Chemical biology of peroxynitrite: kinetics, diffusion, and radicals.
Peroxynitrite is formed by the very fast reaction of nitric oxide and superoxide radicals, a reaction that kinetically competes with other routes that chemically consume or physically sequester the reagents. It can behave either as an endogenous cytotoxin toward host tissues or a cytotoxic effector molecule against invading pathogens, depending on the cellular source and pathophysiological setting. Peroxynitrite is in itself very reactive against a few specific targets that range from efficient detoxification systems, such as peroxiredoxins, to reactions eventually leading to enhanced radical formation (e.g., nitrogen dioxide and carbonate radicals), such as the reaction with carbon dioxide. Thus, the chemical biology of peroxynitrite is dictated by the chemical kinetics of its formation and decay and by the diffusion across membranes of the species involved, including peroxynitrite itself. On the other hand, most durable traces of peroxynitrite passing (such as 3-nitrotyrosine) are derived from radicals formed from peroxynitrite by routes that represent extremely low-yield processes but that have potentially critical biological consequences. Here we have reviewed the chemical kinetics of peroxynitrite as a biochemical transient species in order to estimate its rates of formation and decay and then its steady-state concentration in different intra- or extracellular compartments, trying to provide a quantitative basis for its reactivity; additionally, we have considered diffusion across membranes to locate its possible effects. Finally, we have assessed the most successful attempts to intercept peroxynitrite by pharmacological intervention in their potential to increment the existing biological defenses that routinely deal with this cytotoxin.
Ferrer-Sueta
Gerardo
G
Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11800, Uruguay.
Radi
Rafael
R
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D002245:Carbon Dioxide / Q000737:chemistry / Q000378:metabolism; D004058:Diffusion; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010544:Peroxidases / Q000737:chemistry / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism
D000975:Antioxidants; D006420:Hemeproteins; D013481:Superoxides; D002245:Carbon Dioxide; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D010544:Peroxidases; D019001:Nitric Oxide Synthase; D010100:Oxygen