SLC15 family of peptide transporters | Transporters | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

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SLC15 family of peptide transporters

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

Targets of relevance to immunopharmacology are highlighted in blue

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

Target Id

984

Nomenclature

Peptide transporter 1

Systematic nomenclature

SLC15A1

Common abbreviation

PEPT1

Previous and unofficial names

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)

RESOLUTE

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 pK_i 5.7 [58]

Lys[Z(NO₂)]-Pro pK_i 5.0 – 5.3 [60]

Lys[Z(NO₂)]-Lys[Z(NO₂)] pK_i 4.9 [12]

4-AMBA pK_i 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 Au^III‐peptidodithiocarbamato complexes of the type [Au^IIIBr2(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 »« Hide summary

Target Id

985

Nomenclature

Peptide transporter 2

Systematic nomenclature

SLC15A2

Common abbreviation

PEPT2

Previous and unofficial names

high affinity peptide transporter | Kidney H⁺/peptide cotransporter | oligopeptide transporter, kidney isoform | solute carrier family 15 (H+/peptide transporter) member 2 | solute carrier family 15 member 2 | solute carrier family 15 (oligopeptide transporter), member 2 | solute carrier family 15 (H+/peptide transporter)

Genes

SLC15A2 (Hs), Slc15a2 (Mm), Slc15a2 (Rn)

Ensembl ID

ENSG00000163406 (Hs), ENSMUSG00000022899 (Mm), ENSRNOG00000002305 (Rn)

UniProtKB AC

Q16348 (Hs), Q9ES07 (Mm), Q63424 (Rn)

Bioparadigms SLC Tables

SLC15A2 (Hs)

RESOLUTE

SLC15A2 (Hs)

Endogenous substrates

5-aminolevulinic acid [26,52,137]

di/tripeptides including peptides with high intrinsic hydrolysis resistance such as carnosine and anserine [1,34,89,105,137,146]

Substrates

muramyl dipeptide [49,105]

D-Ala-Lys-AMCA [63,108,132]

β-Ala-Lys-AMCA [1,24,63,93-94,105,147-148]

alafosfalin [87]

γ-iE-DAP [105,107]

Inhibitors

Lys[Z(NO₂)]-Lys[Z(NO₂)] pK_i 8.0 [12,117]

Lys[Z(NO₂)]-Val pK_i 7.0 [12,117]

Lys[Z(NO₂)]-Pro pK_i 6.2 [12,117]

4-AMBA pK_i 2.5 [12,117]

Labelled ligands

[¹¹C]GlySar [84]

[¹⁴C]GlySar [29-32,50,52,59,61,70,73,99,113,115]

[³H]GlySar [68,72,90,97,100,108]

[¹⁸F]FEPPG [83]

(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 PEPT2, not all of them are substrates. The uptake depends on the structural features (charge, hydrophobicity, size, side chain flexibility, etc.) of the di/tripeptide. Like PEPT1, PEPT2 interacts with dipeptides and drugs including D-Phe-Ala [26,116], nateglinide [115], glibenclamide [99], penicillin G (benzylpenicillin) [88], polymyxins (i.e. polymyxin B and colistin) [72] and entecavir [138]. PEPT2 has been shown to interact with 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 with 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].

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

Target Id

986

Nomenclature

Peptide transporter 3

Systematic nomenclature

SLC15A3

Common abbreviation

PHT2

Previous and unofficial names

solute carrier family 15 | peptide/histidine transporter PHT2 | PTR3 | solute carrier family 15 member 3 | solute carrier family 15 (oligopeptide transporter), member 3

Genes

SLC15A3 (Hs), Slc15a3 (Mm), Slc15a3 (Rn)

Ensembl ID

ENSG00000110446 (Hs), ENSMUSG00000024737 (Mm), ENSRNOG00000021644 (Rn)

UniProtKB AC

Q8IY34 (Hs), Q8BPX9 (Mm), Q924V4 (Rn)

Bioparadigms SLC Tables

SLC15A3 (Hs)

RESOLUTE

SLC15A3 (Hs)

Endogenous substrates

L-histidine [95,130]

carnosine [89,95]

glycyl-glycyl-glycine [130]

Substrates

valacyclovir [130]

cefadroxil [130]

muramyl dipeptide [85,129]

glycyl-sarcosine [130]

MDP-rhodamine [85]

Tri-DAP [129]

Labelled ligands

[¹⁴C]histidine [95]

Stoichiometry

PHT2 has not been analyzed systematically with respect to driving force, mode of transport, and substrate specificity. The pH dependence observed for transport of histidine [95] and the model peptides used, i.e., carnosine [95] and histidyl-leucine [95], suggest a similar mode of operation as PEPT1 and PEPT2 proteins.

Comment

Other PHT2 ligands include d3-L-histidine [130] and [³H]carnosine [95].

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

Target Id

987

Nomenclature

Peptide transporter 4

Systematic nomenclature

SLC15A4

Common abbreviation

PHT1

Previous and unofficial names

PHT1 | solute carrier family 15 member 4 | Peptide/histidine transporter 1 | solute carrier family 15 (oligopeptide transporter), member 4 | solute carrier family 15

Genes

SLC15A4 (Hs), Slc15a4 (Mm), Slc15a4 (Rn)

Ensembl ID

ENSG00000139370 (Hs), ENSMUSG00000029416 (Mm), ENSRNOG00000000962 (Rn)

UniProtKB AC

Q8N697 (Hs), Q91W98 (Mm), O09014 (Rn)

Bioparadigms SLC Tables

SLC15A4 (Hs)

RESOLUTE

SLC15A4 (Hs)

Endogenous substrates

L-histidine [9,62,75,127,142]

carnosine [9,89,142]

glycyl-glycyl-glycine [89]

Substrates

valacyclovir [9]

muramyl dipeptide [85,101]

His-Leu-lopinavir [75]

glycyl-sarcosine [9,50,101,108]

MDP-rhodamine [49,85]

Tri-DAP [67,98,101]

C12-iE-DAP [67]

Labelled ligands

[¹⁴C]histidine (Binding) [127-128,142]

[³H]histidine [9,75,108,127]

Stoichiometry

PHT1 has not been analyzed systematically with respect to driving force, mode of transport, and substrate specificity. The pH dependence observed for transport of histidine [9,62,75,127,142] and the model peptide used, i.e., carnosine [9,142], suggest a similar mode of operation as PEPT1 and PEPT2 proteins.

Comment

Other PHT1 ligands include d3-L-histidine [101], [³H]carnosine [9,142], [¹⁴C]GlySar [50], [³H]GlySar [9,108] and [³H]valacyclovir [9].

Comments

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References

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1. Agu R, Cowley E, Shao D, Macdonald C, Kirkpatrick D, Renton K, Massoud E. (2011) Proton-coupled oligopeptide transporter (POT) family expression in human nasal epithelium and their drug transport potential. Mol Pharm, 8 (3): 664-72. [PMID:21366347]

2. Akazawa T, Yoshida S, Ohnishi S, Kanazu T, Kawai M, Takahashi K. (2018) Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine. Drug Metab Dispos, 46 (11): 1497-1506. [PMID:30135242]

3. Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL et al.. (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol, 176 Suppl 1: S397-S493. [PMID:31710713]

4. 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]

5. 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]

6. 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]

7. 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]

8. Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH, Tsuji A, Sinko PJ. (1998) Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophys Res Commun, 250 (2): 246-51. [PMID:9753615]

9. Bhardwaj RK, Herrera-Ruiz D, Eltoukhy N, Saad M, Knipp GT. (2006) The functional evaluation of human peptide/histidine transporter 1 (hPHT1) in transiently transfected COS-7 cells. Eur J Pharm Sci, 27 (5): 533-42. [PMID:16289537]

10. Bhardwaj RK, Herrera-Ruiz D, Sinko PJ, Gudmundsson OS, Knipp G. (2005) Delineation of human peptide transporter 1 (hPepT1)-mediated uptake and transport of substrates with varying transporter affinities utilizing stably transfected hPepT1/Madin-Darby canine kidney clones and Caco-2 cells. J Pharmacol Exp Ther, 314 (3): 1093-100. [PMID:15901802]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. Charrier L, Driss A, Yan Y, Nduati V, Klapproth JM, Sitaraman SV, Merlin D. (2006) hPepT1 mediates bacterial tripeptide fMLP uptake in human monocytes. Lab Invest, 86 (5): 490-503. [PMID:16568107]

18. 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]

19. 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]

20. 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]

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25. 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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35. 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]

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42. Gu Y, Xu C, Wang Y, Zhou X, Fang L, Cao F. (2019) Multifunctional Nanocomposites Based on Liposomes and Layered Double Hydroxides Conjugated with Glycylsarcosine for Efficient Topical Drug Delivery to the Posterior Segment of the Eye. Mol Pharm, 16 (7): 2845-2857. [PMID:31244219]

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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.