SII-SWORD/CoKE huggingface dataset:
MFS transporter, metabolite:H symporter (MHS_symport)
Type: Family

Recent genome-sequencing data and a wealth of biochemical and molecular genetic investigations have revealed the occurrence of dozens of families of primary and secondary transporters. Two such families have been found to occur ubiquitously in all classifications of living organisms. These are the ATP-binding cassette (ABC) superfamily and the major facilitator superfamily (MFS), also called the uniporter-symporter-antiporter family. While ABC family permeases are in general multicomponent primary active transporters, capable of transporting both small molecules and macromolecules in response to ATP hydrolysis the MFS transporters are single-polypeptide secondary carriers capable only of transporting small solutes in response to chemiosmotic ion gradients. Although well over 100 families of transporters have now been recognised and classified, the ABC superfamily and MFS account for nearly half of the solute transporters encoded within the genomes of microorganisms. They are also prevalent in higher organisms. The importance of these two families of transport systems to living organisms can therefore not be overestimated .

The MFS was originally believed to function primarily in the uptake of sugars but subsequent studies revealed that drug efflux systems, Krebs cycle metabolites, organophosphate:phosphate exchangers, oligosaccharide:H1 symport permeases, and bacterial aromatic acid permeases were all members of the MFS. These observations led to the probability that the MFS is far more widespread in nature and far more diverse in function than had been thought previously. 17 subgroups of the MFS have been identified .

Evidence suggests that the MFS permeases arose by a tandem intragenic duplication event in the early prokaryotes. This event generated a 2-transmembrane-spanner (TMS) protein topology from a primordial 6-TMS unit. Surprisingly, all currently recognised MFS permeases retain the two six-TMS units within a single polypeptide chain, although in 3 of the 17 MFS families, an additional two TMSs are found . Moreover, the well-conserved MFS specific motif between TMS2 and TMS3 and the related but less well conserved motif between TMS8 and TMS9 prove to be a characteristic of virtually all of the more than 300 MFS proteins identified.

This entry represents the metabolite-H(+) symport (MHS) subfamily of the MFS. Members include citrate-proton symporters , alpha-ketoglutarate permease , shikimate transporters , glycine betaine/proline/ectoine/pipecolic acid transporter OusA and the proline/betaine transporter ProP .
Nitrate transporter NarK/NarU-like (NO3_transporter_NarK/NarU-like)
Type: Family

This family represents nitrate/nitrite antiporters in bacteria, fungi, algae and marine diatoms. Nitrate transporters in Escherichia coli are involved in excretion of nitrite produced by the dissimilatory reduction of nitrate. NarK is polytopic membrane protein with 12 transmembrane domains which is involved in nitrate uptake and nitrite excretion and is thought to function as a nitrate/nitrite antiporter . At low concentrations of nitrate, NarK mediates the electrogenic excretion of nitrite rather than nitrate/nitrite exchange. This process prevents intracellular accumulation of toxic levels of nitrite and allows further detoxification in the periplasm through the action of nitrite reductase .

In the opportunistic fungal pathogen Aspergillus fumigatus the nitrate transporter crnA clusters with nitrite reductase (niiA) and nitrate reductase (niaD). NiaD, niiA and crnA are induced by nitrate and repressed by ammonium at the transcriptional level . In Hebeloma cylindrosporum the nitrate transporter polypeptide (NRT2) is characterised by 12 transmembrane domains and presents both a long putative intracellular loop and a short C-terminal tail, two structural features which distinguish fungal high-affinity transporters from their plant homologues. Transcription is repressed by ammonium and strongly stimulated by nitrate but also by organic nitrogen or nitrogen deficiency.
Phosphate permease (Phos_permease)
Type: Family

In yeast the high-affinity transporter for external inorganic phosphate is not essential since a constitutive, low-affinity transporter exists. The induction of the yeast protein is depressed by phosphate starvation.
GMP synthase, glutamine amidotransferase (GMP_synth_GATase)
Type: Domain

This entry represents the N-terminal domain of bacterial GMP synthase [glutamine-hydrolyzing]

and similar sequences found in all cellular organisms. This domain covers the whole protein length in some archaeal members of this group.

GMP synthase catalyses the synthesis of GMP from XMP .

ATP + xanthosine 5'-phosphate + L-glutamine + H(2)O = AMP + diphosphate + GMP + L-glutamate

GMP synthetase is a glutamine amidotransferase from the de novo purine biosynthetic pathway. It belongs to the triad family of amidotransferases having a conserved Cys-His-Glu catalytic triad in the glutaminase active site .

Glutamine amidotransferase (GATase) activity catalyses the transfer of ammonia from the amide side chain of glutamine to an acceptor substrate.
Nucleoside:H+ symporter (Nuc_H_symport)
Type: Family

This family of proteins transports nucleosides at a high affinity. The transport mechanism is driven by proton motive force. This family includes nucleoside permease (NupG) and xanthosine permease (XapB) from Escherichia coli.
Oxalate/formate antiporter family transporter (Oxa_For_antiport_fam_transptr)
Type: Family

This subfamily belongs to the major facilitator family. Members include the oxalate/formate antiporter of Oxalobacter formigenes, where one substrate is decarboxylated in the cytosol into the other to consume a proton and drive an ion gradient.
Sialic acid transporter (SA_transporter)
Type: Family

This entry represents sialic acid transporters.

The sugar transporters belong to a family of membrane proteins responsible for the transport of various sugars in a wide range of prokaryotic and eukaryotic organisms . These integral membrane proteins are predicted to comprise twelve membrane spanning domains. It is likely that the transporters have evolved from an ancient protein present in living organisms before the divergence into prokaryotes and eukaryotes . In mammals, these proteins are expressed in a number of organs . Proteins transporting sugars and other substrates are related in this broader family.
Monocarboxylate transporter (MCT)
Type: Family

Monocarboxylate transporters (MCTs) catalyse the proton-linked transport of monocarboxylates such as L-lactate, pyruvate, and the ketone bodies across the plasma membrane . All of the MCT family (also known as SLC16 solute carrier family) members share conserved sequence motifs. They are are predicted to have 12-transmembrane helices (TMs) with intracellular C and N termini and a large cytosolic loop between TMs 6 and 7. Four mammalian isoforms, MCTs 1-4, have been identified, each with distinct substrate and inhibitor affinities . MCT1-4 have been linked to cancer maintenance and aggressiveness .
Na-dependent inorganic phosphate cotransporter (Pi_cotranspt)
Type: Family

Na(+)-dependent inorganic phosphate cotransporter proteins belong to this group. The mammalian proteins are important for the resorption of phosphate by the kidney and may be involved in actively transporting phosphate into cells via sodium ion cotransport in the renal brush border membrane.
Major facilitator superfamily, aromatic acid:H+ symporter family (MFS_AAHS)
Type: Family

The aromatic acid:H+ symporter family (AAHS) is classified as family 15 of the major facilitator superfamily (MFS) . Members of the AAHS family show fairly uniform sizes (418 to 460 residues). They transport a variety of aromatic acids as well as cis,cis-muconate . 4-hydroxybenzoate transporter (PcaK Ppu), a member of this family, has been implicated in chemotaxis, allowing the bacteria to swim up concentration gradients of its substrates . This is the only documented case where an MFS protein apparently serves as a chemoreceptor. One of the AAHS proteins (BenK Aca) transports benzoate . Under the transporter classification (TC) system , this family is classified as TC number 2.A.1.15.
Cyanate transport protein CynX-like (CynX-like)
Type: Family

This entry includes the cyanate transport protein CynX and 2-nitroimidazole transporter yeaN from E. coli.

Protein yeaN is involved in efflux of 2-nitroimidazole .
Polyol permease-like (Polyol_permease-like)
Type: Family

This entry represents a group of related bacterial proteins, including known or predicted polyol transporters. The best characterised of these proteins are DalT and RbtT from Klebsiella pneumoniae, which tranpsort D-arabinatol and ribotol respectively. Like other members of the Major Facilitator Superfamily (MFS), DalT and RbtT appear to be secondary transporters capable only of transporting solutes in response to chemiosmotic ion gradients . They contain a total of twelve predicted transmembrane helices; six in the N-terminal portion of the protein, and six in the C-terminal portion. Residues defining substrate specificity lie in the N-terminal region of these proteins.

Alpha-ketoglutarate permease (CsbX, ) and the Putative transporter YoaB from Bacillus subtilis are also included in this familly.
Organic cation transport protein/SVOP (Orgcat_transp/SVOP)
Type: Family

This family consists of organic cation transporters, members of the solute carrier family 22 (SLC22) , and also includes transporter-like protein SVOP (synaptic vesicle 2-related protein), which has similarity to the SLC22 family . SVOP may contribute to neuronal development, but its role is not clear and no transport substrate has been confirmed to date .

Organic anion transporter 3 from mammals (SLC22A8 or OAT3) also belongs to this entry. This protein plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain .
Sugar efflux (Sugar_efflux)
Type: Family

This family of proteins is an efflux system for lactose, glucose, aromatic glucosides and galactosides, cellobiose, maltose, a-methyl glucoside and other sugar compounds. They are found in both Gram-negative and Gram-positive bacteria.
Drug antiporter protein (Drug_antiport)
Type: Family

Drug antiporters which use the proton motive force for the active efflux of the drug. This family includes tetracycline-resistance determinant (TetV) and macrolide efflux protein A (MefA) .
AmpG-like permease/Acetyl-coenzyme A transporter 1 (AmpG_permease/AT-1)
Type: Family

This family consists of AmpG-like permease and acetyl-coenzyme A transporter 1 (AT-1). AT-1 is a probable acetyl-CoA transporter necessary for O-acetylation of gangliosides . The signal transducer encoded by AmpG is essential for induction of chromosomal AmpC beta-lactamase in Escherichia coli by beta-lactam antibiotics and 'unspecific' inducers . The AmpG protein probably acts as a permease in the beta-lactamase induction system and in peptidoglycan recycling.
Cell shape determining protein MreB (MreB)
Type: Family

MreB proteins are essential for cell-shape maintenance and cell morphogenesis in most non-spherical bacteria . Most rod-shaped or non-spherical bacteria possess at least one mreB homologue. In Bacillus subtilis, sidewall elongation during vegetative growth is controlled by three MreB isoforms: MreB, Mbl and MreBH . MreB proteins are found in rod-shaped bacteria, such as E. coli and B. subtilis, that grow by dispersed intercalation of new wall material along the long axis of the cell, as opposed to those that grow from the cell pole .

The crystal structure of MreB from Thermotoga maritima was resolved using X-ray crystallography, and the results suggested that MreB proteins form long filaments that wrap around the long axis of the cell close to the cell membrane, forming helix-like structures. They act by regulating cell wall synthesis and cell elongation, and thus cell shape. The feedback loops between cell geometry and their localisations may maintain elongated cell shape by targeting cell wall growth to regions of negative cell wall curvature. Filaments rotate around the cell circumference in concert with the cell wall synthesis enzymes. The process is driven by the cell wall synthesis machinery and does not depend on their polymerisation. They organise peptidoglycan synthesis in the lateral cell wall .
Amino acid antiporter (Amino_acid_antiprt)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

Proteins in this group catalyse an electroneutral exchange between arginine and ornithine to allow high-efficiency energy conversions in the arginine deiminase pathway.
Cationic amino acid transport permease (Cat_AA_permease)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

Proteins in this family are permeases involved in the transport of arginine, lysine and ornithine, the cationic amino acids.
Amino acid permease subfamily (AA_permease)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.
Ethanolamine permease (EtNH_permease)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.
Amino acid transporter (AA_transporter)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

This entry represents a group of amino acid permeases from bacteria, including Branched-chain amino acid permease BcaP from Bacillus subtilis and other uncharacterised sequences. BcaP is involved in the uptake of isoleucine, valine and probably leucine. It can also transport threonine, and is active as a minor serine permease .
Spore germination GerAB (Spore_GerAB)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

Spore germination protein (amino acid permease) is involved in the response to the germinative mixture of L-asparagine, glucose, fructose and potassium ions (AFFK). These proteins could be amino acid transporters.
Amino acid permease, fungi (Amino_acid_permease_fungi)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

This family is specific for the fungal amino acid permeases including the general amino acid permease AGP1, which perferentially transports Asp and Glu but can transport other amino acids ; GAP1, which transports Leu and Phe, and GAP3 which transports Phe .
Cation efflux system CusA-like (CusA-like)
Type: Family

This family consists of the H+/heavy metal cation antiporters.

CzcA has a low cation transport activity for cobalt and is essential for the expression of cobalt, zinc and cadmium resistance.

CusA is a part of a cation efflux system that mediates resistance to copper and silver .
Multidrug resistance protein MdtF-like (MdtF-like)
Type: Family

This entry represents a group of resistance-nodulation-cell division (RND) from bacteria, including Multidrug resistance protein MdtF from Escherichia coli. MdtF id part of the tripartite efflux system MdtEF-TolC, which confers resistance to compounds such as rhodamine 6G, erythromycin, doxorubicin, ethidium bromide, TPP, SDS, deoxycholate, crystal violet and benzalkonium .
NPC1-like (NPC1-like)
Type: Family

This family includes mammalian Niemann-Pick C1 (NPC1) protein and its homologues from plants and yeasts. Human NPC1 is a endosomal/lysosomal membrane protein that facilitates the trafficking of cholesterol and other cargo from lysosomes, and is involved in cholesterol homeostasis. Mutations in the NPC1 gene cause the rare neurodegenerative disease Niemann-Pick Type C (NPC) .
Transmembrane receptor, patched (TM_rcpt_patched)
Type: Family

Patched (Ptc) is a Drosophila melanogaster (Fruit fly) membrane protein that plays a critical role in patterning embryonic and imaginal tissues. It constitutively inactivates the transcription of genes wingless, decapentaplegic, and patched itself. The secreted protein, hedgehog (Hh) induces transcription of genes by opposing the patched signalling pathway .

In humans, mutations affecting patched (Ptc) or smoothened (Smo) homologues that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with tumours such as basal cell carcinoma (BCC) and medulloblastoma .

Patched is associated with a complex belonging to the hedgehog pathway. Members of the complex include cubitus interruptus, sex-lethal, patched and smoothened. The complex is present at the plasma membrane and the association of patched changes depending on the activation state of the pathway .
Oligopeptide transporter (Oligopep_transport)
Type: Family

This entry represents a subfamily of OPT proteins that are involved in oligopeptide transport. Their transport activity is proton dependent . These proteins may constitute a major route for the absorption of the end products of protein digestion .
Adenylosuccinate lyase (Pur_lyase)
Type: Family

This family consists of adenylosuccinate lyase, the enzyme that catalyses step 8 in the purine biosynthesis pathway for de novo synthesis of IMP, and also the final reaction in the two-step sequence from IMP to AMP . It is a member of lyase class I family, which functions as homotetramers. The four active sites of the homotetrameric enzyme are each formed by residues from three different subunits .
Na+/H+ antiporter NhaC (Na/H_antiport_NhaC)
Type: Family

Members of the NhaC family of antiporters are found in bacteria and Archaea. The family member from Bacillus firmus has been functionally characterised and is involved in pH homeostasis and sodium extrusion . In Bacillus subtilis, this antiporter influence bacterial growth, alkaline phosphatase synthesis, and its own expression depending on external Na concentration . The archaeal family member, ArcD, acts as an arginine/ornithine antiporter .
K+/H+ exchanger (K/H_exchanger)
Type: Domain

The monovalent Cation:Proton antiporter-2 (CPA2) family acts as a K+/H+ exchangers that facilitate potassium-efflux, possibly by potassium-proton antiport. This family includes KefB and KefC transporters, which are part of a glutathione-gated K(+) efflux system in Escherichia coli . The activity of the KefB and KefC potassium channels protects E. coli cells against methylglyoxal and limits the amount of DNA damage .
TrkH potassium transport family (TrkH)
Type: Family

The Trk system is a low to medium affinity potassium uptake system, widely found in both in bacteria and archaea, where the uptake of K(+) is believed to be linked to H(+) symport . The core Trk system consists of two proteins, the integral membrane K(+)-translocating protein TrkH (or TrkG), and the regulatory NAD-binding peripheral membrane protein TrkA . In Escherichia coli the activity of TrkH is dependent on the ATP-binding protein SapD (also known as TrkE) which is part of the SapABCDF ABC transporter, involved in putrescine export . Not all Trk systems are dependent on SapD however -it is thought that these may utilise ATP-binding proteins from other ABC transporters .

Also included in this entry is the homologous subunit J of a V-type Na(+) ATP synthase found in some bacteria such as Enterococcus hirae. The function of this subunit is unknown, but as K(+) transport is dependent on the activity of the V-type Na(+) ATP synthase in this organism, it may function to exchange Na(+) for K(+) .
Potassium/sodium transporter Trk1/HKT1 (K/Na_transp_Trk1/HKT1)
Type: Family

Trk1 (also known as Trk) transporters play a crucial roles in K(+) transport in yeasts and filamentous fungi .

A related transporter from plants is known as HKT1 (also known as HKT). It was identified in barley as a high-affinity potassium transporter . In Arabidopsis, HKT1 functions as a salt tolerance determinant that controls Na+ entry into plant roots .
Na(+)/H(+) antiporter subunit D1 (MnhD1)
Type: Family

This entry represents the Na(+)/H(+) antiporter subunit D1. It forms a complex (consists of seven subunits:MrpA, MrpB, MrpC, MrpD, MrpE, MrpF and MrpG) that is involved in Na+ and/or Li+ excretion . Na+/H+ antiport consumes a transmembrane electrical potential, and is thus inferred to be electrogenic . It shares protein sequence similarity with various chains of the NADH-ubiquinone/plastoquinone (complex I) .
Membrane transport PIN-like (Mem_transp_PIN-like)
Type: Family

This entry represents a family of membrane transport proteins found in eukaryotes, bacteria and archaea. Most characterised members of this family are the PIN components of auxin efflux systems from plants . These carriers are saturable, auxin-specific, and localized to the basal ends of auxin transport-competent cells . Plants typically possess several of these proteins, each displaying a unique tissue-specific expression pattern. They are expressed in almost all plant tissues including vascular tissues and roots, and influence many processes including the establishment of embryonic polarity, plant growth, apical hook formation in seedlings and the photo- and gravitropic responses. These plant proteins are typically 600-700 amino acyl residues long and exhibit 8-12 transmembrane segments. This entry also covers the transmembrane region of GPR1155 from human, a cholesterol-binding protein that acts as a regulator of mTORC1 signaling pathway .
L-lysine exporter/arginine exporter (Lys/arg_exporter)
Type: Family

L-lysine exporter, LysE is an exporter, which: (i) structurally represents a new type of translocator; (ii) demonstrates that exporters are also present for primary metabolites such as amino acids; and (iii) serves in one physiological function to link import with export activity .

The arginine exporter protein ArgO is involved in the export of arginine and is important to control the intracellular level of arginine and the correct balance between arginine and lysine .
Homoserine/Threonine efflux protein (Homoserine/Threonine_efflux)
Type: Family

Proteins in this group include:

A chemotactic transduction protein from Pseudomonas aeruginosa.

The homoserine/homoserine lactone efflux protein from Escherichia coli.

and a number of hypothetical proteins.