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Received for publication June 24, 2004.
Revised July 21, 2004.
Accepted for publication July 27, 2004.
PEPT2 is a high-affinity H + /dipeptide transporter expressed in kidney, brain, lung and mammary gland. The physiologic role of PEPT2 in kidney is to reabsorb small peptides generated by luminal peptidases. PEPT2 is also a transporter for peptide-like drugs such as penicillins and cephalosporins. We have conducted a haplotype analysis of 27 SNPs located in or near exons of the human gene encoding hPEPT2, SLC15A2, using genotyping data from 247 genomic DNA samples from the Coriell collection. Our analysis reveals that the hPept2 gene has a >6 kb sequence block with at least 10 abundant polymorphisms in almost complete linkage disequilibrium. As a result, only two main hPEPT2 variants exist (hPEPT2*1 and *2) with several phased amino acid substitutions, present in substantial frequencies in all ethnic groups tested. hPEPT2*1 and *2 displayed similar Vmax values for GlySar, but differed significantly in their K m values (83±16 µM and 233±38 µM, respectively). Moreover, hPEPT2*1 and *2 differed in their pH sensitivity for H+ /GlySar transport. In addition, hPEPT2*1 and *2 generated varying levels of mRNA in 9 heterozygous kidney tissue samples, including one allele expressing no detectable mRNA, suggesting the presence of cis-acting polymorphisms affecting transcription or mRNA processing. The results indicate that polymorphisms in the gene encoding hPEPT2 can alter substrate transport and therefore could affect drug disposition in vivo.
Key words:
Haplotype, Peptide transporter, allele-specific, protein variant, single nucleotide polymorphism, uptake
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