Peroxynitrite ion

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

Peroxynitrite ion. This ion, produced by oxidizing azide solutions by O3 or NH2CI by O2, apparently exists in methanol solutions for weeks. Its presence has been demonstrated by its u.v. absorption spectrum, but no solid salts have been obtained. The structure (0=N—0—0) has been suggested. ... 

S.V. Lymar and J.K. Hurst, Rapid reaction between peroxynitrite ion and carbon dioxide implications for biological activity, J. Am. Chem. Soc., 117 (1995) 8867. 

In mammals and other vertebrates, nitrogen monoxide plays several important roles. For example, it acts as agaseous mediator in producing such responses as dilation of blood vessels, relaxation of smooth muscle, and inhibition of platelet aggregation, and it acts as a neurotransmitter in the central nervous systems. In certain cells of the immune system it is converted to the peroxynitrite ion ("0-0-N=0), which has activity against pathogens. 

If reactants are involved in protolytic equilibria, there is often a proton ambiguity as to the state of protonation of the actual reacting species. In the case of the reaction of peroxynitrite ion with carbon dioxide, Lymar and Hurst were able to show that the reactants are COj and ONOj". The overall system can be described by the following scheme ... 

Because NO is a radical, we expect it to be reactive. Its half-life is estimated at approximately 1-5 s, so it needs to be synthesized often in the cell. As we saw in Case study 10.1, there is a biochemical price to be paid for the reactivity of biological radicals. Like Oj, NO participates in some reactions that are not beneficial to the cell. Indeed, the radicals O2 and NO combine to form the peroxynitrite ion (5) ... 

The peroxynitrite ion is a reactive oxygen species that damages proteins, DNA, and hpids, possibly leading to heart disease, amyotrophic lateral sclerosis (Lou Gehrig s disease), Alzheimer s disease, and multiple sclerosis. We note that the structure of the ion is consistent with the bonding scheme of Fig. 10.35 because the unpaired electron in NO is slightly more localized on the N atom, we expect that atom to form a bond with an O atom from the O2 ion. 

Write the Lewis structure for the peroxynitrite ion, ONOO". Label each atom with its state of hybridization and specify the composition of each of the different types of bond. 

This mode of superoxide-dependent free radical-mediated damaging activity remains an important one although the nature of the generated reactive species (free hydroxyl radicals or perferryl, or ferryl ions) is still obscure. However, after the discovery of the fact that many cells produce nitric oxide in relatively large amounts (see below), it became clear that there is another and possibly a more portent mechanism of superoxide-induced free radical damage, namely, the formation of highly reactive peroxynitrite. 

The rate constant for Reaction (3) is in the range of 108 to 1091 mol-1s-1 [20]. Therefore, Reactions (3) and (4) may significantly enhance the concentration of ferrous ions and make Fenton reaction a better competitor with the peroxynitrite-inducible damage [21]. The formation of hydroxyl radicals in the reaction of superoxide with mitochondrial aconitase has... 

Interestingly, that the reactions of peroxynitrite with phenols were accelerated in the presence of ferric and cupric ions [112,114]. Until now, there seems no explanation of transition metal effects in these reactions. We just wonder if it is possible that ferric and cupric ions are able to oxidize peroxynitrite ... 

Rodenas et al. [77] studied PMN-stimulated lipid peroxidation of arachidonic acid. As MDA formation was inhibited both with L-arginine (supposedly due to the formation of excess NO) and DTPA (an iron ion chelator), it was concluded that about 40% of peroxidation was initiated by hydroxyl radicals formed via the Fenton reaction and about 60% was mediated by peroxynitrite. However, it should be noted that the probability of hydroxyl radical-initiated lipid peroxidation is very small (see above). Phagocyte-mediated LDL oxidation is considered below. 

However, at high rates of nitric oxide flux, the formation of nitrated and oxidized products became insensitive to the presence of catalase or MPO inhibitors but increasingly inhibited by SOD, suggesting the participation of peroxynitrite. (It is interesting that Reaction (30) might be a one-electron reduction of hydrogen peroxide by nitrite ion. If such a process really takes... 

Flavonoids exhibit protective action against LDL oxidation. It has been shown [145] that the pretreatment of macrophages and endothelial cells with tea flavonoids such as theaflavin digallate diminished cell-mediated LDL oxidation probably due to the interaction with superoxide and the chelation of iron ions. Quercetin and epicatechin inhibited LDL oxidation catalyzed by mammalian 15-lipoxygenase, and are much more effective antioxidants than ascorbic acid and a-tocopherol [146], Luteolin, rutin, quercetin, and catechin suppressed copper-stimulated LDL oxidation and protected endogenous urate from oxidative degradation [147]. Quercetin was also able to suppress peroxynitrite-induced oxidative modification of LDL [148],... 

In 1998, Schlotte et al. [259] showed that uric acid inhibited LDL oxidation. However, subsequent studies showed that in the case of copper-initiated LDL oxidation uric acid behaves itself as prooxidant [260,261]. It has been suggested that in this case uric acid enhances LDL oxidation by the reduction of cupric into cuprous ions and that the prooxidant effect of uric acid may be prevented by ascorbate. On the other hand, urate radicals formed during the interaction of uric acid with peroxyl radicals are able to react with other compounds, for example, flavonoids [262], and by that participate in the propagation of free radical damaging reactions. In addition to the inhibition of oxygen radical-mediated processes, uric acid is an effective scavenger of peroxynitrite [263]. 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

Cuprous and cupric ions may substitute for ferrous and ferric ions in the Haber-Weiss reaction [22]. Peroxynitrite can be formed from the reaction of NO with 02 ... 

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