Document Detail

Inactivation of the glutamine/amino acid transporter ASCT2 by 1,2,3-dithiazoles: Proteoliposomes as a tool to gain insights in the molecular mechanism of action and of antitumour activity.
MedLine Citation:
PMID:  23010140     Owner:  NLM     Status:  Publisher    
The ASCT2 transport system catalyses a sodium-dependent antiport of glutamine and other neutral amino acids which is involved in amino acid metabolism. A library of 1,2,3-dithiazoles was designed, synthesized and evaluated as inhibitors of the glutamine/amino acid ASCT2 transporter in the model system of proteoliposomes reconstituted with the rat liver transporter. 15 of the tested compounds at concentration of 20μM or below, inhibited more than 50% the glutamine/glutamine antiport catalysed by the reconstituted transporter. These good inhibitors bear a phenyl ring with electron withdrawing substituents. The inhibition was reversed by 1,4-dithioerythritol indicating that the effect was likely owed to the formation of mixed sulfides with the protein's Cys residue(s). A dose-response analysis of the most active compounds gave IC(50) values in the range of 3-30μM. Kinetic inhibition studies indicated a non-competitive inhibition, presumably because of a potential covalent interaction of the dithiazoles with cysteine thiol groups that are not located at the substrate binding site. Indeed, computational studies using a homology structural model of ASCT2 transporter, suggested as possible binding targets, Cys-207 or Cys-210, that belong to the CXXC motif of the protein.
Francesca Oppedisano; Marco Catto; Panayiotis A Koutentis; Orazio Nicolotti; Lorena Pochini; Maria Koyioni; Antonellina Introcaso; Sophia S Michaelidou; Angelo Carotti; Cesare Indiveri
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-22
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  -     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Dipartimento di Biologia Cellulare Università della Calabria, via P. Bucci 4 c, 87036 Arcavacata di Rende (CS), Italy.
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