Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide

Abstract

The roles of superoxide (O 2 •−), peroxynitrite, and carbon dioxide in the oxidative chemistry of nitric oxide ( NO) are reviewed. The formation of peroxynitrite from NO and O 2 •− is controlled by superoxide dismutase (SOD), which can lower the concentration of superoxide ions. The concentration of CO 2 in vivo is high ( ca. 1 mM), and the rate constant for reaction of CO 2 with −OONO is large (pH-independent k = 5.8 × 10 4 M −1s −1). Consequently, the rate of reaction of peroxynitrite with CO 2 is so fast that most commonly used scavengers would need to be present at very high, near toxic levels in order to compete with peroxynitrite for CO 2. Therefore, in the presence of physiological levels of bicarbonate, only a limited number of biotargets react directly with peroxynitrite. These include heme-containing proteins such as hemoglobin, peroxidases such as myeloperoxidase, seleno-proteins such as glutathione peroxidase, proteins containing zinc-thiolate centers such as the DNA-binding transcription factors, and the synthetic antioxidant ebselen. The mechanism of the reaction of CO 2 with −OONO produces metastable nitrating, nitrosating, and oxidizing species as intermediates. An analysis of the lifetimes of the possible intermediates and of the catalysis of peroxynitrite decompositions suggests that the reactive intermediates responsible for reactions with a variety of substrates may be the free radicals NO 2 and CO 3 •−. Biologically important reactions of these free radicals are, for example, the nitration of tyrosine residues. These nitrations can be pathological, but they also may play a signal transduction role, because nitration of tyrosine can modulate phosphorylation and thus control enzymatic activity. In principle, it might be possible to block the biological effects of peroxynitrite by scavenging the free radicals NO 2 and CO 3 •−. Because it is difficult to directly scavenge peroxynitrite because of its fast reaction with CO 2, scavenging of intermediates from the peroxynitrite/CO 2 reaction would provide an additional way of preventing peroxynitrite-mediated cellular effects. The biological effects of peroxynitrite also can be prevented by limiting the formation of peroxynitrite from NO by lowering the concentration of O 2 •− using SOD or SOD mimics. Increased formation of peroxynitrite has been linked to Alzheimer’s disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, and other diseases.