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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).
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].
PEPT1 (Peptide transporter 1 / SLC15A1) C Show summary »« Hide summary
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PEPT2 (Peptide transporter 2 / SLC15A2) C Show summary »« Hide summary
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PHT2 (Peptide transporter 3 / SLC15A3)
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PHT1 (Peptide transporter 4 / SLC15A4)
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* Key recommended reading is highlighted with an asterisk
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* Brandsch M. (2013) Drug transport via the intestinal peptide transporter PepT1. Curr Opin Pharmacol, 13 (6): 881-7. [PMID:24007794]
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Daniel H. (2004) Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol, 66: 361-84. [PMID:14977407]
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* Fredriksson R, Nordström KJ, Stephansson O, Hägglund MG, Schiöth HB. (2008) The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett, 582 (27): 3811-6. [PMID:18948099]
Höglund PJ, Nordström KJ, Schiöth HB, Fredriksson R. (2011) The solute carrier families have a remarkably long evolutionary history with the majority of the human families present before divergence of Bilaterian species. Mol Biol Evol, 28 (4): 1531-41. [PMID:21186191]
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* Minhas GS, Newstead S. (2020) Recent advances in understanding prodrug transport through the SLC15 family of proton-coupled transporters. Biochem Soc Trans, 48 (2): 337-346. [PMID:32219385]
Newstead S. (2011) Towards a structural understanding of drug and peptide transport within the proton-dependent oligopeptide transporter (POT) family. Biochem Soc Trans, 39 (5): 1353-8. [PMID:21936814]
* Newstead S. (2015) Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters. Biochim Biophys Acta, 1850 (3): 488-499. [PMID:24859687]
* Newstead S. (2017) Recent advances in understanding proton coupled peptide transport via the POT family. Curr Opin Struct Biol, 45: 17-24. [PMID:27865112]
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* Smith DE, Clémençon B, Hediger MA. (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med, 34 (2-3): 323-36. [PMID:23506874]
Sreedharan S, Stephansson O, Schiöth HB, Fredriksson R. (2011) Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters. Gene, 478 (1-2): 11-8. [PMID:21044875]
Terada T, Inui K. (2007) Gene expression and regulation of drug transporters in the intestine and kidney. Biochem Pharmacol, 73 (3): 440-9. [PMID:17137557]
Terada T, Inui K. (2012) Recent advances in structural biology of peptide transporters. Curr Top Membr, 70: 257-74. [PMID:23177989]
* Thwaites DT, Anderson CM. (2007) H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol, 92 (4): 603-19. [PMID:17468205]
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Subcommittee members:
Tiziano Verri (Chairperson) |
Other contributors:
David T. Thwaites |
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Transporters. Br J Pharmacol. 178 Suppl 1:S412-S513.
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The members of the SLC15 family of peptide transporters are particularly promiscuous in the transport of di/tripeptides, and D-amino acid containing peptides are also transported. While SLC15A3 and SLC15A4 transport histidine, none of them transport tetrapeptides. In addition, many molecules, among which beta-lactam antibacterials, angiotensin-converting enzyme inhibitors and sartans, variably interact with the SLC15 family transporters. Known substrates include cefadroxil, valacyclovir, 5-aminolevulinic acid, L-Dopa prodrugs, gemcitabine prodrugs, floxuridine prodrugs, Maillard reaction products, JBP485 and JBP485 prodrugs, zanamivir prodrugs, oseltamivir prodrugs, doxorubicin prodrugs, polymyxins, didanosine prodrugs, decitabine prodrugs, peramivir prodrugs, ibuprofen and propofol thiodipeptide prodrugs, curcumin-peptide derivatives, 5-aminosalicylic acid derivatives, cinnabar, dipeptide conjugates of scutellarin, Flammulina velutipes polysaccharide-iron(III) complex, p-borono-L-phenylalanine-containing dipeptides and AuIII-peptidodithiocarbamato complexes. Notably, PEPT1 interacts with a variety of specifically PEPT1-targeted (via peptide- or amino acid-functionalization) nanoparticles, (nano)micelles and nanocomposites. Frequently used pharmaceutical excipients such as Tween® 20, Tween® 80, Solutol® HS 15 and Cremophor EL® strongly inhibit cellular uptake of Gly-Sar by SLC15A1 and/or SLC15A2 [90].
There is evidence to suggest the existence of a fifth member of this transporter family, SLC15A5 (A6NIM6; ENSG00000188991), but to date there is no established biological function or reported pharmacology for this protein [103].