Reaction of NO with Superoxide

More recently, however, it has been demonstrated on thermodynamic grounds that HOONO itself is a potent oxidizing agent that may have -OH-like reactivity and is not a precursor for -OH formation (Koppenol et al., 

Regardless, OONO has been shown to oxidize a variety of biological 

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Figure I. Reaction of NO with superoxide (02 0form the toxic peroxynitrite (0=N00 ).

The stable free radical nitric oxide (NO) has an important role as a biological messenger. The reaction of NO with superoxide (O2 ) forms the powerful oxidant peroxynitrite (ONOO ), and a mechanism for the reaction of ONOO resulting in the abstraction of H from C—H bonds is shown (equations 109, 110). The formation of HO from the spontaneous decomposition of peroxynitrite, and of COJ radicals from CO2 catalyzed decomposition of peroxynitrite, have been demonstrated. ... 

The above examples point out at the direct stimulation of apoptosis by nitric oxide. At the same time, the exclusively rapid reaction of NO with superoxide always suggests the possibility of peroxynitrite participation in this process [141] correspondingly, the role peroxynitrite in the stimulation of apoptosis has been considered. Bonfoco et al. [144] has found that the producers of low peroxynitrite concentrations during the exposure of cortical neurons to the low level of NMDA or the use of peroxynitrite donors resulted in an apoptosis in neurons, while the high concentrations of peroxynitrite induced necrotic cell damage. The formation of peroxynitrite is apparently responsible for NO-stimulated apoptosis in superoxide-generating transformed fibroblasts because nontransformed cells, which do not produce superoxide, were not affected by nitric oxide [145]. It is of interest that proapoptotic effect of peroxynitrite may depend on the cell type. Thus, the formation of peroxynitrite enhanced the NO-induced apoptosis in glomerular endothelial cells, while superoxide inhibited the formation of ceramide and apoptosis in these cells exposed to nitric oxide probably due to peroxynitrite formation... 

Fluie RE, Padmaja S (1993) The reaction of NO with superoxide. Free Rad ResCommun 18 195-199 FluieRE, Brault D, Neta P (1987) Rate constants for one-electron oxidation by theCFjCV, CCI3O2, and CBr302 radicals in aqueous solutions. Chem Biol Interact 62 227-235 Inouye S (1984) Site-specific cleavage of double-strand DNA by hydroperoxide of linoleic acid. FEBS Lett 172 231-234... 

Huie, R., Padmaja, S. The reaction of NO with superoxide. Free Radio. Res. Commun. 1993,18 195-199. 

In recent years it has become apparent that the reaction of NO with superoxide radical is possibly the most likely reaction to occur in vivo. Peroxynitrite is a strong oxidant and the cytotoxicity previously ascribed to NO or superoxide alone may actually be due to their reaction and degradation products. The reactions are shown below. 

The recent discovery that nitric oxide (NO) is a signaling molecule ubiquitous in tissue has raised the question that one of the pathways contributing to superoxide toxicity in vivo might be the formation of the highly reactive peroxynitrite anion (ONOO") produced by spontaneous reaction of NO with superoxide (77). It has been shown that perox5mitrite is a substrate of SOD (78). The interaction of SOD with peroxynitrite leads to a permanent modification of the enzyme at Tyr-108. The structural determination of the peroxynitrite-modified Cu2Zn2SOD has been conducted on monoclinic crystals (79). The structure confirms that peroxynitrite permanently modifies the Tyr-108 side chain with formation of 3-nitroty-rosine. The modification does not alter active site residues and the enzyme remains fully active. 

Pryor, W. and Squadrito, G.L. (1995) The chemistry of peroxynitrite a product from the reaction of NO with superoxide. Am. J. Physiol. 268, L699-722. 

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