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PAT1

Target Synonyms and Classification: The Proton-dependent Amino acid Transporter 1 (PAT1, LYAAT-1) belongs to the Amino Acid/Auxin Permease Family (AAAPF, TCDB: 2.A.18), which catalyze the H+ coupled uptake of auxins or amino acids. Since it is a human transporter, it’s also classified as an SLC transporter: PAT1 equals to SLC36A1 and belongs to the proton-coupled amino acid transporters (SLC36).

Function and Mechanism: The physiological role of PAT1 is manifold: In the small intestine it is responsible for the absorption of amino acids, while it serves as an efflux pathway in lysosomes after intralysosomal protein breakdown. It is also capable of regulating cell growth and sensing the availability of amino acids. H+/amino acid symport occurs with 1:1 stoichiometry. PAT1 is a low affinity / high capacity transporter and exhibits KM values in the range between 1 and 10 mM. Proline uptake in rPAT1 occurs with an KM of 2 mM and an pH optimum of 5.0. Proton affinity corresponds to an pK of 7.0 and is independent of substrate.

Organism and Localization: Members of the AAAP Family are only found in eukaryotes; PAT1 is a mammalian transporter. It is localized at the luminal surface of the small intestine and - in many cell types - also in lysosomes. In addition a nuclear localization was described. Diseases associated with defects of human PAT1 include Spinocerebellar Ataxia 45 and Iminoglycinuria. Moreover regulation of PAT1 by FLCN plays a crucial role in the Birt-Hogg-Dubé (BHD) syndrome.

Substrates and Inhibitors: PAT1 transports small neutral amino and imino acids: L-Gly, L-Ala and L-Pro are transported with similar rates; PAT1 does not discriminate between D- and L-isoforms of these amino acids. In additon β-Alanine is transported with similar affinity as α-Alanine. Other substrates include γ-amino butyrate, Hydroxyproline and taurine. PAT1 is also relevant in pharmacology and known to transport amino acid-based drugs to treat epilepsy, schizophrenia, bacterial infections, hyperglycemia and cancer. Serotonin, L-tryptophan, and tryptamine are not transported by, but effective inhibitors of PAT1 with IC50 values in the range of 5 – 10 mM.

Related Transporters: Within the SLC36 family are three other members with different tissue distributions and slightly different kinetic properties. PAT2 (SLC36a2) is more active at neutral and alkaline pH and has higher apparent affinites for its main substrates (KM < 1 mM).

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