Document Detail


Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal.
MedLine Citation:
PMID:  20970495     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
4-Hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product formed during oxidative stress that can alter protein function via adduction of nucleophilic amino acid residues. 4-HNE detoxification occurs mainly via glutathione (GSH) conjugation and transporter-mediated efflux. This results in a net loss of cellular GSH, and restoration of GSH homeostasis requires de novo GSH biosynthesis. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate-cysteine ligase (GCL), a heterodimeric holoenzyme composed of a catalytic (GCLC) and a modulatory (GCLM) subunit. The relative levels of the GCL subunits are a major determinant of cellular GSH biosynthetic capacity and 4-HNE induces the expression of both GCL subunits. In this study, we demonstrate that 4-HNE can alter GCL holoenzyme formation and activity via direct posttranslational modification of the GCL subunits in vitro. 4-HNE directly modified Cys553 of GCLC and Cys35 of GCLM in vitro, which significantly increased monomeric GCLC enzymatic activity, but reduced GCL holoenzyme activity and formation of the GCL holoenzyme complex. In silico molecular modeling studies also indicate these residues are likely to be functionally relevant. Within a cellular context, this novel posttranslational regulation of GCL activity could significantly affect cellular GSH homeostasis and GSH-dependent detoxification during periods of oxidative stress.
Authors:
Donald S Backos; Kristofer S Fritz; James R Roede; Dennis R Petersen; Christopher C Franklin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-10-21
Journal Detail:
Title:  Free radical biology & medicine     Volume:  50     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-03     Completed Date:  2011-05-09     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14-26     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pharmaceutical Sciences, Graduate Program in Toxicology, School of Pharmacy, University of Colorado at Denver, Aurora, CO 80045, USA.
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MeSH Terms
Descriptor/Qualifier:
Aldehydes / chemistry,  metabolism,  pharmacology*
Animals
Cysteine / metabolism
Cysteine Proteinase Inhibitors / pharmacology
Glutamate-Cysteine Ligase / chemistry,  metabolism*
Humans
Lipid Peroxidation / drug effects,  physiology
Lysine / metabolism
Mass Spectrometry
Metabolic Detoxication, Phase I / physiology
Mice
Oxidative Stress / drug effects,  physiology
Protein Processing, Post-Translational / drug effects*
Protein Subunits / analysis,  chemistry,  metabolism
Stereoisomerism
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA75316/CA/NCI NIH HHS; CA90473/CA/NCI NIH HHS; ES07033/ES/NIEHS NIH HHS; F31 AA016710-03/AA/NIAAA NIH HHS; F31AA016710/AA/NIAAA NIH HHS; R01 CA090473-05/CA/NCI NIH HHS; R29 CA075316-07/CA/NCI NIH HHS; R37 AA009300-16/AA/NIAAA NIH HHS; R37AA09300/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Aldehydes; 0/Cysteine Proteinase Inhibitors; 0/Protein Subunits; 29343-52-0/4-hydroxy-2-nonenal; 52-90-4/Cysteine; 56-87-1/Lysine; EC 6.3.2.2/Glutamate-Cysteine Ligase; EC 6.3.2.2/glutamate-cysteine ligase modifier subunit, human
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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