Crystal structure of the antioxidant enzyme glutathione reductase inactivated by peroxynitrite
| Autor: | Catharina C. Böhme, Michael Scheiwein, Gavin E. Arteel, Savvas N. Savvides, P. Andrew Karplus, R. Heiner Schirmer, Katja Becker |
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| Rok vydání: | 2001 |
| Předmět: |
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Molecular Antioxidant Nitrogen medicine.medical_treatment Glutathione reductase Plasmodium falciparum Crystallography X-Ray Biochemistry Antioxidants Catalysis chemistry.chemical_compound Oxidoreductase Nitration Glutaredoxin Flavins Peroxynitrous Acid medicine Animals Humans Disulfides Molecular Biology chemistry.chemical_classification Binding Sites Dose-Response Relationship Drug Cell Biology Glutathione Hydrogen-Ion Concentration Kinetics Enzyme Glutathione Reductase chemistry Spectrophotometry Tyrosine Peptides Peroxynitrite Protein Binding Signal Transduction Toluene |
| Zdroj: | The Journal of biological chemistry. 277(4) |
| ISSN: | 0021-9258 |
| Popis: | 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-A 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 (k cat/K m) 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. |
| Databáze: | OpenAIRE |
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