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SLC15 family of peptide transporters C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The Solute Carrier 15 (SLC15) family of peptide transporters, alias H+-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di- and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies [3].

Transporters

984
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PEPT1 (Peptide transporter 1 / SLC15A1) C Show summary »


Target Id 984
Nomenclature Peptide transporter 1
Systematic nomenclature SLC15A1
Common abbreviation PEPT1
Previous and unofficial names Intestinal H+/peptide cotransporter | low affinity peptide transporter | solute carrier family 15 oligopeptide transporter member 1 | oligopeptide transporter, small intestine isoform | proton-coupled dipeptide cotransporter | solute carrier family 15 member 1 | PECT1 | solute carrier family 15 (oligopeptide transporter), member 1 | solute carrier family 15 (oligopeptide transporter)
Genes SLC15A1 (Hs), Slc15a1 (Mm), Slc15a1 (Rn)
Ensembl ID ENSG00000088386 (Hs), ENSMUSG00000025557 (Mm), ENSRNOG00000011598 (Rn)
UniProtKB AC P46059 (Hs), Q9JIP7 (Mm), P51574 (Rn)
Bioparadigms SLC Tables SLC15A1 (Hs)
Endogenous substrates
5-aminolevulinic acid [5,10,26,52,86,96]
di/tripeptides including peptides with high intrinsic hydrolysis resistance such as carnosine, anserine and γ-glutamyl-dipeptides [1,26,34,48,91-92,124,137]
Substrates
fMet-Leu-Phe [15,17,77-78,135]
valganciclovir [104,122]
valacyclovir [7-8,31,43,79]
cefadroxil [73,109,133]
cephalexin [4,21,28,30,73,113-114]
muramyl dipeptide [53,64,74,123]
D-Ala-Lys-AMCA [38,41,63,108]
β-Ala-Lys-AMCA [1,54,63]
His-Leu-lopinavir [75]
alafosfalin [87]
Inhibitors
Lys[Z(NO2)]-Val pKi 5.7 [58]
Lys[Z(NO2)]-Pro pKi 5.0 – 5.3 [60]
Lys[Z(NO2)]-Lys[Z(NO2)] pKi 4.9 [12]
4-AMBA pKi 2.3 [5,23,76]
Labelled ligands
[11C]GlySar [80]
[14C]GlySar [2,8,11,30-32,52,59-61,73,75,99,109,113-115]
[3H]GlySar [4,14,20-21,46,55,68,90,96,108]
[18F]FEPPG [83]
[3H]-IPP [35-36]
[3H]-LKP [35-36]
(3,5)-[19F]2-Phe-ψ-Ala [6]
Stoichiometry Transport is electrogenic and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono- or polyvalently charged peptides, as well as the other substrates tested to date.
Comment Although most di/tripeptides can bind PEPT1, not all of them are substrates. The uptake depends on the structural features (charge, hydrophobicity, size, side chain flexibility, etc.) of the di/tripeptide. A variety of dipeptides and drugs interact with PEPT1, including D-Phe-Ala [26,60], D-Phe-Gln [5], cyclo(L-Hyp-L-Ser) (i.e. JBP485) [16,71], nateglinide [115], glibenclamide [99] and penicillin G (benzylpenicillin) [10]. Among many other molecules, PEPT1 has been shown to interact with L-Dopa-L-Phe [110,119], D-Phe-Gly-L-Dopa [125], JBP485 prodrugs (e.g. JBP485-3-CH2-O-valine, J3V) [56], 5-Aminosalicylic acid (5-ASA) derivatives (i.e. Gly-ASA, Glu-ASA, Val-ASA) [82,144], cinnabar (i.e. α-HgS >96%) [134], doxorubicin-tripeptide (i.e. doxorubicin-Gly-Gly-Gly) [37], scutellarin methyl ester-4'-dipeptide conjugates (e.g. scutellarin methyl ester-4'-Val-homo-Leu) [69], curcumin (CUR)-peptide derivatives (i.e. CUR-Phe-Val, CUR-Ile-Val) [145], gemcitabine amino acid ester prodrugs (i.e. 5'-L-valyl-gemcitabine, V-Gem) [102,118], decitabine amino acid ester prodrugs (e.g. 5'-O-L-valyl-decitabine, L-Val-DAC) [111-112], didanosine amino acid ester prodrugs (e.g. 5'-O-L-valyl-didanosine, L-Val-DDI) [143], floxuridine amino acid ester prodrugs (e.g. 5'-L-isoleucyl and 5'-L-valyl amino acid ester prodrugs of floxuridine) [65-66], floxuridine amino acid monoester prodrugs (e.g. 5'-O-D-valyl-floxuridine) [121], floxuridine dipeptide monoester prodrugs (e.g. 5'-L-phenylalanyl-L-tyrosyl-floxuridine, 5'-L-phenylalanyl-L-glycyl-floxuridine, and 5'-L-isoleucyl-L-glycyl-floxuridine) [120], amino acid acyloxy ester prodrugs of guanidine oseltamivir carboxylate (GOC) (e.g. GOC-L-Val, the L-valyl acyloxy ethyl prodrug of GOC) [44] and the valyl amino acid prodrug of GOC with the isopropyl-methylene-dioxy linker (i.e. GOC-ISP-Val) [51], amino acid acyloxy ester prodrugs of zanamivir (Zan, e.g. Zan-L-Val, the L-valyl acycloxy ethyl prodrug of Zan) [45], peramivir-(CH2)2-L-Val and peramivir-L-Ile [106], thiodipeptide prodrugs of for example, ibuprofen and propofol [27], alanylpyrraline (Ala-Pyrr) and pyrralylalanine (Pyrr-Ala) [33], dipeptide-bound derivatives of N6-(carboxymethyl)lysine (CML) and N6-(1-carboxyethyl)-lysine (CEL) (i.e. Ala-CML, CML-Ala, Ala-CEL, CEL-Ala) [47], Flammulina velutipes polysaccharide(FVP)-iron(III) complex [FVP-Fe(III) complex] [18], dipeptides of p-borono-L-phenylalanine (BPA) and tyrosine (i.e. L-Tyr-p-L-BPA (Tyr-BPA), p-L-BPA-L-tyrosine (BPA-Tyr)) [81] and AuIII‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR], in which AA1 = N‐methylglycine (Sar), L/D-Pro; AA2 = L/D-Ala, α‐aminoisobutyric acid (Aib); R = OtBu, triethylene glycol methyl ether) (e.g. dtc‐Pro‐Aib‐OtBu) [13]. In recent years, PEPT1 has been shown to interact with a large variety of specifically targeted (i.e. peptide- or amino acid-functionalized) nanoparticles [19,22,25,39-40,136], (nano)micelles [57,126,141] and nanocomposites [42,131,139-140].

PEPT2 (Peptide transporter 2 / SLC15A2) C Show summary »

PHT2 (Peptide transporter 3 / SLC15A3) C Show summary » More detailed page go icon to follow link

PHT1 (Peptide transporter 4 / SLC15A4) C Show summary » More detailed page go icon to follow link

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol. 176 Issue S1: S397-S493.