Disease relevance of SLC15A2

• PEPT2 is also responsible for the transport of delta-aminolevulinic acid, which is used for photodynamic therapy and the diagnostics of pulmonary neoplasms [1].
• Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung [2].
• However, PEPT2 mRNA appears to be absent from two glioma cell lines [3].

High impact information on SLC15A2

• 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 [4].
• Recently, cultured cell lines of intestinal and renal origin that express PEPT 1 and PEPT 2 have been identified [5].
• 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 [6].
• Detailed kinetic analysis has provided unequivocal evidence for participation of PEPT 2 in SKPT cells in the transport of the dipeptide glycylsarcosine and the aminocephalosporin cephalexin [6].
• 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 [6].

Chemical compound and disease context of SLC15A2

• Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures [3].
• In C6 and F98 glioma cells, [(14)C]GlySar uptake was markedly reduced ( approximately 96-98%) compared to that in neonatal astrocytes and this was reflected by an absence of PEPT2 mRNA expression [3].

Biological context of SLC15A2

• Also, zebrafish pept2 exhibited 23 exons and 22 introns, whereas human and rodent pept2 genes contain 22 exons and 21 introns only [7].
• We characterized the functional properties of a novel zebrafish peptide transporter orthologous to mammalian and avian PEPT2, described its gene (pept2) structure, and determined mRNA tissue distribution [7].
• We then compared transepithelial transport of the prototypical substrate (3)H-glycylsarcosine in all donor cultures in the absence and presence of known inhibitors of hPEPT2 to ascertain the phenotype of functionally expressed hPepT2 in the upper airway epithelium [8].
• Real-time PCR analysis of the hPepT2 mRNA message revealed no significant differences among genotypes. hPEPT2 was expressed on the apical membrane in all donor specimens, demonstrated by cell surface biotinylation and Western analysis (104 kD) [8].
• Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions [9].
• Epidermal growth factor (EGF) inhibited the expression of PEPT2 and the uptake of the dipeptide glycylsarcosine in the rat kidney proximal cell line SKPT0193 Cl.2 [10].

Anatomical context of SLC15A2

• 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 [11].
• These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium [12].
• Transport of the phosphonodipeptide alafosfalin by the H+/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells [13].
• Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2 [14].
• PEPT2 is a high-affinity H+/dipeptide transporter expressed in kidney, brain, lung, and mammary gland [9].

Associations of SLC15A2 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 [13].
• An array of inhibitors included dipeptides, beta-lactam antibiotics, bestatin, and ACE inhibitors. hPEPT2 exhibited saturable Michaelis-Menten-type kinetic parameters for GlySar, corroborating previously reported values for K(T) and J(max) [8].
• The physiological role of PEPT2 in kidney is to reabsorb small peptides generated by luminal peptidases [9].
• Transfection of PDZK1 increased the uptake of glycylsarcosine by PEPT2, whereas such stimulation was not observed for PEPT2 with the last four amino acids deleted [15].
• 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 [16].

Physical interactions of SLC15A2

• PDZK1 directly interacts with PEPT2, exerting functional regulation of its transporting activity [15].

Regulatory relationships of SLC15A2

• 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 [17].
• Furthermore, we clarified the mechanism of enhanced glycylsarcosine (Gly-Sar) transport activity in PEPT2-expressing HEK293 cells after the PDZK1 coexpression [18].

Other interactions of SLC15A2

• The current findings imply the localization of PEPT2 within a protein network constructed from PDZK1 and other transporter proteins [15].
• In contrast, PEPT2 and PHT2 were expressed only in bovine and human retina, and PEPT1 could not be detected [19].
• Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes [20].

Analytical, diagnostic and therapeutic context of SLC15A2

• 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 [11].
• The expression of the R57H variant at the plasma membrane was confirmed by indirect immunofluorescence in Xenopus oocytes, suggesting that the loss of transport function of hPEPT2 R57H was not due to a change in membrane protein expression [21].
• RT-PCR and rapid amplification of cDNA ends (RACE) were then used to clone monkey PEPT1 and PEPT2 [22].
• Molecular cloning of PEPT 2, a new member of the H+/peptide cotransporter family, from human kidney [23].
• Thyroidectomy increased Pept1 and Pept2 mRNA in male rat kidney; such increases were abolished by thyroid hormone replacement [24].

References