Structure-function studies of SLC15 peptide transporters
type: CreativeWork
description: The proton coupled oligopeptide transporter (POT) family of proteins includes mammalian PepT1 (SLC15A1; high capacity, low affinity) and PepT2 (SLC15A2; low capacity, high affinity) transporters which are involved in the co-transport of protons and di- and tri- peptides and drugs similar in structure (peptidomimetics). PepT1, and to a lesser extent PepT2, have therefore gained attention due to their role in determining the absorption, retention and elimination of transported drugs. In this study three novel prodrug-carriers namely Amino-Isobutynyl-Alanyl-Serine (Aib), Cyclo-Leucyl-Serine (cLu) and Alanyl-[ψCS-NH]-Serine (Thio) were tested for PepT1 mediated transport in PepT1 expressing Xenopus laevis oocytes and differentiated Caco-2 cells grown on Transwell® inserts. The cLu- carrier was found to exhibit higher binding affinity towards PepT1 compared to Aib- and Thio- carriers and to transport the conjugated drugs both in the oocyte and Caco-2 assays. The Aib-and Thio- carriers exhibited similar affinities towards PepT1 and were also found to be transported. Therefore all three carriers were shown to have the potential to deliver a range of conjugated drugs/compounds with differing physicochemical properties through PepT1. Homology models for PepT1/2 have been proposed due to the lack of crystal structure data available for mammalian peptide transporters, based on recent crystal structures of the bacterial POT family members. Although offering invaluable insights, all the bacterial transporters lack the mammalian large extracellular domain (ECD) between transmembrane (TMD) 9 and 10. Human PepT1 (hPepT1) and hPepT2 mutants with their ECD deleted (ECDΔ) or swapped (hPepT1-ECD2, hPepT2-ECD1) were tested for functional effects. The hPepT1-ECDΔ and hPepT1-ECD2 transporters were found not to express, showing a critical structural role for the ECD in hPepT1. In contrast, hPepT2-ECDΔ and hPepT2-ECD1 were found to function as the wild type hPepT2. In a collaborative projec…
abstract: The proton coupled oligopeptide transporter (POT) family of proteins includes mammalian PepT1 (SLC15A1; high capacity, low affinity) and PepT2 (SLC15A2; low capacity, high affinity) transporters which are involved in the co-transport of protons and di- and tri- peptides and drugs similar in structure (peptidomimetics). PepT1, and to a lesser extent PepT2, have therefore gained attention due to their role in determining the absorption, retention and elimination of transported drugs. In this study three novel prodrug-carriers namely Amino-Isobutynyl-Alanyl-Serine (Aib), Cyclo-Leucyl-Serine (cLu) and Alanyl-[ψCS-NH]-Serine (Thio) were tested for PepT1 mediated transport in PepT1 expressing Xenopus laevis oocytes and differentiated Caco-2 cells grown on Transwell® inserts. The cLu- carrier was found to exhibit higher binding affinity towards PepT1 compared to Aib- and Thio- carriers and to transport the conjugated drugs both in the oocyte and Caco-2 assays. The Aib-and Thio- carriers exhibited similar affinities towards PepT1 and were also found to be transported. Therefore all three carriers were shown to have the potential to deliver a range of conjugated drugs/compounds with differing physicochemical properties through PepT1. Homology models for PepT1/2 have been proposed due to the lack of crystal structure data available for mammalian peptide transporters, based on recent crystal structures of the bacterial POT family members. Although offering invaluable insights, all the bacterial transporters lack the mammalian large extracellular domain (ECD) between transmembrane (TMD) 9 and 10. Human PepT1 (hPepT1) and hPepT2 mutants with their ECD deleted (ECDΔ) or swapped (hPepT1-ECD2, hPepT2-ECD1) were tested for functional effects. The hPepT1-ECDΔ and hPepT1-ECD2 transporters were found not to express, showing a critical structural role for the ECD in hPepT1. In contrast, hPepT2-ECDΔ and hPepT2-ECD1 were found to function as the wild type hPepT2. In a collaborative projec…
author: Senan, Anish
language: en
date published: 2015
date modified: 2026-07-24T03:43:16Z
provider: Oxford Brookes University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Oxford Brookes University

PropertyValue
property ID: DOI
value: 10.24384/9xg1-da24