Peroxynitrite (ONOO-) is a relatively long-lived toxic compound formed from the reaction of the radical species superoxide and nitric oxide. The latter is formed in vivo from the enzymatic conversion of arginine to citrulline in a variety of tissues, and is involved in vasodilation, cell communication and cell regulation. The superoxide anion contributes to the inactivation of nitric oxide. Peroxynitrite is not stable and isomerizes to nitrate. The anion or the protonated form (ONOOH, pkalpha = 6.8) oxidizes biomolecules through multiple, presently poorly understood, pathways. These pathways may involve the hydroxyl radical, OH (from homolysis of the peroxide bond in peroxynitrous acid), the nitronium cation, NO2+ (from heterolysis), or peroxynitrite itself. The elucidation of these pathways is the broad aim of the proposed studies. Peroxynitrite formation in vivo is important for the mechanism of oxidative damage, because this reaction is inhibitable by superoxide dismutase, unlike the pathway to the hydroxyl radical which via hydrogen peroxide and Fenton chemistry, is prevented by catalase. Peroxynitrite is of physiological importance especially near activated macrophages and neutrophils where significant amounts of superoxide and nitric oxide are produced. Peroxynitrous acid is known to both hydroxylate and nitrate aromatic compounds. Such derivatives of polynuclear aromatic compounds are among the most potent environmental mutagens. Peroxynitrous acid may therefore play a role in the production of such mutagens in the lung. Since the mechanisms of these reactions may involve radical species, it is important to determine whether radical scavengers or antioxidants interfere with the nitration and hydroxylation of aromatic compounds. Furthermore, the reactivity of peroxy-nitrite toward superoxide and ferrocytochrome c, which would interfere with the assay for superoxide, has not been studied. Based on our thermodynamic and kinetic analysis of the decay of peroxynitrite the working hypotheses of this proposal are that peroxynitrite is a strongly oxidizing species, and that the decay of peroxynitrous acid does not result in """"""""free"""""""" NO2+ or OH. The following projects are deemed most relevant to the oxyradical field: (1) A novel synthesis of peroxynitrite from nitric oxide and superoxide that models the putative biosynthetic route. (2) The determination of the mechanism of hydroxylation and nitration aromatic compounds. (3) A study of the reactions of peroxynitrite with ascorbate and vitamin E. (4) The reactivity of peroxynitrite towards superoxide and ferrocytochrome c.
| Koppenol, W H (1994) Thermodynamic considerations on the formation of reactive species from hypochlorite, superoxide and nitrogen monoxide. Could nitrosyl chloride be produced by neutrophils and macrophages? FEBS Lett 347:5-8 |
| Bullesbach, E E; Schwabe, C (1994) Functional importance of the A chain loop in relaxin and insulin. J Biol Chem 269:13124-8 |
| Koppenol, W H (1993) The centennial of the Fenton reaction. Free Radic Biol Med 15:645-51 |
