title: Analysis of the transport properties of side chain modified dipeptides at the mammalian peptide transporter PEPT1.
abstract: This study was initiated to examine systematically the effect of side chain modifications at dipeptides on their transport via PEPT1. We synthesized a series of Xaa(R)-Ala and Ala-Xaa(R) dipeptides with the functional groups of the side chains modified by structurally different blocking groups R. Recognition and transport of these derivatives by PEPT1 was measured in Caco-2 cells, in transgenic Pichia pastoris cells and in Xenopus laevis oocytes expressing PEPT1. The dipeptide derivatives displayed K(i) values between 0.002 and 4 mM. Electrophysiological analyses showed that the Ala-Xaa(R) derivatives were transported by PEPT1. In contrast, most Xaa(R)-Ala derivatives--although recognized--did not show significant transport rates. Substitution of a terminal phenyl residue in the side chain blocking group by a p-nitrophenyl residue enhanced the affinity of several dipeptide derivatives for interaction with PEPT1. However, none of these compounds showed electrogenic transport in oocytes. With a K(i) value of 0.002 mM, Lys[Z(NO(2))]-Val displayed the highest affinity to PEPT1 ever reported. We conclude that the transport of side chain modified dipeptides into enterocytes depends (a) on the position of the modified trifunctional amino acid in the dipeptide, (b) the distance between its alpha-carbon and the side chain blocking group and (c) the hydrophobic character of the side chain modification.
authors.affiliation: Institute of Biochemistry, Department of Biochemistry/Biotechnology, and Membrane Transport Group, Biozentrum, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, D-06120 Halle, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Knütter
authors.forename: Bianka
authors.initials: B
authors.lastname: Hartrodt
authors.forename: Stephan
authors.initials: S
authors.lastname: Theis
authors.forename: Martin
authors.initials: M
authors.lastname: Foltz
authors.forename: Matthias
authors.initials: M
authors.lastname: Rastetter
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandsch
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000074011:Peptide Transporter 1; D011817:Rabbits; D027981:Symporters; D014982:Xenopus laevis
chemical_list: D002352:Carrier Proteins; D004151:Dipeptides; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters