Binding specificity of the l-arginine transport systems in mouse macrophages and human cells overexpressing the cationic amino acid transporter hCAT-1

Dániel Eros, László Orfi, Ildikó Csuka, György Kéri, András Hrabák

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The uptake of l-arginine into mouse peritoneal macrophages can be inhibited by numerous amino acids and derivatives. Kinetic studies showed an almost entirely competitive inhibition for both cationic and neutral amino acids and derivatives suggesting that the comparison of their binding specificity by using a quantitative structure-activity relationship (QSAR) study is reasonable. The properties of the most efficient inhibitors were the following: the length of the aliphatic side chain, a general structural similarity to l-arginine (>0.79), cationic character, l-configuration, the presence of an α-amino group (with a mean pKa of 9.41), the van der Waals volume (mean 225 Å3) and a low logP value (mean: -2.99). The significance of four other descriptors (neutral character, presence and the pKa of an α-carboxyl group, and the presence of a modified guanidino group) is much lower. Similar results were obtained for the hCAT-1 cell line, but the significance of the descriptors was slightly different. The l-configuration, van der Waals volume, the low logP value and the length of aliphatic side chain were the most significant, while the pKa value of the side chain (mean pKa = 11.6) was found to be more important than that of the α-amino group. In addition, the general similarity to l-arginine, the presence of an amino group in the terminal position of the side chain (Orn, Lys) and the basic character were significant descriptors, while the significance of the acidity is negligibly low. As a final conclusion, the following descriptors were found to be important generally for the cationic transporters: the van der Waals volume, hydrophobicity (log P); l-configuration; the size of the side chain; the general similarity to l-arginine; the presence of an α-amino group; the general basicity of the molecule; the pK a values of the α-amino group (in macrophages) or that of the side chain (in CAT-1 cells). These descriptors can be regarded as the general structurally important binding characteristics of the cationic amino transporters.

Original languageEnglish
Pages (from-to)483-492
Number of pages10
JournalAmino Acids
Volume36
Issue number3
DOIs
Publication statusPublished - Mar 1 2009

Keywords

  • Arginine
  • Binding specificity
  • Cationic amino acid transporter
  • Inhibition
  • Quantitative structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

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