| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
|
2.A.23.1.1 | Glutamate/aspartate:H+ symporter, GltP or GltT; has 8 TMSs with 2 re-entrant loops as for GltPh (TC# 2.A.23.1.5). GltP residues involved in substrate binding and transport have been identified, especially in transmembrane helices VII and VIII (Rahman et al. 2016). | Bacteria |
Proteobacteria | GltP of E. coli |
|
2.A.23.1.2 | Glutamate/aspartate:Na+ + H+ symporter | Bacteria |
Firmicutes | GltT of Bacillus stearothermophilus |
|
2.A.23.1.3 | C4-dicarboxylate transporter (substrates: fumarate, D- and L-malate, succinate, succinamide, orotate, iticonate, mesaconate). This protein is 85% identical to the Sinorhizobium melitoti ortholog, mutants of which have an alterred substrate specificity and inability to support N2 fixing symbiosis (Yurgel and Kahn 2005). | Bacteria |
Proteobacteria | DctA of Rhizobium leguminosarum |
|
2.A.23.1.4 | The L-cystine/L-selenocystine:H+ symporter, TcyP (YhcL) (Burguière et al., 2004) | Bacteria |
Firmicutes | TcyP (YhcL) of Bacillus subtilis (P54596) |
|
2.A.23.1.5 | Archaeal aspartate transporter, Gltph (GltPh) (3-D structure known; 3V8F and 3V8G) (Boudker et al., 2007; Yernool et al., 2004). Cotransports aspartate with 2 Na+ (Ryan et al., 2009) or 3 Na+ (Groeneveld and Slotboom, 2010) or 1Na+ plus 1 H+ plus 1 K+ (Machtens et al. 2015). Reyes et al. (2009) have solved the structure of the inward facing state by cysteine crosslinking. The loop between TMSs 3 and 4 plays an essential role in transport (Compton et al., 2010). Gltph shows opposite movement of the external gate upon binding cotransported sodium compared with substrate (Focke et al., 2011). The transport pathway and the conformational changes involved have been suggested based on modeling studies (Stolzenberg et al. 2012; Wang et al. 2018). Individual transport domains may alternate between periods of quiescence and periods of rapid transitions. The switch to the dynamic mode may be due to separation of the transport domain from the trimeric scaffold which precedes domain movements across the bilayer (Akyuz et al. 2013). This spontaneous dislodging of the substrate-loaded transport domain is approximately 100-fold slower than subsequent transmembrane movements and may be rate determining in the transport cycle. Interactions between the transporter and specific lipids in artificial membranes have revealed effects on activity, and mechanisms have been proposed (McIlwain et al. 2015). The system can also function as an anion channel (Machtens et al. 2015). Millisecond dynamics have been described (Matin et al. 2020). | Archaea |
Euryarchaeota | Gltph of Pyrococcus horikoshii (LXFHA) |
|
2.A.23.1.6 | The dicarboxylate (succinate, fumarate, malate and oxaloacetate):H+ symporter, DctA (probably 3H+ are transported per succinate taken up (Groeneveld et al., 2010). | Bacteria |
Firmicutes | DctA of Bacillus subtilis (P96603) |
|
2.A.23.1.7 | Aerobic dicarboxylate transporter, DctA. Interacts with the DcuS sensor kinase (Witan et al., 2012). The interaction of DctA with DcuS has been studied extensively and reviewed (Unden et al. 2016). | Bacteria |
Proteobacteria | DctA of E. coli (P0A830) |
|
2.A.23.1.8 | Cystine transporter, YdjN, of 463 aas. Also transports L-selenaproline (L-selenazolidine-4-carboxylic acid) and L-selenocystine, both toxic analogues that inhibit growth of urinary tract pathogenic E. coli (Deutch et al. 2014). | Bacteria |
Proteobacteria | YdjN of E. coli |
|
2.A.23.1.9 | Fumarate:H+ symporter of 442 aas and 14 established TMSs, DctA. Responsible for the transport of dicarboxylates such as succinate, fumarate, and malate. The 3-d structure has been solved (Geertsma et al. 2015). It reveals an inward facing transmembrane domain of two 7 TMS intertwined inverted repeats similar to that of UraA as well as a STAS domain (Geertsma et al. 2015). | Bacteria |
Deinococcus-Thermus | Fumarate transporter of Deinococcus geothermalis |
|
2.A.23.1.10 | Organic acid uptake porter, DctA of 444 aas and 8 - 10 putative TMSs. Based on mutant analyses, it may transport succinate, benzoate, acetate, fumarate and malate (Nam et al. 2003). A dctA mutant colonized tobacco roots to a lesser extent than the wild-type during early seedling development. Colonization by the dctA mutant, as compared to the wild type, also reduced the level of systemically induced resistance against the soft rot pathogen Erwinia carotovora SCC1 (Nam et al. 2006). | Bacteria |
Proteobacteria | DctA of Pseudomonas chlororaphis (Pseudomonas aureofaciens) |
|
2.A.23.1.11 | Dicarboxylate transporter, DctA of 458 aas and 10 TMSs. Transports L-aspartate, succinate and fumarate. Functions under high oxygen conditions although constitutively synthesized (Wösten et al. 2017). | Bacteria |
Proteobacteria | DctA of Campylobacter jejuni |
|
2.A.23.1.12 | DAACS family amino acid uptake system, All0342, possibly an acidic amino acid transporter, that also catalyzes amino acid efflux (including γ-amino isobutyrate) by a passive mechanism (Pernil et al. 2015). | Bacteria |
Cyanobacteria | All0342 of Anabaena (Nostoc) strain PCC7120 |
|
2.A.23.1.13 | Serine/threonine:Na+ symporter, SstT | Bacteria |
Proteobacteria | SstT (YgjU) of E. coli (P0AGE4) |
|
2.A.23.1.14 | Sodium:glutamate cotransporter (symporter), Glt, of 430 aas and probably 9 TMSs in a 3 + 3 + 3 TMS arrangement. Several 3-d structures are known (Jensen et al. 2013). The binding and transport of L- and D-aspartate have been studied, revealing that both the L- and D-aspartate bound GltTk structures with only minor rearrangements in the structure of the binding site (Arkhipova et al. 2019). A conserved methionine residue plays a role in the ion symport process, apparently by influencing the specific kinetics in the binding reaction, which, while influential for the turnover rate, does not fundamentally explain the ion-coupling mechanism (Zhou et al. 2021). The 3-d structure is available (PDB # 6XWO). It has a covalent trimeric transporter structure with an interconnecting rigid scafford domain (trimerization domain) on the inside. This seems to be a unique structure for a transporter (Colucci et al. 2023). The structure of the P208R mutant is also known (Colucci et al. 2023). | Archaea |
Euryarchaeota | Glt of Thermococcus (Pyrococcus) kodakarensis |
|
2.A.23.2.1 | Glutamate/aspartate:Na+ symporter, GLAST or EAAT1, Structural rearrangements have been probed by Leighton et al., 2006). EAAT1 interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). CEAT1 couples glutamate uptake to the symport of 3 Na+ and 1 H+ followed by the antiport of 1 K+. It can function as an uncoupled anion, water and/or urea channel (Vandenberg et al., 2011). Large collective motions regulate the functional properties of EAAT1 trimers (Jiang et al., 2011). The reentrant helical hairpin loop, HP1, functions during the transport cycle as the proposed internal gate. HP1 is packed against transmembrane domain, TMS 2 and TMS5 in its closed state, and two residues located in TM2 and HP2 of EAAT1 are in close proximity (Zhang et al. 2014). In EAAT1, R388 is a critical element for the structural coupling between the substrate translocation and the gating mechanisms of the EAAT-associated anion channel, and conversion to E or D creates a constitutively open anion channel (Torres-Salazar et al. 2015). | Eukaryota |
Metazoa | Glutamate/aspartate permease (excitatory amino acid transporter-1, EAAT1) of Rattus norvegicus |
|
2.A.23.2.2 | Glutamate/aspartate:Na+ symporter, GLT1; GLUT-R; EAAT2. Interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). Cotransports glutamic acid with three Na+ followed by countertransport of K+ (Teichman et al., 2009). The C-terminal 74aa domain regulates transport activity (Leinenweber et al., 2011). Hippocampal glutamate transporter 1 (GLT-1) levels parallel memory training (Heo et al., 2011). GLT-1 is regulated by MAGI-1 (Zou et al., 2011). Venom from the spider Parawixia bistriata and a purified compound (Parawixin1) stimulate EAAT2 activity and protect retinal tissue from ischemic damage (Mortensen et al. 2015). Determinants of this stimulation are at the interface of the trimerization and substrate transport domains ((Mortensen et al. 2015). TMS4 of GLT-1 undergoes a complex conformational shift during substrate translocation (Rong et al. 2016). Both reentrant loops determine the cation specificity (Silverstein et al. 2018). A tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019Bartolomé-Martín et al. 2019Bartolomé-Martín et al. 2019).
| Eukaryota |
Metazoa | Glutamate permease (excitatory amino acid transporter-2, EAAT2) of Rattus norvegicus |
|
2.A.23.2.3 | Glutamate/aspartate/cysteine:Na+ symporter, EAAC1; EAAT3, SLC1A1 (Li+ can replace Na+; EAAC1 also mediates glutamate-independent anion conductance.) Cotransports glutamic acid with three Na+ followed by countertransport of K+(Teichman et al., 2009). The 50 residue 4B-4C loop (following TMS4) binds Na+ (Koch et al., 2007). (The dicarboxylic aminoaciduria protein in humans; NP_004161; Bröer, 2008a; 2008b). Neutralizing aspartate 83 modifies substrate translocation (Hotzy et al., 2012). An SLC1A1 deletion segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family (Myles-Worsley et al. 2013). Thr101 in TMS3 is essential for Na+ binding (Tao et al. 2010). Klotho, a 1012 aa protein with N- and C-terminal TMSs, is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). The 3 Na+ binding sites in SLC1A porters have been identified, and both reentrant loops determine cation selectivity (Silverstein et al. 2018). | Eukaryota |
Metazoa | SLC1A1 of Homo sapiens |
|
2.A.23.2.4 | Aspartate/taurine (not glutamate):Na+ symporter, dEAAT2 (mediates both uptake and heteroexchange of its two substrates, both dependent on external Na+ (with taurine outside and Asp inside)); L-glutamate is transported with low affinity and efficiency (Besson et al., 2005). | Eukaryota |
Metazoa | dEAAT2 of Drosophila melanogaster (E1JHQ6) |
|
2.A.23.2.5 | solute carrier family 1 (glutamate transporter), member 7 | Eukaryota |
Metazoa | SLC1A7 of Homo sapiens |
|
2.A.23.2.6 | Excitatory amino acid transporter 1 (EAAT1) (Sodium-dependent glutamate/aspartate transporter 1) (GLAST-1) (Solute carrier family 1 member 3). Mutations cause episodic ataxia type 6 (EA6) (Choi et al. 2016; Iwama et al. 2017). EAAT1 regulates the extent and duration of glutamate-mediated signals by the clearance of glutamate after synaptic release. It also has an anion channel activity that prevents additional glutamate release. This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Substrate-induced structural rearrangements occur between the TMS4b-4c loop and TMS7 during the transport cycle (Zhang et al. 2019). GLAST serves as a cell surface biomarker for astrocytes (Kumar et al. 2021). It interacts with NHERF1 and NHERF2 (see TC# 8.A.24.1.1) which modify its cell surface expression (Sato et al. 2013). The inhibitor, UCPH-101 slows substrate translocation rather than substrate or Na+ binding, confirming a non-competitive inhibitory mechanism. However, it only partially inhibits wild-type ASCT2 with relatively low affinity (Dong et al. 2023). | Eukaryota |
Metazoa | SLC1A3 of Homo sapiens |
|
2.A.23.2.7 | Excitatory amino acid transporter 2, EAAT2 (Glutamate/aspartate transporter II) (Sodium-dependent glutamate/aspartate transporter 2) (Solute carrier family 1 member 2). This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Amino acids in the TMS2 of EAAT2 are essential for membrane-bound localization, substrate binding, transporter function and anion currents (Mai et al. 2021). The distance between the TMS3-TMS4 loop and TMS7 changes when substrates are transported (Qu et al. 2021). SLC1A2 and SLC1A3 encode the glial glutamate transporters EAAT2 and EAAT1, which are not only the predominant glutamate uptake carriers in the brain, but also function as anion channels. Two homologous mutations, which substitute prolines in the center of the fifth TMS by arginine (P289R EAAT2, P290R EAAT1) cause epileptic encephalopathy (SLC1A2) or with episodic ataxia type 6 (SLC1A3). Both mutations impair glutamate uptake and increase anion conduction (Suslova et al. 2023). Additionally, the P312R mutation generates an anion conducting state that is accessible in the outward facing apo state that is the main determinant of the increased anion conduction of EAAT transporters carrying this mutation. | Eukaryota |
Metazoa | SLC1A2 (EAAT2) of Homo sapiens |
|
2.A.23.2.8 | Excitatory amino acid transporter 4, EAAT4 (Sodium-dependent glutamate/aspartate transporter) (Solute carrier family 1 member 6). Klotho, a 1012 aa protein with N- and C-terminal TMSs, is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, enhanced Cl- currents via EAAT4, but this increased Cl- current was not thermodynamically coupled to glutamate transport. These PMA-enhanced Cl- currents were partially blocked by staurosporine, chelerythrine, and calphostin C, the three PKC inhibitors, implying that PKC-mediated phsophorylation was responsible (Fang et al. 2006). | Eukaryota |
Metazoa | SLC1A6 of Homo sapiens |
|
2.A.23.2.9 | Putative sodium-dependent excitatory amino acid transporter Glt-3 | Eukaryota |
Metazoa | Glt-3 of Caenorhabditis elegans |
|
2.A.23.2.10 | Excitatory amino acid transporter (Sodium-dependent glutamate/aspartate transporter), Gkt-1 of 503 aas and 9 - 11 TMSs (Radice and Lustigman 1996). | Eukaryota |
Metazoa | Glt-1 of Caenorhabditis elegans |
|
2.A.23.2.11 | EAAT homologue, a glutamate/aspartate preferring transporter of 483 aas. TMS8 includes residues important for substrate and cation binding (Wang et al. 2013). | Eukaryota |
Metazoa | EAAT homoloue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
|
2.A.23.2.12 | Dicarboxylic acid over dicarboxylic amino acid preferring EAAT3 homologue of 483 aas (Wang et al. 2013). | Eukaryota |
Metazoa | EAAT3 homologue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
|
2.A.23.3.1 | Neutral amino acid (alanine, serine, cysteine, threonine):Na+ symporter. Also transports homocysteine (Jiang et al., 2007). AscT1 is the Syncytin-1 (Q9UQF0) receptor. Syncytin-1, of 538 aas with 4-7 TMSs, is a viral fusion protein and is involved in the development of multiple sclerosis (Antony et al. 2007). Mutation causes nuerological problems including global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) (Heimer et al. 2015). | Eukaryota |
Metazoa | SLC1A4 of Homo sapiens |
|
2.A.23.3.2 | Insulin-activated, Na+-dependet amino acid (serine, alanine, glutamate, glutamine and other neutral amino acids):amino acid antiporter (Ndaru et al. 2019). Also transports homocysteine (Jiang et al., 2007). V-9302 is a selective and potent competitive small molecule antagonist of glutamine uptake via ASCT2. Blockage of ASCT2 activity with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo (Schulte et al. 2018). The glutamine transporter ASCT2 plays a role in antineoplastic therapy (Teixeira et al. 2021). | Eukaryota |
Metazoa | Insulin-dependent amino acid transporter B of Mus musculus, AscT2 |
|
2.A.23.3.3 | Broad-specificity amino acid:Na+ symporter, LAT1, M7V1, RDR, RDRC, or SLC1A5 (transports most neutral, zwitterionic and dibasic amino acids either uptake or bidirectional transport) (Scalise et al. 2018). Required for intracellular multiplication of Legionella pneumophila (Wieland et al., 2005). SLC7A5 with accessory protein SLC3A2 (the heavy chain; TC# 8.A.9.2.2) mediates bidirectional transport of amino acids and regulates mTOR and autophagy (Nicklin et al., 2009; Estrach et al. 2014). LAT1 is the sole transport competent subunit of the heterodimer (Napolitano et al. 2015). l-Leucine inhibits uptake of LAT1 substrates as well as cell growth, and it potentiates the efficacy of bestatin and cisplatin, even at low concentrations (25 muM) (Huttunen et al. 2016). Transports certain thyroid hormones and their derivatives (Krause and Hinz 2017). It interacts with scaffold proteins and is glycosylated on two asn residues, N163 and N212. Also serves as the receptor by a group of retroviruses (Scalise et al. 2018). Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of the SLC1A5 and the mTORC1 signaling pathway (Pan et al. 2022). LAT1 expression is alterred in patients with pediatric scoliosis (development of skeletal deformities) (Demura et al. 2022). The expression of SLC1A5 is upregulated in glioblastoma tissues compared with low-grade gliomas. SLC1A5 knockdown inhibits glioma cell proliferation and invasion, and reduces the sensitivity of ferroptosis via the GPX4-dependent pathway (Han et al. 2022). It acts as a cell surface receptor for Feline endogenous virus RD114, Baboon M7 endogenous virus, and type D simian retroviruses. LAT1 plays a role in the activation of pathogenic T cell subsets under inflammatory conditions (Estrach et al. 2014). LAT1 is the sole transport competent subunit of the heterodimer (Napolitano et al. 2015). l-Leucine inhibits uptake of LAT1 substrates as well as cell growth, and it potentiates the efficacy of bestatin and cisplatin, even at low concentrations (25 muM) (Huttunen et al. 2016). Transports certain thyroid hormones and their derivatives (Krause and Hinz 2017). It interacts with scaffold proteins and is glycosylated on two asn residues, N163 and N212. Also serves as the receptor by a group of retroviruses (Scalise et al. 2018). Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of the SLC1A5 and the mTORC1 signaling pathway (Pan et al. 2022). LAT1 expression is alterred in patients with pediatric scoliosis (development of skeletal deformities) (Demura et al. 2022). The expression of SLC1A5 is upregulated in glioblastoma tissues compared with low-grade gliomas. SLC1A5 knockdown inhibits glioma cell proliferation and invasion, and reduces the sensitivity of ferroptosis via the GPX4-dependent pathway (Han et al. 2022). It acts as a cell surface receptor for Feline endogenous virus RD114, Baboon M7 endogenous virus, and type D simian retroviruses. LAT1 plays a role in the activation of pathogenic T cell subsets under inflammatory conditions (Ogbechi et al. 2023). | Eukaryota |
Metazoa | SLC1A5 of Homo sapiens |
|
2.A.23.3.4 | Uncharaterized protein of 409 aas and 10 TMSs. | Bacteria |
Spirochaetes | UP of Treponema denticola |