Connecting the chemical and biological properties of nitric oxide

Nitric oxide (NO(•); nitrogen monoxide) is known to be a critical regulator of cell and tissue function through mechanisms that utilize its unique physicochemical properties as a small and uncharged free radical with limited reactivity. Here, the basic chemistry and biochemistry of NO(•) are summarized through the description of its chemical reactivity, biological sources, physiological and pathophysiological levels, and cellular transport. The complexity of the interactions of NO(•) with biotargets, which vary from irreversible second-order reactions to reversible formation of nonreactive and reactive nitrosyl complexes, is noted. Emphasis is placed on the kinetics and physiological consequences of the reactions of NO(•) with its better characterized biotargets. These targets are soluble guanylate cyclase (sCG), oxyhemoglobin/hemoglobin (HbO(2)/Hb) and cytochrome c oxidase (CcOx), all of which are ferrous heme proteins that react with NO(•) with second-order rate constants approaching the diffusion limit (k(on) approximately 10(7) to 10(8) M(-1) s(-1)). Likewise, the biotarget responsible for the most described pathophysiological actions of NO(•) is the superoxide anion radical (O(2)(•-)), which reacts with NO(•) in a diffusion-controlled process (k approximately 10(10) M(-1) s(-1)). The reactions of NO(•) with proteins containing iron-sulfur clusters ([FeS]) remain little studied and the reported rate constants of the first steps of these reactions are considerable (k approximately 10(5) M(-1) s(-1)). Not surprisingly, the interactions of proteins containing iron-sulfur clusters with NO(•) remain ambiguous and have been associated with both physiological and pathophysiological effects. Overall, it is emphasized that any claimed biological action of NO(•) should be connected with its interaction with kinetically relevant biotargets. Although reactivity toward biotargets is only one of the factors contributing to cellular and tissue responses mediated by short-lived species, such as NO(•) and other oxygen-derived species, it is a critical factor. Therefore, taking reactivity into account is important to advancing our knowledge on redox signaling mechanisms.