2.A.18 The Amino Acid/Auxin Permease (AAAP) Family

The AAAP family includes hundreds of proteins from plants, animals, yeast and fungi. Individual permeases of the AAAP family transport auxin (indole-3-acetic acid), a single amino acid or multiple amino acids. Some of these permeases exhibit very broad specificities transporting all twenty amino acids naturally found in proteins. Some also transport D-amino acids. There are 7 AAAP paralogues in Saccharomyces cerevisiae, at least 9 in Arabidopsis thaliana and at least 5 in Caenorhabditis elegans. Six AAPs in A. thaliana transport neutral and charged amino acids with varying specificities and affinities (Fischer et al., 2002). All transport neutral amino acids and some acidic amino acids, always with just one proton. AAP3 and AAP5 are the only ones transporting basic amino acids, and only AAP6 transports aspartate (Fischer et al., 2002).

AAAP family proteins, all from eukaryotes, vary from 376 to 713 amino acyl residues in length, but most are of 400-500 residues. Most of the size variation occurs as a result of the presence of long N-terminal hydrophilic extensions in some of the proteins. Some of the yeast proteins are particularly long. Variation in the loops and the C-termini also occurs. These proteins exhibit 11 (or 10) putative transmembrane α-helical spanners. One homologue, AAP1 of A. thaliana (TC #2.A.18.2.1), has 11 established TMSs (Chang and Bush, 1997).

Among animal AAAP family members are numerous growth regulating System A and System N isoforms, each exhibiting distinctive tissue and subcellular localizations. The different isoforms also exhibit different relative affinities for the amino acid substrates. Some catalyze H+ antiport and can function bidirectionally. Since Systems A are electrogenic although Systems N are not, the amino acid:cation stoichiometries may differ (Chaudhry et al., 2001, 2002; Varoqui et al., 2000).

 

Six auxin/amino acid permeases (AAAPs) from Arabidopsis mediate transport of a wide spectrum of amino acids (Fischer et al., 2002). AAAPs are distantly related to plasma membrane amino acid transport systems N and A and to vesicular transporters such as VGAT from mammals. Although capable of recognizing and transporting a wide spectrum of amino acids, individual AAAPs differ with respect to specificity. Apparent substrate affinities are influenced by structure and net charge and vary by three orders of magnitude (Fischer et al., 2002). AAAPs mediate cotransport of neutral amino acids with one proton, and uncharged forms of acidic and basic amino acids are cotransported with one proton. Since all AAAPs are differentially expressed, different tissues may be supplied with a different spectrum of amino acids.

Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought into cells by the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) subfamily, and the Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) subfamily, both members of the AAAP family. Members of both families can act as amino acid-stimulated receptors, or so-called 'transceptors,' connecting amino acids to mTORC1 activation (Fan and Goberdhan 2018). PATs and SNATs at the surfaces of multiple intracellular compartments are linked to the recruitment and activation of different pools of mTORC1. Late endosomes and lysosomes are mTORC1 regulatory hubs, but a Golgi-localized PAT is also required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity (Fan and Goberdhan 2018).

 

The generalized transport reaction catalyzed by the proteins of the AAAP family is:

Substrate (out) + nH+ (out) → Substrate (in) + nH+ (in)

 



This family belongs to the APC Superfamily.

 

References:

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Chardwiriyapreecha S., Mukaiyama H., Sekito T., Iwaki T., Takegawa K. and Kakinuma Y. (2010). Avt5p is required for vacuolar uptake of amino acids in the fission yeast Schizosaccharomyces pombe. FEBS Lett. 584(11):2339-45.

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Chen, L. and D.R. Bush. (1997). LHT1, a lysine- and histidine-specific amino acid transporter in arabidopsis. Plant Physiol. 115: 1127-1134.

Chowdhury, B., Y.B. Chan, and E.A. Kravitz. (2017). Putative transmembrane transporter modulates higher-level aggression in Drosophila. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Dorn M., Weiwad M., Markwardt F., Laug L., Rudolph R., Brandsch M. and Bosse-Doenecke E. (2009). Identification of a disulfide bridge essential for transport function of the human proton-coupled amino acid transporter hPAT1. J Biol Chem. 284(33):22123-32.

Fan, S.J. and D.C.I. Goberdhan. (2018). PATs and SNATs: Amino Acid Sensors in Disguise. Front Pharmacol 9: 640.

Farsi, Z., J. Preobraschenski, G. van den Bogaart, D. Riedel, R. Jahn, and A. Woehler. (2016). Single-vesicle imaging reveals different transport mechanisms between glutamatergic and GABAergic vesicles. Science 351: 981-984.

Fei, Y., M. Sugawara, T. Nakanishi, W. Huang, H. Wang, P.D. Prasad, F.H. Leibach, and V. Ganapathy. (2000). Primary structure, genomic organization, and functional and electrogenic characteristics of human system N1, a Na+- and H+-coupled glutamine transporter. J. Biol. Chem. 275: 23707-23717.

Fischer, W-N., M. Kwart, S. Hummel, and W.B. Frommer. (1995). Substrate specificity and expression profile of amino acid transporters (AAPs) in Arabidopsis. J. Biol. Chem. 270: 16315-16320.

Fischer, W.N., D.D. Loo, W. Koch, U. Ludewig, K.J. Boorer, M. Tegeder, D. Rentsch, E.M. Wright, and W.B. Frommer. (2002). Low and high affinity amino acid H+-cotransporters for cellular import of neutral and charged amino acids. Plant J. 29: 717-731.

Forde, N., C.A. Simintiras, R. Sturmey, S. Mamo, A.K. Kelly, T.E. Spencer, F.W. Bazer, and P. Lonergan. (2014). Amino acids in the uterine luminal fluid reflects the temporal changes in transporter expression in the endometrium and conceptus during early pregnancy in cattle. PLoS One 9: e100010.

Gasnier, B. (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch 447: 756-759.

Ge, Y., Y. Gu, J. Wang, and Z. Zhang. (2018). Membrane topology of rat sodium-coupled neutral amino acid transporter 2 (SNAT2). Biochim. Biophys. Acta. 1860: 1460-1469.

Goberdhan, D.C., D. Meredith, C.A. Boyd, and C. Wilson. (2005). PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development. 132: 2365-2375.

Gu, S., H.L. Roderick, P. Camacho, and J.X. Jiang. (2000). Identification and characterization of an amino acid transporter expressed differentially in liver. Proc. Natl. Acad. Sci. USA 97: 3230-3235.

Gu, X., J.M. Orozco, R.A. Saxton, K.J. Condon, G.Y. Liu, P.A. Krawczyk, S.M. Scaria, J.W. Harper, S.P. Gygi, and D.M. Sabatini. (2017). SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358: 813-818.

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Hatanaka, T., W. Huang, H. Wang, M. Sugawara, P.D. Prasad, F.H. Leibach, and V. Ganapathy. (2000). Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A. Biochim. Biophys. Acta 1467: 1-6.

Hatanaka, T., Y. Hatanaka, and M. Setou. (2006b). Regulation of amino acid transporter ATA2 by ubiquitin ligase Nedd4-2. J. Biol. Chem. 281: 35922-35930.

Hatanaka, T., Y. Hatanaka, J. Tsuchida, V. Ganapathy, and M. Setou. (2006a). Amino acid transporter ATA2 is stored at the trans-Golgi network and released by insulin stimulus in adipocytes. J. Biol. Chem. 281: 39273-39284.

Hellsten, S.V., M.G. Hägglund, M.M. Eriksson, and R. Fredriksson. (2017). The neuronal and astrocytic protein SLC38A10 transports glutamine, glutamate, and aspartate, suggesting a role in neurotransmission. FEBS Open Bio 7: 730-746.

Hyde, R., E.L. Cwiklinski, K. MacAulay, P.M. Taylor, and H.S. Hundal. (2007). Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability. J. Biol. Chem. 282: 19788-19798.

Jiang, H., Y. Li, H. Qin, Y. Li, H. Qi, C. Li, N. Wang, R. Li, Y. Zhao, S. Huang, J. Yu, X. Wang, R. Zhu, C. Liu, Z. Hu, Z. Qi, D. Xin, X. Wu, and Q. Chen. (2018). Identification of Major QTLs Associated With First Pod Height and Candidate Gene Mining in Soybean. Front Plant Sci 9: 1280.

Juge, N., A. Muroyama, M. Hiasa, H. Omote, and Y. Moriyama. (2009). Vesicular inhibitory amino acid transporter is a Cl-/γ-aminobutyrate Co-transporter. J. Biol. Chem. 284: 35073-35078.

Jung, J., H.M. Genau, and C. Behrends. (2015). Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9. Mol. Cell Biol. 35: 2479-2494.

Lei, H.T., J. Ma, S. Sanchez Martinez, and T. Gonen. (2018). Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state. Nat Struct Mol Biol 25: 522-527.

McIntire, S.L., R.J. Reimer, K. Schuske, R.H. Edwards, and E.M. Jorgensen. (1997). Identification and characterization of the vesicular GABA transporter. Nature 389: 870-876.

Miyauchi, S., E.L. Abbot, L. Zhuang, R. Subramanian, V. Ganapathy, and D.T. Thwaites. (2005). Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Mol. Membr. Biol. 22: 549-559.

Mohanta, T.K., N. Mohanta, and H. Bae. (2015). Identification and Expression Analysis of PIN-Like (PILS) Gene Family of Rice Treated with Auxin and Cytokinin. Genes (Basel) 6: 622-640.

Nakanishi, T., R. Kekuda, Y.J. Fei, T. Hatanaka, M. Sugawara, R.G. Martindale, F.H. Leibach, P.D. Prasad, and V. Ganapathy. (2001). Cloning and functional characterization of a new subtype of the amino acid transport system N. Am. J. Physiol. Cell Physiol. 281: C1757-1768.

Okumoto, S., R. Schmidt, M. Tegeder, W.N. Fischer, D. Rentsch, W.B. Frommer, and W. Koch. (2002). High affinity amino acid transporters specifically expressed in xylem parenchyma and developing seeds of Arabidopsis. J. Biol. Chem. 277: 45338-45346.

Perez, Y., L. Gradstein, H. Flusser, B. Markus, I. Cohen, Y. Langer, M. Marcus, T. Lifshitz, R. Kadir, and O.S. Birk. (2014). Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation. Eur J Hum Genet 22: 703-706.

Rebsamen, M., L. Pochini, T. Stasyk, M.E. de Araújo, M. Galluccio, R.K. Kandasamy, B. Snijder, A. Fauster, E.L. Rudashevskaya, M. Bruckner, S. Scorzoni, P.A. Filipek, K.V. Huber, J.W. Bigenzahn, L.X. Heinz, C. Kraft, K.L. Bennett, C. Indiveri, L.A. Huber, and G. Superti-Furga. (2015). SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519: 477-481.

Reimer, R.J., F.A. Chaudhury, A.T. Gray, and R.H. Edwards. (2000). Amino acid transport System A resembles System N in sequence but differs in mechanism. Proc. Natl. Acad. Sci. USA 97: 7715-7720.

Reinhardt, D., E.-R. Pesce, P. Stieger, T. Mandel, K. Baltensperger, M. Bennett, J. Traas, J. Friml, and C. Kuhlemeier. (2003). Regulation of phyllotaxis by polar auxin transport. Nature 426: 255-260.

Rentsch, D., B. Hirner, E. Schmeizer, and W.B. Frommer. (1996). Salt stress-induced proline transporters and salt stress-repressed broad specificity amino acid permeases identified by suppression of a yeast amino acid permease-targeting mutant. Plant Cell 8: 1437-1446.

Rodríguez, A., A. Ortega, L.C. Berumen, M.G. García-Alcocer, C. Giménez, and F. Zafra. (2014). Expression of the System N transporter (SNAT5/SN2) during development indicates its plausible role in glutamatergic neurotransmission. Neurochem Int 73: 166-171.

Rubio-Aliaga, I., M. Boll, D.M.V. Weisenhorn, M. Foltz, G. Kottra, and H. Daniel. (2004). The proton/amino acid cotransporter PAT2 is expressed in neurons with a different subcellular localization than its paralog PAT1. J. Biol. Chem. 279: 2754-2760.

Russnak, R., D. Konczal, and S.L. McIntire. (2001). A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J. Biol. Chem. 276: 23849-23857.

Sakaew, W., A. Tachow, W. Thoungseabyoun, S. Khrongyut, A. Rawangwong, Y. Polsan, W. Masahiko, H. Kondo, and W. Hipkaeo. (2018). Expression and localization of VIAAT in distal uriniferous tubular epithelium of mouse. Ann Anat 222: 21-27. [Epub: Ahead of Print]

Schlisselberg, D., E. Mazarib, E. Inbar, D. Rentsch, P.J. Myler, and D. Zilberstein. (2015). Size does matter: 18 amino acids at the N-terminal tip of an amino acid transporter in Leishmania determine substrate specificity. Sci Rep 5: 16289.

Schmidt, R.S., J.P. Macêdo, M.E. Steinmann, A.G. Salgado, P. Bütikofer, E. Sigel, D. Rentsch, and P. Mäser. (2018). Transporters of Trypanosoma brucei-phylogeny, physiology, pharmacology. FEBS J. 285: 1012-1023.

Shaked-Mishan, P., M. Suter-Grotemeyer, T. Yoel-Almagor, N. Holland, D. Zilberstein, and D. Rentsch D. (2006). A novel high-affinity arginine transporter from the human parasitic protozoan Leishmania donovani. Mol. Microbiol. 60: 30-38.

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Sundberg, B.E., E. Wååg, J.A. Jacobsson, O. Stephansson, J. Rumaks, S. Svirskis, J. Alsiö, E. Roman, T. Ebendal, V. Klusa, and R. Fredriksson. (2008). The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38. J Mol Neurosci 35: 179-193.

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Young, G.B., D.L. Jack, D.W. Smith, and M.H. Saier, Jr. (1999). The amino acid/auxin:proton symport permease family. Biochim. Biophys. Acta 1415: 306-322.

Zhang, Z. and C. Grewer. (2007). The sodium-coupled neutral amino acid transporter SNAT2 mediates an anion leak conductance that is differentially inhibited by transported substrates. Biophys. J. 92: 2621-2632.

Zhang, Z., C.B. Zander, and C. Grewer. (2011). The C-terminal domain of the neutral amino acid transporter SNAT2 regulates transport activity through voltage-dependent processes. Biochem. J. 434: 287-296.

Zhao, L., X. Ji, X. Zhang, L. Li, Y. Jin, and W. Liu. (2018). FLCN is a novel Rab11A-interacting protein and is involved in the Rab11A-mediated recycling transport. J Cell Sci. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
2.A.18.1.1

Auxin:H+ symporter (auxin influx), AUX or LAX (Reinhardt et al., 2003; Carraro et al., 2012).  In the PILS (Pin-like) family; members are located in the endoplasmic reticular membrane (Balzan et al. 2014).  Expression patterns of PILS family members have been studied (Mohanta et al. 2015). Involved in determination of first pod height (FPH), a quantitative trait in soybean [Glycine max (L.) Merr.] that affects mechanized harvesting (Jiang et al. 2018).

Plants

Aux-1 of Arabidopsis thaliana

 
Examples:

TC#NameOrganismal TypeExample
2.A.18.10.1

Putative amino acid transporter, AAT

Animals

AAT of Homo sapiens (Q8NE00)

 
2.A.18.10.2

Putative amino acid transporter, AAT

Amoebozoa

AAT of Entamoeba histolytica (C4LSN3)

 
2.A.18.10.3

Putative amino acid transporter, AAT

Diplomonadida

AAT of Giardia intestinalis (C6LXJ3)

 
2.A.18.10.4

AAAP homologue

Ciliates

AAAP homologue of Tetrahymena thermophilus

 
Examples:

TC#NameOrganismal TypeExample
2.A.18.2.1General amino acid permease 1, AAP1 (transports most neutral and acidic amino acids but not aspartate or the basic amino acids) Plants AAP1 of Arabidopsis thaliana
 
2.A.18.2.10Probable amino acid permease 7 (Amino acid transporter AAP7)PlantsAAP7 of Arabidopsis thaliana
 
2.A.18.2.2Lysine/histidine transporter, LHT1 Plants LHT1 of Arabidopsis thaliana
 
2.A.18.2.3General amino acid transporter 3, AAP3 (transports all neutral, acidic and basic amino acids tested)PlantsAAP3 of Arabidopsis thaliana
 
2.A.18.2.4General amino acid transporter 6, AAP6 (transports all neutral and acidic amino acids tested including aspartate, and basic amino acids are transported with low affinity) (Okumoto et al., 2002)PlantsAAP6 of Arabidopsis thaliana
 
2.A.18.2.5General amino acid transporter 8, AAP8 (transports all amino acids, but the basic amino acids are transported
with low affinity (Okumoto et al., 2002))
PlantsAAP8 of Arabidopsis thaliana
 
2.A.18.2.6

Lysine-Histidine Transporter-7 (LHT7) found in mature pollen (Bock et al., 2006) (most like 2.A.18.2.2; 30% identity)

Plants

LHT7 of Arabidopsis thaliana (Q84WE9)

 
2.A.18.2.7Amino acid permease 2 (Amino acid transporter AAP2)PlantsAAP2 of Arabidopsis thaliana
 
2.A.18.2.8Lysine histidine transporter-like 8 (Amino acid transporter-like protein 1)PlantsAATL1 of Arabidopsis thaliana
 
2.A.18.2.9

Lysine/histidine transporter 2 (AtLHT2) (Amino acid transporter-like protein 2)

PlantsLHT2 of Arabidopsis thaliana
 
Examples:

TC#NameOrganismal TypeExample
2.A.18.3.1Proline permease 1 Plants Prt1 of Arabidopsis thaliana
 
2.A.18.3.2Proline/GABA/glycine betaine permease, ProT1PlantsProT1 of Lycopersicon esculentum
 
Examples:

TC#NameOrganismal TypeExample
2.A.18.4.1Neutral amino acid permease Fungi AAP1 of Neurospora crassa
 
2.A.18.4.2Aromatic and neutral amino acid permease, PcMtr (Trip et al., 2004)FungiPcMtr of Penicillium chrysogenum (AAT45727)
 
Examples:

TC#NameOrganismal TypeExample
2.A.18.5.1

Vesicular γ-aminobutyric acid (GABA) and glycine transporter (Aubrey et al., 2007)

Animals

UNC-47 of Caenorhabditis elegans

 
2.A.18.5.2The vacuolar amino acid transporter AVT1 (catalyzes uptake into yeast vacuoles of large neutral amino acids including tyr, gln, asn, leu and ile)YeastAVT1 of Saccharomyces cerevisiae
 
2.A.18.5.3

The vacuolar GABA and glycine uptake transporter, VGAT. Also called "vesicular inhibitory amino acid transporter" (VIAAT); it is a 2Cl-/γ-aminobutyrate or glycine co-transporter in synaptic vesicles (Juge et al., 2009). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007).

Animals

VGAT of Mus musculus (O35633)

 
2.A.18.5.4

Vesicular inhibitory amino acid transporter (GABA and glycine transporter; Solute carrier family 32 member 1; Vesicular GABA transporter; VGAT; hVIAAT).  Probably functions by GABA:H+ antiport (Farsi et al. 2016). It localizes to the distal kidney tubule epithelia, especially in the inner medulla and basal portions of the lateral plasma membranes, but not in vesicles or vacuoles (Sakaew et al. 2018).

Animals

SLC32A1 of Homo sapiens

 
2.A.18.5.5

The aggression-related transporter, CG13646 of 527 aas and 11 TMSs. Reduction in expression of CG13646 by approximately half leads to a hyperaggressive phenotype partially resembling that seen in Bully flies (Chowdhury et al. 2017). Members of this family are involved in glutamine/glutamate and GABA cycles of metabolism in excitatory and inhibitory nerve terminals.

CG13646 of Drosophila melanogaster

 
Examples:

TC#NameOrganismal TypeExample
2.A.18.6.1Neuronal glutamine (System A-like) transporter, GlnT Animals GlnT of Rattus norvegicus (Q9JM15)
 
2.A.18.6.10

Vacuolar broad specificity amino acid transporter 5 Avt5. Transports histidine, gluatmate, tyrosine, arginine, lysine and serine (Chardwiriyapreecha et al., 2010).

Yeast

Avt5 of Saccharomyces cerevisiae (P38176)

 
2.A.18.6.11

SLC38 member 6, SNAT6. Na+-dependent synaptic vesicle amino acid release porter (Gasnier, 2004) (transports amino acids, glutamine, glycine and γ-amino butyric acid (GABA)).  It seems to be the only glutamine transporter in the brain, being present in excitatory neurons, particularly at the synapses (Bagchi et al. 2014).

Animals

SLC38A6 of Homo sapiens

 
2.A.18.6.12

Solute carrier family 38, member 8, SLC38A8, expressed only in the eye.  This protein is probably a Na+/H+-dependent amino acid transporter which when defective, gives rise to foveal hypoplasia associated with congenital nystagmus and reduced visual acuity (Perez et al. 2014).

Animals

SLC38A8 of Homo sapiens

 
2.A.18.6.13

Sodium-coupled neutral amino acid transporter 7, SNAT7.  Transports L-glutamine in excitatory neurons 9but not astrocytes) as the preferred substrate, particularly at synapses, but also transports L-glutamate and other amino acids with polar side chains such as L-histidine and L-alanine (Hägglund et al. 2011).

Animals

SLC38A7 of Homo sapiens

 
2.A.18.6.14

Sodium-coupled neutral amino acid transporter 1 (Amino acid transporter A1; SLC38A1; SNAT1; N-system amino acid transporter 2; Solute carrier family 38 member 1; System A amino acid transporter 1; System N amino acid transporter 1).  When overexpressed, it causes Rett syndrome (RTT), an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator (transcriptional repressor) of SLC38A1, which encodes a major glutamine transporter (SNAT1).  Because glutamine is mainly metabolized in the mitochondria where it is used as an energy substrate and a precursor for glutamate production, SNAT1 overexpression in MeCP2-deficient microglia impairs glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction (Perez et al. 2014).

Animals

SLC38A1 of Homo sapiens

 
2.A.18.6.15

Neutral amino acid transporter 5 (Solute carrier family 38 member 5, SNAT5) (System N transporter 2, SN2).  Transports glutamine, histidine and glycine as well as other amino acids.  Present in glial cells where it probably functions in neurotransmitter clearance from synapses (Rodríguez et al. 2014).

Animals

SLC38A5 of Homo sapiens

 
2.A.18.6.16

Sodium-coupled amino acid transporter 10, SNAT10.  Expressed in several endocrine organs (Sundberg et al. 2008). Transports glutamine, glutamate and aspartate in neuronal and astrocytic cells (Hellsten et al. 2017).

Animals

SLC38A10 of Homo sapiens

 
2.A.18.6.17Sodium-coupled neutral amino acid transporter 4 (Amino acid transporter A3) (Na(+)-coupled neutral amino acid transporter 4) (Solute carrier family 38 member 4) (System A amino acid transporter 3) (System N amino acid transporter 3)AnimalsSLC38A4 of Homo sapiens
 
2.A.18.6.18

Putative sodium-coupled neutral amino acid transporter 11, SNAT11 (Forde et al. 2014).

Animals

SLC38A11 of Homo sapiens

 
2.A.18.6.19Vacuolar amino acid transporter 7FungiAVT7 of Saccharomyces cerevisiae
 
2.A.18.6.2

Liver histidine and glutamine specific system N-like, Na+-dependent amino acid transporter, mNAT. Also called SNAT3. SNAT3 trafficking occurs in a dynamin-independent manner and is influenced by caveolin (Balkrishna et al., 2010).

Animals

mNAT of Mus musculus (Q9JLL8)

 
2.A.18.6.20Vacuolar amino acid transporter 2FungiAVT2 of Saccharomyces cerevisiae
 
2.A.18.6.21

Amino acid transporter 10 of 490 aas and 12 TMSs, AATP10 or AAT4.1.  Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

 

AATP10 of Trypanosoma brucei

 
2.A.18.6.22

Amino acid transporter 17.2, AAT17.2 of 494 aas and 11 TMSs.  Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

AAT17.2 of Trypanosoma brucei

 
2.A.18.6.23

Probable amino acid transporter of 378 aas and 10 TMSs.

aa transporter of Red seabream iridovirus

 
2.A.18.6.24

Uncharacterized putative amino acid transporter of 574 aas and 12 TMSs

UP of Entamoeba histolytica

 
2.A.18.6.3

System N1, SNAT3 [glutamine/histidine/asparagine/alanine]:[Na+ + H+] sym/antiporter (1 aa + 2 Na+ cotransported against 1 H+ antiported out) (probable orthologue of mNAT). Li+ can substitute for Na+; system N1 can function bidirectionally. SNAT3 is a primarily a glutamine transporter required for amino acid homeostasis. Loss cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney (Chan et al. 2015).

Animals

SLC38A3 of Homo sapiens

 
2.A.18.6.4

Plasma membrane System A-like neutral amino acid transporter, SA1, SAT2 or SNAT2 (transports small, neutral aliphatic amino acids including α-(methylamino)isobutyrate, mAIB with Na+ (1:1 stoichiometry; Km = 200-500 μM)). Asparagine 82 controls the interaction of Na+ with the transporter (Zhang and Grewer, 2007). The C-terminal domain regulates transport activity through a voltage-dependent process (Zhang et al., 2011). An 11 TMS topology has been experimentally demonstrated (Ge et al. 2018).

Animals

SAT2 of Rattus norvegicus (Q9JHE5)

 
2.A.18.6.5Na+-dependent system A-like transporter, System A2 or ATA2 (transports neutral amino acids with decreasing affinity in the order: MeAIB, Ala, Gly, Ser, Pro, Met, Asn, Gln, Thr, Leu and Phe). The neuronal system A2 has been reported to transport Asn and Gln with higher affinity than for other neutral amino acids. [ATA2 is stored in the Golgi network and released by insulin stimulus in adipocytes (Hatanaka et al., 2006a).] Its levels are regulated by ubiquitin ligase, Nedd4-2, which causes endocytotic sequestration and proteosomal degradation (Hatanaka et al., 2006b). SNAT2 also functions as a mammalian amino acid transceptor (transporter/receptor), acting in an autoregulatory gene expression pathway (Hyde et al., 2007). It also mediates an anion leak conductance that is differentially inhibited by transported substrates (Zhang and Grewer, 2007). Also transports homocysteine (Tsitsiou et al., 2009).
AnimalsSLC38A2 of Homo sapiens
 
2.A.18.6.6The vacuolar amino acid transporter, AVT6 (catalyzes efflux from yeast vacuoles of acidic amino acids, Asp and Glu)YeastAVT6 of Saccharomyces cerevisiae (P40074)
 
2.A.18.6.7

The Na-dependent alanine/α-(methylamino) isobutyric acid-transporting system A, ATA3 or SNAT4. Transports most neutral short chain amino acids electrogenically. Present only in liver and skeletal muscle. 47% and 57% identical to ATA1 and ATA2, respectively. A 10TMS topology [with N-and C-termini outside and a large N-glycosylated, extracellular loop domain (residues 242-335)] has been established (Shi et al., 2011). (Km(ALA)= 4mM; Na+:Ala= 1:1) (Sugawara et al., 2000)

Animals

ATA3 of Rattus norvegicus (Q9EQ25)

 
2.A.18.6.8

Second subtype of system N; glutamine transporter, SN2. Prevalent in liver, but detectable in other tissues. Amino acid uptake is coupled to Na+ influx and H+ efflux (Nakanishi et al., 2001)

Animals

SN2 of Rattus norvegicus (Q91XR7)

 
2.A.18.6.9Arginine-specific transporter, AAP3 (KM (Arg) = 2μM)ProtozoaAAP3 of Leishmania donovani (Q86G79)
 
Examples:

TC#NameOrganismal TypeExample
2.A.18.7.1The vacuolar amino acid transporter, AVT3 (catalyzes efflux from yeast vacuoles of large neutral amino acids such as tyr, gln, asn, leu and ile)YeastAVT3 of Saccharomyces cerevisiae
 
2.A.18.7.2Vacuolar amino acid transporter 4FungiAVT4 of Saccharomyces cerevisiae
 
2.A.18.7.3

Vacuolar amino acid transporter 3, Avt3.  Catalyzes efflux from vacuoles of large hydrophobic and hydrophilic neutral amino acids, and is required for sporulation.

Yeast

Avt3 of Schizosaccharomyces pombe

 
2.A.18.7.4

Proline/alanine transporter of 488 aas and 10 TMSs, AAP24. The first 18 amino acids of the negatively charged N-terminal LdAAP24 tail are required for alanine transport and may facilitate the electrostatic interactions of the entire negatively charged N-terminal tail with the positively charged internal loops in the transmembrane domain.  This mechanism may underlie regulation of substrate flux rate for this and other transporters (Schlisselberg et al. 2015).

AAP24 of Leishmania infantum

 
2.A.18.7.5

Amino acid transporter-6, AAT6 of 488 aas and 11 TMSs.  Transports neutral amino acids and the drug, eflornithine (Schmidt et al. 2018).

AAT6 of Trypanosoma brucei

 

 

 

 

 

 

 

 
Examples:

TC#NameOrganismal TypeExample
2.A.18.8.1

The electrogenic, proton-dependent amino acid:H+ symporter, PAT1 or LYAAT-1 (Slc36A1). Catalyzes uptake of L-Gly, L-Ala, L-Pro, γ-amino butyrate, and short chain D-amino acids such as proline and hydroxyproline with an aa/ H+ ratio of 1:1 (found in lysosomes) In humans, this is the iminoglycinuria protein (Boll et al., 2004Miyauchi et al., 2005; Broer, 2008). A disulfide bridge is essential for transport function (Dorn et al., 2009). Transports taurine and β-alanine by H+ symport with low affinity and high capacity across the intestinal brush boarder membrane (Anderson et al., 2009). Exhibits low affinity (Km= 1-10 mM) and transports amino acid-based drugs used to treat epilepsy, schizophrenia, bacterial infections, hyperglycemia and cancer (Thwaites and Anderson, 2011). It is regulated by the Birt-Hogg-Dubé (BHD) syndrome related protein FLCN that has been implicated in the vesicular trafficking processes by interacting with several Rab family GTPases.  FLCN binds via its C-terminal DENN-like domain to the recycling transport regulator, Rab11A, and promoted the loading of PAT1 on Rab11A (Zhao et al. 2018).

Animals

mPAT1 of Mus musculus (Q8K4D3)

 
2.A.18.8.2

Electrogenic, proton-coupled, amino acid symporter 2 (PAT2; Tramdorin-1; SLC36A2) (transports small amino acids: glycine, alanine and proline; found in the ER, not in lysosomes, of neuronal cells in the brain and spinal cord; it can catalyze bidirectional transport depending on the driving force) (Boll et al., 2004Rubio-Aliaga et al., 2004). SLC36A2 is expressed at the apical surface of the human renal proximal tubule where it functions in the reabsorption of glycine, proline, hydroxyproline and amino acid derivatives with narrower substrate selectivity and higher affinity (Km 0.1-0.7 mM) than SLC36A1. Mutations in SLC36A2 lead to hyperglycinuria and iminoglycinuria.

Animals

PAT2 of Mus musculus (AAH44800)

 
2.A.18.8.3Amino acid transporter (low capacity, high affinity) and amino acid-dependent signal transduction protein, Pathetic (Path) (Goberdhan et al., 2005)AnimalsPath of Drosophila melanogaster (Q9VT04)
 
2.A.18.8.4

H+-coupled amino acid transporter-3 (SLC36A3).  SLC36A3 is expressed only in testes and has no known function (Thwaites and Anderson 2011).

Animals

SLC36A3 of Homo sapiens

 
2.A.18.8.5

H+-coupled amino acid transporter-4; SLC36A4.  SLC36A4 is widely distributed  and has high-affinity (Km = 2-3 µM) for proline and tryptophan (Thwaites and Anderson 2011).

Animals

SLC36A4 of Homo sapiens

 
2.A.18.8.6Proton-coupled amino acid transporter 2 (Proton/amino acid transporter 2) (Solute carrier family 36 member 2) (Tramdorin-1)AnimalsSLC36A2 of Homo sapiens
 
2.A.18.8.7

Proton-coupled amino acid transporter 1 (Proton/amino acid transporter 1) (hPAT1 or LYAAT-1) (Solute carrier family 36 member 1).  SLC36A1 is expressed at the luminal surface of the small intestine but is also commonly found in lysosomes in many cell types (including neurons), suggesting that it is a multipurpose carrier with distinct roles in different cells including absorption in the small intestine and as an efflux pathway following intralysosomal protein breakdown. SLC36A1 has a relatively low affinity (Km = 1-10 mM) for its substrates, which include zwitterionic amino and imino acids, heterocyclic amino acids and amino acid-based drugs and derivatives used experimentally and/or clinically to treat epilepsy, schizophrenia, bacterial infections, hyperglycaemia and cancer (Thwaites and Anderson 2011).  hPAT1 transports the pyridine alkaloids, arecaidine, guvacine and isoguvacine, across the apical membrane of enterocytes and might be responsible for the intestinal absorption of these drug candidates (Voigt et al. 2013).

Animals

SLC36A1 of Homo sapiens

 
2.A.18.8.8Putative amino acid permease F59B2.2WormF59B2.2 of Caenorhabditis elegans
 
Examples:

TC#NameOrganismal TypeExample
2.A.18.9.1

Na+-coupled high affinity, lysosomal arginine transporter and sensor, SLC38A9 (561aas; 11 TMSs) (Gu et al. 2017). Also transports many other amino acids with low affinity and specificity (Rebsamen et al. 2015). The rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar ATPase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Wang et al. 2015 showed that lysosomal SLC38A9 interacts with Rag GTPases and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is probably the arginine sensor for the mTORC1 pathway.  Jung et al. 2015 confirmed SLC38A9 to be a Rag-Ragulator complex member, transducing amino acid availability to mTORC1. Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017). The Niemann-Pick C1 (NPC1) protein (TC# 2.A.6.6.1), which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function (Castellano et al. 2017). Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state (Shen and Sabatini 2018). Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Thus, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.

Animals

SLC38A9 of Homo sapiens

 
2.A.18.9.2

SLC38A9 of 549 aas and 111 TMSs.  The crystal structure of this lysosomal transporter with arginine bound in the inward facing conformation has been solved (Lei et al. 2018). The bound arginine was locked in a transitional state stabilized by TMS1, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TMS1, and mutations in this motif abolished arginine transport (Lei et al. 2018).

SLC38A9 of Danio rerio (Zebrafish) (Brachydanio rerio)