2-Thioxanthines Are Mechanism-based Inactivators of Myeloperoxidase That Block Oxidative Stress during Inflammation
| Autor: | Anna-Karin Tidén, Stefan Lundquist, Louisa V. Forbes, Nicholas J. Magon, Guy N. L. Jameson, Henrietta Norman, Staffan Schmidt, Alexandra Bernlind, Françoise Auchère, Susanne Gustavsson, Mats Svensson, Anthony J. Kettle, Revathy Senthilmohan, Per-Olof Markgren, Louise N. Paton, Tove Sjögren, Håkan Eriksson |
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| Rok vydání: | 2011 |
| Předmět: |
genetic structures
Hypochlorous acid Neutrophils Peritonitis Crystallography X-Ray medicine.disease_cause Biochemistry Mice chemistry.chemical_compound polycyclic compounds medicine Animals Humans Enzyme Inhibitors Molecular Biology Heme Peroxidase 3-Chlorotyrosine Inflammation chemistry.chemical_classification Reactive oxygen species biology Chemistry Superoxide Cell Biology Disease Models Animal Oxidative Stress Xanthines Myeloperoxidase Enzymology biology.protein sense organs Oxidation-Reduction Oxidative stress |
| Zdroj: | Journal of Biological Chemistry. 286:37578-37589 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m111.266981 |
| Popis: | Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation. |
| Databáze: | OpenAIRE |
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