement.

UP of Marmoricola solisilvae

2.A.7.43.8

Uncharacterized protein of 149 aas and 4 TMSs

UP of Chloroflexi bacterium (marine sediment metagenome)

2.A.7.43.9

Uncharacterized protein of 482 aas and 14 TMSs in a 4 + 2 + 4 + 4 TMS arrangement. The first 4 TMSs are homologous to proteins in subfamily 2.A.7.43, but the C-terminal region shows sequence similarity with 9.B.241.2.5, an integral membrane geranylgeranylglycerol-phosphate geranylgeranyltransferase with 9 TMSs.

UP of candidate division Zixibacteria bacterium HGW-Zixibacteria-1].

Examples:

TC#

Name

Organismal Type

Example

2.A.7.44.1

DUF2227 family putative metal-binding protein of 156 aas and 4 TMSs in a 2 + 2 arrangement.

DUF2227 protein of Methanococcoides methylutens

2.A.7.44.10

Uncharacterized protein of 289 aas and 7 TMSs in a 1 + 1 + 1 + 2 + 2 TMS arrangement

UP of Proteobacteria bacterium (phyllosphere metagenome)

2.A.7.44.11

Metal-dependent hydrolase of 317 aas and 6 TMSs in a 1 + 2 + 2 + 1 arrangement.

Hydrolase of Geosporobacter subterraneus

2.A.7.44.2

Uncharacterized protein of 164 aas and 4 TMSs in a 2 + 2 arrangement.

UP of Gemmatimonadetes bacterium (sponge metagenome)

2.A.7.44.3

Uncharacterized protein of 149 aas and 4 TMSs in a 2 + 2 arrangement.

UP of Thermus aquaticus

2.A.7.44.4

DUF2227 family putative metal-binding protein of 152 aas and 4 TMSs.

DUF2227 protein of Abditibacterium utsteinense

2.A.7.44.5

Uncharacterized protein of 151 aas and 5 TMSs

UP of Chloroflexi bacterium

2.A.7.44.6

Uncharacterized protein of 156 aas and 3 or 4 TMSs.

UP of candidate division Zixibacteria

bacterium

2.A.7.44.7

Metal-dependent hydrolase of 173 aas and 4 TMSs

Putative hydrolase of Butyrivibrio proteoclasticus

2.A.7.44.8

Membrane-bound metal-dependent hydrolase of 318 aas and 5 TMSs with an N-terminal YdjM domain.

Hydrolase of Calderihabitans maritimus

2.A.7.44.9

Uncharacterized protein of 190 aas and 3 or 4 TMSs

UP of Candidatus Woesebacteria bacterium

Examples:

TC#

Name

Organismal Type

Example

2.A.7.45.1

DMT!. putative organic solute transporter of 434 aas and 9 apparent TMSs in a 2 + 7 TMS arrangement (Wunderlich 2022).

DMT1 of Plasmodium falciparum

2.A.7.5 The Glucose/Ribose Porter (GRP) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.5.1

Glucose uptake permease, GlcU

Gram-positive bacteria

GlcU (GltT) of Staphylococcus xylosus

2.A.7.5.2

Probable ribose transporter, RbsU

Gram-positive bacteria

RbsU of Lactobacillus sakei

2.A.7.5.3

Glucose:H⁺ symporter, GlcU (YxfA) (high specificity, low affinity) (Castro et al., 2009). The effect of glucose stress on metabolic adaptation of Lactococcus lactis revealed that glucose stress up-regulated organic acid transport but down-regulated amino acid transport, resulted in a decrease in nitrogen metabolism (Qi et al. 2020).

Low G+C, Gram-positive Bacteria

GlcU of Lactococcus lactis (Q9CDF7)

2.A.7.5.4

Glucose permease, GlcU (also called YcxE). (Fiegler et al., 1999) (similar to 2.A.7.5.1).

GlcU of Bacillus subtilis (P40420)

2.A.7.5.5

The glucose uptake porter of 285 aas, GlcU (Aké et al. 2011).

Firmicutes

GlcU of Listeria monocytogenes

2.A.7.5.6

DMT putative multidrug efflux pump of 284 aas and 10 TMSs (Chanket et al. 2024).

Putative DMT-type MDR exporter of Clostridioides difficile (strain 630) (Peptoclostridium difficile)

2.A.7.6 The L-Rhamnose Transporter (RhaT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.6.1

Rhamnose:H⁺ symporter, RhaT (Garcia-Martin et al. 1992) of 344 aas and 10 TMSs in a 5 + 5 TMS arrangement (Tate and Henderson 1993). IT belongs to the TMEM144 family. Transcriptional regulation of rhaT is due to the RhaS activator, and L-rhamnose, L-lyxose and L-mannose activate (Vía et al. 1996).

Gram-negative bacteria

RhaT of E. coli

2.A.7.6.2

L-rhamnose-proton symporter, RhaT, of 340 aas and 10 TMSs

RhaT of Rhodopirellula sallentina

2.A.7.6.3

L-rhamnose-proton symport protein, RhaT, of 337 aas and 10 TMSs

RhaT of Joostella marina

2.A.7.6.4

Uncharacterized protein of 627 aas and 8 - 10 TMSs.

UP of Guillardia theta

2.A.7.7 The Chloramphenicol-Sensitivity Protein (RarD) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.7.1

The chloramphenicol-sensitive protein, RarD

Gram-negative bacteria

RarD of Pseudomonas aeruginosa

2.A.7.7.2

Protein RarD. Involved in antibiotic resistance (Carruthers et al. 2010).

Bacteria

RarD of Escherichia coli

2.A.7.7.3

Uncharacterized transporter HI_0680

Bacteria

HI_0680 of Haemophilus influenzae

2.A.7.8 The Caenorhabditis elegans ORF (CEO) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.8.1

Hypothetical protein, Yrr6

Animals

Yrr6 of Caenorhabditis elegans

2.A.7.8.2

TM protein 144 homologue 2 (DUF1632 homologue).

Slime molds

TMP144-2 of Dictyostelium discoideum (Q54V96)

2.A.7.8.3

TMEM144 protein of 345 aas and 9 TMSs in a 4 + 5 TMS arrangement. TMEM144 is up-regulated in the hypothalamus (Prentice et al. 2011).

TMEM144 of Homo sapiens

2.A.7.9 The Triose-phosphate Transporter (TPT) Family

Examples:

TC#

Name

Organismal Type

Example

2.A.7.9.1

Chloroplast triose-P/glycerate-3-P:P_i antiporter (TPT) (phosphoenolpyruvate and 2-phosphoglycerate are poor substrates).

Plants

TPT of Zea mays

2.A.7.9.10

solute carrier family 35, member E3

Animals

member E3 of Mus musculus (Q6PGC7)

2.A.7.9.11

The putative thiamine pyrophosphate transporter, SLC35E4, of 350 aas and 10 TMSs. A competing endogenous RNA network involving the gene for SLC35E4 is related to the prognosis of cholangiocarcinoma (Wang et al. 2021).

Animals

SLC35E4 of Homo sapiens

2.A.7.9.12

UDP-galactose, UDP-rhamnose, (and maybe UDP-glucose and UDP-fructose) transporter 2, UGAL2 (At1g76670) (Bakker et al. 2005; Rautengarten et al. 2014).

Plants

UGAL2 of Arabidopsis thaliana (Q9SRE4)

2.A.7.9.13

Golgi nucleotide-sugar (probable UDP-galactose/UDP-rhamnose) transporter (At1g21070; EamA superfamily member), of 335 aas and 10 TMSs.

Plants

At1g21070 of Arabidopsis thaliana (Q9LPU2)

2.A.7.9.14

Putative nucleotide-sugar transporter YMD8

Fungi

YMD8 of Saccharomyces cerevisiae

2.A.7.9.15

Solute carrier family 35 member E3 (Bladder cancer-overexpressed gene 1 protein). SLC35E3 has been identified as a target of novel‑m1061‑5p via microRNA profiling of patients with cardiovascular disease (Gao et al. 2018).

Animals

SLC35E3 of Homo sapiens

2.A.7.9.16

Solute carrier family 35 member C2, SLC35C2. (Ovarian cancer-overexpressed gene 1 protein) of 365 aas and 10 TMSs. It may play a role in the cellular response to tissue hypoxia, and may be either a GDP-fucose transporter that competes with SLC35C1 for GDP-fucose, or a factor that otherwise enhances the fucosylation of Notch and is required for optimal Notch signaling in mammalian cells (Lu et al. 2010). It may transport GDP-fucose (Lu et al. 2023).

Animals

SLC35C2 of Homo sapiens

2.A.7.9.17

Probable sugar phosphate/phosphate translocator At2g25520

Plants

At2g25520 of Arabidopsis thaliana

2.A.7.9.18

Putative transporter C83.11

Yeast

SPBC83.11 of Schizosaccharomyces pombe

2.A.7.9.19

Glucose-6-phosphate/phosphate-translocator-like protein 1

Plants

At4g03950 of Arabidopsis thaliana

2.A.7.9.2

Nongreen plastid/chloroplast glucose-P/triose-P/glycerate-P:P_i antiporter (GPT) (Both glucose-6-P and glucose-1-P are substrates; other hexose-Ps may also be transported). (Exchanges phosphoenolpyruvate for inorganic phosphate (Nozawa et al., 2007)

Plants

GPT of Brassica oleracea

2.A.7.9.20

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).

UgtA of Aspergillus niger

2.A.7.9.21

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.

GlfB of Neosartorya fumigata (Aspergillus fumigatus)

2.A.7.9.22

Xylulose-5-P:Pi antiporter, Xpt or Rpt of 417 aas (Knappe et al. 2003).

Xpt of Arabidopsis thaliana

2.A.7.9.23

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.

TPT of Arabidopsis thaliana

2.A.7.9.24

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).

pPT of Plasmodium falciparum

2.A.7.9.25

Putative triose-P (PEP, Gly-2-P and Gly-3-P) uptake porter of 342 aas and 8 - 10 TMSs.

Triose-P transporter of Plasmodiium falciparum

2.A.7.9.26

Triose-P:P antiporter of 478 aas and 10 TMSs (residues 180 - 478). The first 180 aas are strongly hydrophilic.

Triose-P of Plasmodium falciparum

2.A.7.9.3

Chloroplast phosphoenolpyruvate:P_i antiporter (PPT) (triose-Ps and glycerate- Ps are poor substrates).

Plants

PPT of Zea mays

2.A.7.9.4

Sly41p (transport function unknown)

Yeast

Sly41p of Saccharomyces cerevisiae

2.A.7.9.5

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).

Red algae

TPT Galdieria sulphuraria (B5AJT1)

2.A.7.9.6

Chloroplast Glucose-6-P/P_iantiporter-2, Gpt2

Plants

Gpt2 of Arabidopsis thaliana (Q94B38)

2.A.7.9.7

solute carrier family 35, member E2B, SLC35A2B, of 405 aas and 8-10 TMSs. It may take up a nucleobase-containing compounds (Yamada et al. 2017). Mutations in SLC35E2B and the Flrt3 (FLRT3; TC# 8.A.43.1.27) protein can give rise to high myopia, an eye disorder in which both environmental and genetic factors are involved (Swierkowska et al. 2021).

Animals

SLC35E2B of Homo sapiens

2.A.7.9.8

solute carrier family 35, member C2

Homo sapiens

SLC35C2 of Homo sapiens (Q8VCX2)

2.A.7.9.9

solute carrier family 35, member E1 of 410 aas and 10 TMSs. It may play a role in heroin addition (Shi et al. 2020) as well as in the nuclear rgress of Herpes Simplex Virus 1(Maeda et al. 2022).

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Animals

SLC35E1 of Homo sapiens