Crystal Structure of the Antioxidant Enzyme Glutathione Reductase Inactivated by Peroxynitrite

As part of our studies on the nitric oxide-related pathology of cerebral malaria, we show that the antioxidative enzyme glutathione reductase (GR) is inactivated by peroxynitrite, with GR from the malarial parasite Plasmodium falciparum being more sensitive than human GR. The crystal structure of mo...

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Published inThe Journal of biological chemistry Vol. 277; no. 4; pp. 2779 - 2784
Main Authors Savvides, Savvas N., Scheiwein, Michael, Böhme, Catharina C., Arteel, Gavin E., Karplus, P. Andrew, Becker, Katja, Schirmer, R. Heiner
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 25.01.2002
American Society for Biochemistry and Molecular Biology
Subjects
Animals
Antioxidants - chemistry
Binding Sites
Catalysis
Crystallography, X-Ray
Disulfides - chemistry
Dose-Response Relationship, Drug
Flavins - chemistry
glutathione reductase
Glutathione Reductase - chemistry
Glutathione Reductase - metabolism
Humans
Hydrogen-Ion Concentration
Kinetics
Models, Molecular
Nitrogen - metabolism
Peptides - chemistry
Peroxynitrous Acid - metabolism
Peroxynitrous Acid - pharmacology
Plasmodium falciparum
Plasmodium falciparum - metabolism
Protein Binding
Signal Transduction
Spectrophotometry
Toluene - analogs & derivatives
Toluene - chemistry
Tyrosine - chemistry
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Summary:As part of our studies on the nitric oxide-related pathology of cerebral malaria, we show that the antioxidative enzyme glutathione reductase (GR) is inactivated by peroxynitrite, with GR from the malarial parasite Plasmodium falciparum being more sensitive than human GR. The crystal structure of modified human GR at 1.9-Å resolution provides the first picture of protein inactivation by peroxynitrite and reveals that this is due to the exclusive nitration of 2 Tyr residues (residues 106 and 114) at the glutathione disulfide-binding site. The selective nitration explains the impairment of binding the peptide substrate and thus the nearly 1000-fold decrease in catalytic efficiency (kcat/Km) of glutathione reductase observed at physiologic pH. By oxidizing the catalytic dithiol to a disulfide, peroxynitrite itself can act as a substrate of unmodified and bisnitrated P. falciparum glutathione reductase.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
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ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M108190200