Peroxynitrite reaction with nitric oxide

Apoptosis is induced by various intra- and extracellular stimuli, and recently nitric oxide was reported to induce apoptosis in cultured cerebellar granule cells and cultured cortical neurons. The toxicity of nitric oxide is mainly ascribed to peroxynitrite, a reaction product of nitric oxide with superoxide (Figure 13.8). Cells producing an increased amount of SOD (superoxide, superoxide oxidoreductase EC 1.15.1.1) are resistant to nitric oxide-mediated apoptosis. In contrast, superoxide levels that have been increased by downregulation of Cu,Zn-SOD lead to apoptotic cell death in PC 12 cells, which required the reaction with nitric oxide to generate peroxynitrite. Peroxynitrite itself was found to induce apoptosis in PC12 cells and in cultured cortical neurons. 

Pfeiffer, S., Gorren, ACF, Schmidt, K, Werner, ER, Hansert, B, Bohle, DS, and Mayer, B (1997). Metabolic fate of peroxynitrite in aqueous solution. Reaction with nitric oxide and pH-dependent decomposition to nitrite and oxygen in a 2 1 stoichiometry. 7B/o/ Chem 272(6) 3465-3470. 

Tortora V, Quijano C et al (2007) Mitochondrial aconitase reaction with nitric oxide, S-nitrosoglutathione, and peroxynitrite mechanisms and relative contributions to aconitase inactivation. Free Radic Biol Med 42 1075-1088... 

Reaction of nitric oxide with superoxide is undoubtedly the most important reaction of nitric oxide, resulting in the formation of peroxynitrite, one of the main reactive species in free radical-mediated damaging processes. This reaction is a diffusion-controlled one, with the rate constant (which has been measured by many workers, see, for example, Ref. [41]), of about 2 x 109 1 mol-1 s-1. Goldstein and Czapski [41] also measured the rate constant for Reaction (11) ... 

Nitric oxide is a physiological substrate for mammalian peroxidases [myeloperoxide (MPO), eosinophil peroxide, and lactoperoxide), which catalytically consume NO in the presence of hydrogen peroxide [60], On the other hand, NO does not affect the activity of xanthine oxidase while peroxynitrite inhibits it [61]. Nitric oxide suppresses the inactivation of CuZnSOD and NO synthase supposedly via the reaction with hydroxyl radicals [62,63]. On the other hand, SOD is able to modulate the nitrosation reactions of nitric oxide [64]. 

In the last 10 to 15 years, many experimental and theoretical studies have been dedicated to the study of peroxynitrite reactions. Free radical and non-free radical mechanisms of peroxynitrite action have been proposed, which were discussed in numerous studies (see for example, Refs. [103-110]). In accord with non-radical mechanism an activated form of peroxynitrous acid is formed in the reaction of superoxide with nitric oxide, which is able to react with biomolecules without the decomposition to HO and N02 radicals. 

Deleterious protein cross-linking can also be induced by reactive nitrogen species (RNS) such as peroxynitrite ONOO formed by the reaction of superoxide with nitric oxide (NO). The cross-links are formed between tyrosine residues following nitration by peroxynitrite (Sitte, 2003). Carnosine appears to play roles not only in NO generation but also in protection against excess NO production by inducible nitric oxide synthetase (NOS), thereby preventing ONOO-mediated protein modification (Fontana et ah, 2002). Evidence for a carnosine-NO adduct has also been published (Nicoletti et al., 2007). 

The reaction of nitric oxide with superoxide dismutase is a simple reversible equilibrium, whereas the catalytic cycle with superoxide involves a two step sequence. Consequently, superoxide dismutase may be reduced by superoxide and then react with nitric oxide to form nitroxyl anion. Nitroxyl anion may react with molecular oxygen to form peroxynitrite anion (ONOO"). 

Trapping of peroxynitrite from rat alveolar macrophages by superoxide dismutase. Although the fotmation of peroxynitrite is drawn as superoxide reacting with nitric oxide in the extracellular space, the actual reactions may be a combination of the pathways shown in Fig. 40. 

The direct reaction of superoxide with nitric oxide is only one of at least four possible pathways that can form peroxynitrite (Fig. 40). For example, superoxide should also efficiently reduce nitrosyldioxyl radical to peroxynitrite. Alternatively, nitric oxide may be reduced to nitroxyl anion, which reacts with oxygen to form peroxynitrite. Superoxide dismutase could even catalyze the formation of peroxynitrite, since reduced (Cu or cuprous) superoxide dismutase can reduce nitric oxide to nitroxyl anion (Murphy and Sies, 1991). Thus, superoxide might first reduce superoxide dismutase to the cuprous form, with nitric oxide reacting with reduced superoxide dismutase to produce nitroxyl anion. A fourth pathway to form peroxynitrite is by the rapid reaction of nitrosonium ion (NO" ) with hydrogen peroxide. This is a convenient synthetic route for experimental studies (Reed et al., 1974), but not likely to be physiologically relevant due to the low concentrations of hydrogen peroxide and the difficulty of oxidizing nitric oxide to nitrosonium ion. 

Four routes to form peroxynitrite from nitric oxide. The reaction of nitric oxide with superoxide is only one mechanism leading to the formation of peroxynitrite. Supetoxide could also reduce the nitrosyidioxyl radical. If nitric oxide is directly reduced to nitroxyl anion, it will react with molecular oxygen to form peroxynitrite. At acidic pH, nitrite may form nitrous acid and nitrosonium ion, which reacts with hydrogen peroxide to form peroxynitrite. 

An important physiological reaction of nitric oxide (NO) is its interaction with the superoxide ion (O2-) to form the peroxynitrite ion (ONOO-). 

Pryor W. A. and Squadrito G. L. (1995). The chemistry of peroxynitrite a product from the reaction of nitric oxide with superoxide. Am. J. Physiol 268 L699-L722. 

M14. Mehl, M., Daiber, A., Herold, S., Shoun, H., and Ullrich, V., Peroxynitrite reaction with heme proteins. Nitric Oxide 3, 142-152 (199). 

Figure 11.7. Reactions of nitric oxide involving sulfhydryl groups, a Hypothetical mechanism of nitrosothiol formation. The superoxide anion generated may reaet with a seeond moleeule of NO to yield peroxynitrite. b Migration of nitroso groups between sulfhydryls. This is experimentally illustrated in Figure 11.9b.

In addition to oxidants that are generated by the Fenton reaction, superoxide radicals (-02 ) readily react with nitric oxide (NO-), generating peroxynitrite anion (ONOO ) in the following reaction ... 

It was recently reported that the tryptophan residues of proteins could be nitrated by the action of peroxynitrite (67). This reactive nitrogen species (RNS) is generated from the reaction of nitric oxide with superoxide at a rate that is ten times greater than the destruction of superoxide by dismutases. The authors propose that the nitration of tryptophan, although less common than tyrosine nitration, could serve to modulate the function of some proteins. However, at this time the in vivo evidence for tryptophan nitration by RNS has yet to be reported. 

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