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SLC15A1  -  solute carrier family 15 (oligopeptide...

Homo sapiens

Synonyms: HPECT1, HPEPT1, Intestinal H(+)/peptide cotransporter, Oligopeptide transporter, small intestine isoform, PEPT1, ...
 
 
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Disease relevance of SLC15A1

  • Overall, the results suggest that the dipeptide prodrugs of ACV have a high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of ocular and oral herpesvirus infections, because cornea and intestinal epithelia seem to express the oligopeptide transporters [1].
  • Patients with intestinal diseases, such as ulcerative colitis, Crohn's disease, and short-bowel syndrome, may have induction of the Pept-1 expression in their colon [2].
  • In the present study, we examined the regulation of PEPT1 by anticancer drugs in the gastric cancer cell line MKN45 [3].
  • The human gastric tumoral cell line HGT-1 was previously shown to contain a membrane somatostatin receptor negatively coupled to adenylate cyclase through a pertussis toxin-sensitive inhibitory GTP-binding regulatory protein (Gi) (Reyl-Desmars, F., Laboisse, C., and Lewin, M. J. M. (1986) Regul. Pept. 16, 207-215) [4].
  • Peptide transporter (TAP-1 and TAP-2)-independent endogenous processing of Epstein-Barr virus (EBV) latent membrane protein 2A: implications for cytotoxic T-lymphocyte control of EBV-associated malignancies [5].
  • The peptide transporter HPET1 can be utilised as uptake pathway for peptidomimetic prodrugs. The study describes design of prodrugs for hPEPT1-mediated uptake and subsequent release [6].
 

Psychiatry related information on SLC15A1

  • Mutation screening of two candidate genes from 13q32 in families affected with Bipolar disorder: human peptide transporter (SLC15A1) and human glypican5 (GPC5) [7].
 

High impact information on SLC15A1

  • A human intestinal cell line (Caco-2), which expresses Pept-1, has been used to investigate the effects of metabolic and pathological factors on dipeptide transport [8].
  • The oligopeptide transporter (Pept-1), which is located in the intestinal brush border membrane, provides a major mechanism for protein absorption in the human intestine [8].
  • These studies suggest that the insulin stimulates dipeptide transport by increasing membrane insertion of oligopeptide transporter from a preformed cytoplasmic pool, and cholera toxin decreases dipeptide transport by inhibiting the activity of Pept-1 through an increase in the intracellular concentration of adenosine 3',5'-cyclic monophosphate [8].
  • Intestinal protein digestion generates a huge variety and quantity of short chain peptides that are absorbed into intestinal epithelial cells by the PEPT1 transporter in the apical membrane of enterocytes [9].
  • The structural similarity of a variety of drugs with the basic structure of di- or tripeptides explains the transport of aminocephalosporins and aminopenicillins, selected angiotensin-converting inhibitors, and amino acid-conjugated nucleoside-based antiviral agents by PEPT1 [9].
 

Chemical compound and disease context of SLC15A1

 

Biological context of SLC15A1

  • Based on peptide-like structures, various drugs and prodrugs are transported as well, allowing efficient intestinal absorption of the compounds via PEPT1 [11].
  • Enzymatic hydrolysis and affinity of the prodrugs toward the human intestinal peptide transporter hPEPT1 were studied using the human intestinal Caco-2 cell line [1].
  • The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors [12].
  • All 23 exons and adjoining intronic sections of PEPT1 (SLC15A1) were sequenced in 247 individuals of various ethnic origins (Coriell collection) [13].
  • SLC15A1 and GPC5 are two of the candidate genes within an approximately 10-cM region of linkage on chromosome 13q32 [7].
  • PEPT1-mediated peptide uptake as function of culture time was characterised the human intestinal cell line Caco-2 [14]
 

Anatomical context of SLC15A1

 

Associations of SLC15A1 with chemical compounds

  • Alafosfalin strongly inhibited the uptake of [(14)C]glycylsarcosine with K(i) values of 0.19 +/- 0.01 mm and 0.07 +/- 0.01 mm for PEPT1 and PEPT2, respectively [16].
  • Expression of PEPT 1 or PEPT 2 in HeLa cells was found to induce H(+)-coupled cephalexin uptake in these cells [17].
  • Cyclacillin was 9-fold more potent than cefadroxil in competing with glycylsacosine for uptake via PEPT 1 [17].
  • Again, the PEPT 1 cDNA-induced dipeptide uptake was inhibited more potently by cyclacillin than by cefadroxil, and the PEPT 2 cDNA-induced dipeptide uptake was inhibited more potently by cefadroxil than by cyclacillin [17].
  • We conclude that valacyclovir is a substrate for the peptide transporters PEPT1 and PEPT2 and that a peptide bond is not a prerequisite for recognition as a substrate by the peptide transporters [19].
  • The interaction between hPEPT1 and the anticancer derivative 4-Toluenesulfonylureido-carnosine was investigated in the human intestinal cell line Caco-2. 4-Toluenesulfonylureido-carnosine was shown to be an inhibitor of transport but not a substrate itself [20].
 

Physical interactions of SLC15A1

  • PEPT2 is known to have similar but not identical structural requirements for substrate recognition and transport compared to PEPT1, its intestinal counterpart [21].
 

Regulatory relationships of SLC15A1

  • RT-PCR analysis using primer pairs specific for the intestinal-type peptide transporter (PEPT1) or kidney-type (PEPT2) revealed that the transport system expressed in SK-ChA-1 and also in cells of the native rabbit bile duct is PEPT1 [22].
  • In conclusion, our studies show that flavonoids with EGF-receptor tyrosine kinase inhibitory activities enhance the intestinal absorption of the beta-lactam antibiotic cefixime in Caco-2 cells by activation of apical Na+/H+-exchange and a concomitant increase of the driving force for PEPT1 [23].
  • The antidiabetic repaglinide and HMG CoA reductase inhibitor fluvastatin were found to inhibit hPEPT1 with sub-millimolar potency (IC(50) 178 +/- 1.0 and 337 +/- 4 microM, respectively) [24].
 

Other interactions of SLC15A1

 

Analytical, diagnostic and therapeutic context of SLC15A1

  • These site-directed mutagenesis studies clearly show that His-57 in hPEPT1 and His-87 in hPEPT2 are the most critical histidyl residues necessary for the catalytic function of these transporters [15].
  • RT-PCR and rapid amplification of cDNA ends (RACE) were then used to clone monkey PEPT1 and PEPT2 [29].
  • Lastly, Pept-1 seems to play important roles in nutritional and pharmacological therapies; for example, it has allowed the use of oligopeptides as a source of nitrogen for enteral feeding and the use of oral route for delivery of peptidomimetic drugs such as beta-lactam antibiotics [8].
  • High levels of PEPT 1 protein expression in AsPc-1 and Capan-2, as multiple glycosylated forms (Mr approximately 90,000-120,000), were confirmed by Western immunoblotting, when compared with Caco-2 cell cultures [30].
  • Northern blot analysis of poly(A)+RNA from these cells using cDNA probes specific for the human intestinal peptide transporter (PEPT 1) or the human kidney-specific peptide transporter (PEPT 2) revealed that the transport system expressed in these cells is PEPT 2 [31].

 

 

References

  1. 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. Anand, B.S., Patel, J., Mitra, A.K. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  2. Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease. Adibi, S.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  3. Regulation of human peptide transporter 1 (PEPT1) in gastric cancer cells by anticancer drugs. Inoue, M., Terada, T., Okuda, M., Inui, K. Cancer Lett. (2005) [Pubmed]
  4. Solubilization and immunopurification of a somatostatin receptor from the human gastric tumoral cell line HGT-1. Reyl-Desmars, F., Le Roux, S., Linard, C., Benkouka, F., Lewin, M.J. J. Biol. Chem. (1989) [Pubmed]
  5. Peptide transporter (TAP-1 and TAP-2)-independent endogenous processing of Epstein-Barr virus (EBV) latent membrane protein 2A: implications for cytotoxic T-lymphocyte control of EBV-associated malignancies. Khanna, R., Burrows, S.R., Moss, D.J., Silins, S.L. J. Virol. (1996) [Pubmed]
  6. Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media. Nielsen, C.U., Andersen, R., Brodin, B., Frokjaer, S., Steffansen, B. J. Control. Release. (2001) [Pubmed]
  7. Mutation screening of two candidate genes from 13q32 in families affected with Bipolar disorder: human peptide transporter (SLC15A1) and human glypican5 (GPC5). Maheshwari, M., Christian, S.L., Liu, C., Badner, J.A., Detera-Wadleigh, S., Gershon, E.S., Gibbs, R.A. BMC Genomics (2002) [Pubmed]
  8. The oligopeptide transporter (Pept-1) in human intestine: biology and function. Adibi, S.A. Gastroenterology (1997) [Pubmed]
  9. Molecular and integrative physiology of intestinal peptide transport. Daniel, H. Annu. Rev. Physiol. (2004) [Pubmed]
  10. Lactobacillus casei alters hPEPT1-mediated glycylsarcosine uptake in Caco-2 cells. Neudeck, B.L., Loeb, J.M., Faith, N.G. J. Nutr. (2004) [Pubmed]
  11. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Daniel, H., Kottra, G. Pflugers Arch. (2004) [Pubmed]
  12. Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Li, M., Anderson, G.D., Phillips, B.R., Kong, W., Shen, D.D., Wang, J. Drug Metab. Dispos. (2006) [Pubmed]
  13. Genetic variants of the human dipeptide transporter PEPT1. Anderle, P., Nielsen, C.U., Pinsonneault, J., Krog, P.L., Brodin, B., Sadée, W. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  14. In-depth evaluation of Gly-Sar transport parameters as a function of culture time in the Caco-2 cell model. Bravo, S.A., Nielsen, C.U., Amstrup, J., Frokjaer, S., Brodin, B. Eur. J. Pharm. Sci. (2004) [Pubmed]
  15. Identification of the histidyl residue obligatory for the catalytic activity of the human H+/peptide cotransporters PEPT1 and PEPT2. Fei, Y.J., Liu, W., Prasad, P.D., Kekuda, R., Oblak, T.G., Ganapathy, V., Leibach, F.H. Biochemistry (1997) [Pubmed]
  16. Transport of the phosphonodipeptide alafosfalin by the H+/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells. Neumann, J., Bruch, M., Gebauer, S., Brandsch, M. Eur. J. Biochem. (2004) [Pubmed]
  17. Differential recognition of beta -lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2. Ganapathy, M.E., Brandsch, M., Prasad, P.D., Ganapathy, V., Leibach, F.H. J. Biol. Chem. (1995) [Pubmed]
  18. hPEPT1 is responsible for uptake and transport of Gly-Sar in the human bronchial airway epithelial cell-line Calu-3. Søndergaard, H.B., Brodin, B., Nielsen, C.U. Pflugers. Arch. (2008) [Pubmed]
  19. Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Ganapathy, M.E., Huang, W., Wang, H., Ganapathy, V., Leibach, F.H. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  20. Transport characteristics of L-carnosine and the anticancer derivative 4-toluenesulfonylureido-carnosine in a human epithelial cell line. Nielsen, C.U., Supuran, C.T., Scozzafava, A., Frokjaer, S., Steffansen, B., Brodin, B. Pharm. Res. (2002) [Pubmed]
  21. The renal type H(+)/peptide symporter PEPT2: structure-affinity relationships. Biegel, A., Knütter, I., Hartrodt, B., Gebauer, S., Theis, S., Luckner, P., Kottra, G., Rastetter, M., Zebisch, K., Thondorf, I., Daniel, H., Neubert, K., Brandsch, M. Amino Acids (2006) [Pubmed]
  22. H+-peptide cotransport in the human bile duct epithelium cell line SK-ChA-1. Knütter, I., Rubio-Aliaga, I., Boll, M., Hause, G., Daniel, H., Neubert, K., Brandsch, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  23. Flavonoids with epidermal growth factor-receptor tyrosine kinase inhibitory activity stimulate PEPT1-mediated cefixime uptake into human intestinal epithelial cells. Wenzel, U., Kuntz, S., Daniel, H. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  24. In vitro and pharmacophore-based discovery of novel hPEPT1 inhibitors. Ekins, S., Johnston, J.S., Bahadduri, P., D'Souza, V.M., Ray, A., Chang, C., Swaan, P.W. Pharm. Res. (2005) [Pubmed]
  25. Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes. Tramonti, G., Xie, P., Wallner, E.I., Danesh, F.R., Kanwar, Y.S. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  26. Loss of HLA molecules in B lymphomas is associated with an aggressive clinical course. Amiot, L., Onno, M., Lamy, T., Dauriac, C., Le Prise, P.Y., Fauchet, R., Drenou, B. Br. J. Haematol. (1998) [Pubmed]
  27. Peptide transporter genes (TAP) polymorphisms and genetic susceptibility to rheumatoid arthritis. Vandevyver, C., Geusens, P., Cassiman, J.J., Raus, J. Br. J. Rheumatol. (1995) [Pubmed]
  28. Genomic structure of proton-coupled oligopeptide transporter hPEPT1 and pH-sensing regulatory splice variant. Urtti, A., Johns, S.J., Sadée, W. AAPS PharmSci (2001) [Pubmed]
  29. Comparison of human and monkey peptide transporters: PEPT1 and PEPT2. Zhang, E.Y., Emerick, R.M., Pak, Y.A., Wrighton, S.A., Hillgren, K.M. Mol. Pharm. (2004) [Pubmed]
  30. An oligopeptide transporter is expressed at high levels in the pancreatic carcinoma cell lines AsPc-1 and Capan-2. Gonzalez, D.E., Covitz, K.M., Sadée, W., Mrsny, R.J. Cancer Res. (1998) [Pubmed]
  31. Identification of a renal cell line that constitutively expresses the kidney-specific high-affinity H+/peptide cotransporter. Brandsch, M., Brandsch, C., Prasad, P.D., Ganapathy, V., Hopfer, U., Leibach, F.H. FASEB J. (1995) [Pubmed]
 
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