Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 50, Issue 1, Pages 14-26Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.10.694
Keywords
Oxidative stress; Glutamate-cysteine ligase; 4-Hydroxynonenal; Glutathione; Antioxidants; Free radicals
Funding
- NIH [CA75316, CA90473, ES07033, R37AA09300, F31AA016710]
- NATIONAL CANCER INSTITUTE [R01CA090473, R29CA075316] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES007033] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R37AA009300, F31AA016710] Funding Source: NIH RePORTER
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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. (C) 2010 Elsevier Inc. All rights reserved.
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