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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) C Show summary »« Hide summary More detailed page
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PHT1 (Peptide transporter 4 / SLC15A4) C Show summary »« Hide summary More detailed page
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* Key recommended reading is highlighted with an asterisk
* Anderson CM, Thwaites DT. (2010) Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda), 25 (6): 364-77. [PMID:21186281]
Daniel H, Zietek T. (2015) Taste and move: glucose and peptide transporters in the gastrointestinal tract. Exp Physiol, 100 (12): 1441-50. [PMID:26140358]
Dranse HJ, Waise TMZ, Hamr SC, Bauer PV, Abraham MA, Rasmussen BA, Lam TKT. (2018) Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing. Nat Commun, 9 (1): 1118. [PMID:29549253]
* Gyimesi G, Hediger MA. (2023) Transporter-Mediated Drug Delivery. Molecules, 28 (3). [PMID:36770817]
Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, César-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A et al.. (2020) TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature, 581 (7808): 316-322. [PMID:32433612]
Killer M, Wald J, Pieprzyk J, Marlovits TC, Löw C. (2021) Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes. Sci Adv, 7 (45): eabk3259. [PMID:34730990]
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]
* Parker JL, Deme JC, Wu Z, Kuteyi G, Huo J, Owens RJ, Biggin PC, Lea SM, Newstead S. (2021) Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals. Sci Adv, 7 (35). [PMID:34433568]
* 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]
* Toyama-Sorimachi N, Kobayashi T. (2021) Lysosomal amino acid transporters as key players in inflammatory diseases. Int Immunol, 33 (12): 853-858. [PMID:34508637]
Ural-Blimke Y, Flayhan A, Strauss J, Rantos V, Bartels K, Nielsen R, Pardon E, Steyaert J, Kosinski J, Quistgaard EM et al.. (2019) Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1. J Am Chem Soc, 141 (6): 2404-2412. [PMID:30644743]
Viennois E, Pujada A, Zen J, Merlin D. (2018) Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol, 8 (2): 731-760. [PMID:29687900]
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6. Anand BS, Patel J, Mitra AK. (2003) Interactions of the dipeptide ester prodrugs of acyclovir with the intestinal oligopeptide transporter: competitive inhibition of glycylsarcosine transport in human intestinal cell line-Caco-2. J Pharmacol Exp Ther, 304 (2): 781-91. [PMID:12538834]
7. Anderson CM, Jevons M, Thangaraju M, Edwards N, Conlon NJ, Woods S, Ganapathy V, Thwaites DT. (2010) Transport of the photodynamic therapy agent 5-aminolevulinic acid by distinct H+-coupled nutrient carriers coexpressed in the small intestine. J Pharmacol Exp Ther, 332 (1): 220-8. [PMID:19789362]
8. Arakawa H, Yamada H, Arai K, Kawanishi T, Nitta N, Shibata S, Matsumoto E, Yano K, Kato Y, Kumamoto T et al.. (2020) Possible utility of peptide-transporter-targeting [19F]dipeptides for visualization of the biodistribution of cancers by nuclear magnetic resonance imaging. Int J Pharm, 586: 119575. [PMID:32622809]
9. Balimane P, Sinko P. (2000) Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepT1) in CHO cells. Biopharm Drug Dispos, 21 (5): 165-74. [PMID:11180195]
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13. Biegel A, Gebauer S, Hartrodt B, Brandsch M, Neubert K, Thondorf I. (2005) Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem, 48 (13): 4410-9. [PMID:15974593]
14. Biegel A, Knütter I, Hartrodt B, Gebauer S, Theis S, Luckner P, Kottra G, Rastetter M, Zebisch K, Thondorf I et al.. (2006) The renal type H+/peptide symporter PEPT2: structure-affinity relationships. Amino Acids, 31 (2): 137-56. [PMID:16868651]
15. Boscutti G, Nardon C, Marchiò L, Crisma M, Biondi B, Dalzoppo D, Dalla Via L, Formaggio F, Casini A, Fregona D. (2018) Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations. ChemMedChem, 13 (11): 1131-1145. [PMID:29570944]
16. Buyse M, Berlioz F, Guilmeau S, Tsocas A, Voisin T, Péranzi G, Merlin D, Laburthe M, Lewin MJ, Rozé C et al.. (2001) PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine. J Clin Invest, 108 (10): 1483-94. [PMID:11714740]
17. Buyse M, Charrier L, Sitaraman S, Gewirtz A, Merlin D. (2003) Interferon-gamma increases hPepT1-mediated uptake of di-tripeptides including the bacterial tripeptide fMLP in polarized intestinal epithelia. Am J Pathol, 163 (5): 1969-77. [PMID:14578196]
18. Cang J, Zhang J, Wang C, Liu Q, Meng Q, Wang D, Sugiyama Y, Tsuji A, Kaku T, Liu K. (2010) Pharmacokinetics and mechanism of intestinal absorption of JBP485 in rats. Drug Metab Pharmacokinet, 25 (5): 500-7. [PMID:20877133]
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20. Cheng C, Huang DC, Zhao LY, Cao CJ, Chen GT. (2019) Preparation and in vitro absorption studies of a novel polysaccharide‑iron (III) complex from Flammulina velutipes. Int J Biol Macromol, 132: 801-810. [PMID:30953722]
21. Chi H, Gu Y, Xu T, Cao F. (2017) Multifunctional organic-inorganic hybrid nanoparticles and nanosheets based on chitosan derivative and layered double hydroxide: cellular uptake mechanism and application for topical ocular drug delivery. Int J Nanomedicine, 12: 1607-1620. [PMID:28280329]
22. Chu XY, Sánchez-Castaño GP, Higaki K, Oh DM, Hsu CP, Amidon GL. (2001) Correlation between epithelial cell permeability of cephalexin and expression of intestinal oligopeptide transporter. J Pharmacol Exp Ther, 299 (2): 575-82. [PMID:11602669]
23. Covitz KM, Amidon GL, Sadée W. (1996) Human dipeptide transporter, hPEPT1, stably transfected into Chinese hamster ovary cells. Pharm Res, 13 (11): 1631-4. [PMID:8956326]
24. Dai T, Li N, Zhang L, Zhang Y, Liu Q. (2016) A new target ligand Ser-Glu for PEPT1-overexpressing cancer imaging. Int J Nanomedicine, 11: 203-12. [PMID:26811678]
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26. Dieck ST, Heuer H, Ehrchen J, Otto C, Bauer K. (1999) The peptide transporter PepT2 is expressed in rat brain and mediates the accumulation of the fluorescent dipeptide derivative beta-Ala-Lys-Nepsilon-AMCA in astrocytes. Glia, 25 (1): 10-20. [PMID:9888294]
27. Du Y, Tian C, Wang M, Huang D, Wei W, Liu Y, Li L, Sun B, Kou L, Kan Q et al.. (2018) Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy. Drug Deliv, 25 (1): 1403-1413. [PMID:29890854]
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31. Fujita T, Kishida T, Wada M, Okada N, Yamamoto A, Leibach FH, Ganapathy V. (2004) Functional characterization of brain peptide transporter in rat cerebral cortex: identification of the high-affinity type H+/peptide transporter PEPT2. Brain Res, 997 (1): 52-61. [PMID:14715149]
32. Ganapathy ME, Brandsch M, Prasad PD, Ganapathy V, Leibach FH. (1995) Differential recognition of beta -lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2. J Biol Chem, 270 (43): 25672-7. [PMID:7592745]
33. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH. (1998) Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun, 246 (2): 470-5. [PMID:9610386]
34. Ganapathy ME, Prasad PD, Mackenzie B, Ganapathy V, Leibach FH. (1997) Interaction of anionic cephalosporins with the intestinal and renal peptide transporters PEPT 1 and PEPT 2. Biochim Biophys Acta, 1324 (2): 296-308. [PMID:9092716]
35. Geissler S, Hellwig M, Zwarg M, Markwardt F, Henle T, Brandsch M. (2010) Transport of the advanced glycation end products alanylpyrraline and pyrralylalanine by the human proton-coupled peptide transporter hPEPT1. J Agric Food Chem, 58 (4): 2543-7. [PMID:20104847]
36. Geissler S, Zwarg M, Knütter I, Markwardt F, Brandsch M. (2010) The bioactive dipeptide anserine is transported by human proton-coupled peptide transporters. FEBS J, 277 (3): 790-5. [PMID:20067523]
37. Gleeson JP, Brayden DJ, Ryan SM. (2017) Evaluation of PepT1 transport of food-derived antihypertensive peptides, Ile-Pro-Pro and Leu-Lys-Pro using in vitro, ex vivo and in vivo transport models. Eur J Pharm Biopharm, 115: 276-284. [PMID:28315445]
38. Gleeson JP, Frías JM, Ryan SM, Brayden DJ. (2018) Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition. Eur J Pharm Biopharm, 128: 179-187. [PMID:29684535]
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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 SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Transporters. Br J Pharmacol. 180 Suppl 2:S374-469.
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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. Known substrates also include mirogabalin, javamide-I/-II esters, acetylated di/tripeptides, LY2140023, paclitaxel small molecule prodrugs, JBP923 enantiomers, fluorescein-labeled dipeptides and peptide-bound derivatives of carboxymethyllysine. 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 [96].
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 [110].