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

• Lactobacillus casei alters hPEPT1-mediated glycylsarcosine uptake in Caco-2 cells [10].
• However, it is unknown whether probiotic bacteria such as Lactobacillus casei alter the expression and function of intestinal transport proteins such as hPEPT1 [10].

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

• Confocal analysis of immunofluorescence in X. laevis oocytes expressing the wild type and the three histidine mutants of hPEPT1 showed that the transporter protein is expressed exclusively in the plasma membrane and that the level of expression is comparable among the wild type and the three mutants [15].
• We have individually mutated each of these histidyl residues in hPEPT1 and in hPEPT2 and compared the catalytic function of the mutants with that of their respective wild type transporters by expressing the transporters in Xenopus laevis oocytes and also in HeLa cells [15].
• Transport of the phosphonodipeptide alafosfalin by the H+/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells [16].
• More recently, other sites of functional expression of the two proteins have been identified such as bile duct epithelium (PEPT1), glia cells and epithelia of the choroid plexus, lung and mammary gland (PEPT2) [11].
• As was the case with Caco-2 cells and SKPT cells, the uptake of glycylsarcosine induced in HeLa cells by PEPT 1 cDNA and PEPT 2 cDNA was inhibitable by cyclacillin and cefadroxil [17].
• hPEPT1 is present in the lung cell line Calu-3 and may participate in lung peptide clearance [18].

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

• Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes [25].
• Cisplatin treatment affected neither PEPT1 nor GLUT1 activity [3].
• Peptide transporter proteins (TAP1) were detected in various degrees by immunocytochemistry [26].
• Peptide transporter genes (TAP) polymorphisms and genetic susceptibility to rheumatoid arthritis [27].
• Analysis of the high-throughput genomic sequence (HTGS) database revealed that hPEPT1 and hPEPT1-RF are splice variants encoded by the same gene located in chromosome 13, consisting of 24 exons. hPEPT1 is encoded by 23 exons and hPEPT1-RF by 6 exons [28].

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