Document Detail

Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein S-nitrosothiols.
MedLine Citation:
PMID:  16277524     Owner:  NLM     Status:  MEDLINE    
The nitrosation of cellular thiols has attracted much interest as a regulatory mechanism that mediates some of the pathophysiological effects of nitric oxide (NO). In cells, virtually all enzymes contain cysteine residues that can be subjected to S-nitrosation, whereby this process often acts as an activity switch. Nitrosation of biological thiols is believed to be mediated by N2O3, metal-nitrosyl complexes, and peroxynitrite. To date, however, enzymatic pathways for S-denitrosation of proteins have not been identified. Herein, we present experimental evidence that two ubiquitous cellular dithiols, thioredoxin and dihydrolipoic acid, catalyze the denitrosation of S-nitrosoglutathione, S-nitrosocaspase 3, S-nitrosoalbumin, and S-nitrosometallothionenin to their reduced state with concomitant generation of nitroxyl (HNO), the one-electron reduction product of NO. In these reactions, formation of NO and HNO was assessed by ESR spectrometry, potentiometric measurements, and quantification of hydroxylamine and sodium nitrite as end reaction products. Nitrosation and denitrosation of caspase 3 was correlated with its proteolytic activity. We also report that thioredoxin-deficient HeLa cells with mutated thioredoxin reductase denitrosate S-nitrosothiols less efficiently. We conclude that both thioredoxin and dihydrolipoic acid may be involved in the regulation of cellular S-nitrosothiols.
Detcho A Stoyanovsky; Yulia Y Tyurina; Vladimir A Tyurin; Deepthi Anand; Dhara N Mandavia; David Gius; Juliana Ivanova; Bruce Pitt; Timothy R Billiar; Valerian E Kagan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  127     ISSN:  0002-7863     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2005 Nov 
Date Detail:
Created Date:  2005-11-09     Completed Date:  2006-01-25     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15815-23     Citation Subset:  IM    
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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MeSH Terms
Caspase 3
Caspases / metabolism
Electron Spin Resonance Spectroscopy
Hela Cells
Hydroxylamine / analysis
Molecular Weight
Nitric Oxide / metabolism
Nitrogen Oxides / metabolism
Nitroso Compounds / metabolism
Proteins / metabolism*
S-Nitrosoglutathione / metabolism
S-Nitrosothiols / metabolism*
Serum Albumin, Bovine / metabolism
Sodium Nitrite / analysis
Thioctic Acid / analogs & derivatives*,  metabolism
Thioredoxin-Disulfide Reductase / genetics,  metabolism
Thioredoxins / metabolism*
Grant Support
Reg. No./Substance:
0/Nitrogen Oxides; 0/Nitroso Compounds; 0/Proteins; 0/S-Nitrosothiols; 0/S-nitrosoalbumin; 0/Serum Albumin, Bovine; 10102-43-9/Nitric Oxide; 14332-28-6/nitroxyl; 462-20-4/dihydrolipoic acid; 52500-60-4/Thioredoxins; 57564-91-7/S-Nitrosoglutathione; 62-46-4/Thioctic Acid; 7632-00-0/Sodium Nitrite; 7803-49-8/Hydroxylamine; EC Reductase; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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