Consequences of MnSOD interactions with nitric oxide: Nitric oxide dismutation and the generation of peroxynitrite and hydrogen peroxide

Abstract

The present study demonstrates that manganese superoxide dismutase (MnSOD) (Escherichia coli), binds nitric oxide (√NO) and stimulates its decay under both anaerobic and aerobic conditions. The results indicate that previously observed MnSOD-catalyzed √NO disproportionation (dismutation) into nitrosonium (NO+) and nitroxyl (NO− ) species under anaerobic conditions is also operative in the presence of molecular oxygen. Upon sustained aerobic exposure to √NO, MnSOD-derived NO− species initiate the formation of peroxynitrite (ONOO− ) leading to enzyme tyrosine nitration, oxidation and (partial) inactivation. The results suggest that both ONOO− decomposition and ONOO− -dependent tyrosine residue nitration and oxidation are enhanced by metal centre-mediated catalysis. We show that the generation of ONOO− is accompanied by the formation of substantial amounts of H2O2. MnSOD is a critical mitochondrial antioxidant enzyme, which has been found to undergo tyrosine nitration and inactivation in various pathologies associated with the overproduction of √NO. The results of the present study can account for the molecular specificity of MnSOD nitration in vivo. The interaction of √NO with MnSOD may represent a novel mechanism by which MnSOD protects the cell from deleterious effects associated with overproduction of √NO.