Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite |
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Authors: | Sebastián Carballal Silvina Bartesaghi Rafael Radi |
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Institution: | 1. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay;2. Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay;3. Departamento de Educación Médica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay |
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Abstract: | BackgroundPeroxynitrite, the product of the reaction between superoxide radicals and nitric oxide, is an elusive oxidant with a short half-life and a low steady-state concentration in biological systems; it promotes nitroxidative damage.Scope of reviewWe will consider kinetic and mechanistic aspects that allow rationalizing the biological fate of peroxynitrite from data obtained by a combination of methods that include fast kinetic techniques, electron paramagnetic resonance and kinetic simulations. In addition, we provide a quantitative analysis of peroxynitrite production rates and conceivable steady–state levels in living systems.Major conclusionsThe preferential reactions of peroxynitrite in vivo include those with carbon dioxide, thiols and metalloproteins; its homolysis represents only < 1% of its fate. To note, carbon dioxide accounts for a significant fraction of peroxynitrite consumption leading to the formation of strong one-electron oxidants, carbonate radicals and nitrogen dioxide. On the other hand, peroxynitrite is rapidly reduced by peroxiredoxins, which represent efficient thiol-based peroxynitrite detoxification systems. Glutathione, present at mM concentration in cells and frequently considered a direct scavenger of peroxynitrite, does not react sufficiently fast with it in vivo; glutathione mainly inhibits peroxynitrite-dependent processes by reactions with secondary radicals. The detection of protein 3-nitrotyrosine, a molecular footprint, can demonstrate peroxynitrite formation in vivo. Basal peroxynitrite formation rates in cells can be estimated in the order of 0.1 to 0.5 μM s− 1 and its steady-state concentration at ~ 1 nM.General significanceThe analysis provides a handle to predict the preferential fate and steady-state levels of peroxynitrite in living systems. This is useful to understand pathophysiological aspects and pharmacological prospects connected to peroxynitrite. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. |
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Keywords: | ABTS2 &minus 2 2&prime -azinobis (3-ethylbenzthiazoline-6-sulfonic acid) DTPA diethylenetriaminepentaacetic acid DMPO 5 5-dimethyl-1-pyrroline-N-oxide MPO myeloperoxidase EPO eosinophil peroxidase NT 3-nitrotyrosine NOS nitric oxide synthase SOD superoxide dismutase GSH glutathione Prx peroxiredoxin |
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