Nitrosyldioxyl radical

Another possibility that deserves further investigation is the formation of a transient and reversible complex of nitric oxide and oxygen to yield the nitro-syldioxyl radical (ONOO ) The nitrosyldioxyl radical may be stabilized by hydrogen bonding to water, which may prevent it from activating guanylate cyclase (Beckman and Koppenol, 1992). 

When nitric oxide is present in much lower concentrations than oxygen, the formation of nitrogen dioxide shown in Reaction 4 is initiated by the reversible reaction of nitric oxide with molecular oxygen to form nitrosyldioxyl radical. 

The subsequent rate-limiting or slowest step is then the addition of a second nitric oxide to nitrosyldioxyl radical... 

The nitrosyldioxyl radical has largely been ignored in the chemical literature because it is relatively unstable in air. Nitrosyldioxyl radical is approximately 4.8 kcal/mol less stable than nitric oxide and oxygen in the gas phase less than 0.1% of the nitric oxide will combine with oxygen under standard conditions in the gas phase. Although present in low concentrations, the infrared spectrum of nitrosyldioxyl radical has been reported in the gas phase (Guillory and Johnston, 1965) and ab initio quantum mechanics calculations have been performed (Boehm and Lohr, 1989). 

However, thermodynamic and quantum mechanical calculations indicate that the stability of nitrosyldioxyl radical will be greatly increased by hydrogen bonding with water (Beckman and Koppenol, 1992). TTie reason for this increased stability can be readily visualized in Fig. 7. Nitrosyldioxyl radical is most stable when bent into the cis (or C-shaped) conformation (Boehm and Lohr, 1989). In this conformation, the lobes of the highest occupied molecular orbital from... 

Possible equilibrium involved in the rapid activation of soluble guanylate cyclase and the slower inactivation by reaction of nitric oxide with oxygen. Nitric oxide dissolved in membranes may be more stable than in solution, because the nitrosyldioxyl radical cannot be stabilized by hydrogen bonding to water. 

The spontaneous reaction of nitric oxide with thiols is slow at physiological pH and the final product under anaerobic conditions is not a nitrosothiol (Pryor et al., 1982). The reaction is slow because it involves the conjugate base of the thiol (R—S"). At pH 7.0, the oxidation of cysteine by nitric oxide required 6 hr to reach completion and yields RSSR and N 2O as the products. The synthetic preparation of nitrosothiols usually involves the addition of nitrosonium ion from acidified nitrite to the thiol, or oxidation of the thiol with nitrogen dioxide under anaerobic conditions in organic solvents. Nitric oxide will form nitrosothiols by reaction with ferric heme groups, such as found in metmyoglobin or methemoglobin (Wade and Castro, 1990). It is also possible that nitrosyldioxyl radical also reacts with thiols to form a nitrosothiol. 

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. 

Reaction 7.24 describes the formation of a new covalent bond between bound NO and 02 (Figure 7.15). Rather than proposing the formation of a Fe(II)-nitrosyldioxyl radical, the DFT computations suggest a two-electron reduction for 02, with the binding of a peroxynitrite anion to Fe(III). 

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