The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology

Mammalian members of the SLC15 family are electrogenic transporters that utilize the proton-motive force for uphill transport of short chain peptides and peptido-mimetics into a variety of cells. The prototype transporters of this family are PEPT1 (SLC15A1) and PEPT2 (SLC15A2), which mediate the uptake of peptide substrates into intestinal and renal epithelial cells. 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). Both proteins can transport essentially every possible di- and tripeptide regardless of the substrate's net charge, but operate stereoselectively. Based on peptide-like structures, various drugs and prodrugs are transported as well, allowing efficient intestinal absorption of the compounds via PEPT1. In kidney tubules both peptide transporters can mediate the renal reabsorption of the filtered compounds thus affecting their pharmacokinetics. Recently, two new peptide transporters, PHT1 (SLC15A4) and PHT2 (SLC15A3), were identified in mammals. They possess an overall amino acid identity with the PEPT-series of 20% to 25%. PHT1 and PHT2 were shown to transport free histidine and certain di- and tripeptides, but it is not yet clear whether they are located on the plasma membrane or represent lysosomal transporters for the proton-dependent export of histidine and dipeptides from lysosomal protein degradation into the cytosol.