Structure and function of eukaryotic peptide transporters

Abstract

The cotransport of protons and peptides is now recognised as a major route by which dietary nitrogen is absorbed from the intestine, and filtered protein reabsorbed in the kidney. Recently, molecular biology has had a very substantial impact on the study of peptide transport, and here we review the molecular and functional information available within the framework of physiology. To this end we consider not only the mammalian peptide transporters and their tissue distribution and regulation but also those from other species (including Caenorhabditis elegans) which make up the proton-dependent oligopeptide transport superfamily. In addition, understanding the binding requirements for transported substrates may allow future design and targeted tissue delivery of peptide and peptidomimetic drugs. Finally, we aim to highlight some of the less well understood areas of peptide transport, in the hope that it will stimulate further research into this challenging yet exciting topic.

PepT1-Mediated Tripeptide KPV Uptake Reduces Intestinal Inflammation

“…This is mediated via the H + -coupled oligopeptide transporter (PepT1) which is located at the apical membrane of intestinal epithelial cells (IEC) and which cotransports peptides and H + (2). The specificity of hPepT1 is broad and includes many di-and tripeptides in addition to various peptide-derived drugs (3)(4)(5)(6)(7)(8). PepT1 is mainly expressed in brush-border membranes of enterocytes in the small intestine, in proximal tubular cells of the S1 segment of the kidney, and in bile-duct epithelial cells (4,5,(9)(10)(11)(12)(13)(14)(15).…”

Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 In Vitro cell culture model, and multiple human tissues

“…Peptides and peptide-based agents, due largely to multiple side chain functionalities, tend to be polar molecules that do not readily traverse biological barriers via passive diffusion (1,(7)(8)(9)(10)(11). In the past several years, considerable work has been performed to explore the active peptide transporters that are known to facilitate peptide transport (5,12,13). Several human small oligopeptide transporters are now known, including peptide transporter 1 (PepT1) and human intestinal peptide transporter 1 (HPT1) (5,(14)(15)(16).…”

Characterisation of intestinal peptide transporter of the Antarctic haemoglobinless teleostChionodraco hamatus

“…2A), with a relatively low substrate specificity, as it has generally been found for the PepT1 isoforms studied to date ( Fig. 2B; Ganapathy et al, 1994;Liang et al, 1995;Thamotharan et al, 1996;Maffia et al, 1997;Verri et al, 2000;Meredith and Boyd, 2000). Proton influx shows a hyperbolic function with substrate concentration typical of a carrier-mediated process (Fig.…”

“…These transporters are driven by electric potential gradients and couple the transport of oligopeptides with H + . In addition to their natural substrates, peptide transporters are also capable of binding and translocating many pharmacologically active peptidomimetics (Amidon et al, 1994;Tsuji, 1995;Meredith and Boyd, 2000). Two H + /peptide cotransporters, a lower affinity PepT1 and a higher affinity PepT2, have been cloned and functionally characterised in higher vertebrates (Fei et al, 1994;Liu et al, 1995).…”

“…The [ 3 H]-D-Phe-L-Ala uptake in waterinjected oocytes can be explained by a simple diffusion mechanism and/or the presence of an endogenous transport activity in the frog oocyte membrane. Icefish peptide transporter appears to share the same low substrate specificity as the mammalian protein PepT1 (Meredith and Boyd, 2000), characterised by its ability to transport a variety of di-/tripeptides. The capacity of unlabeled peptide (glycylglutamine, Gly-Gln) to compete with radiolabeled D-Phe-L-Ala for the uptake process in mRNA-injected oocytes (Fig.…”