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.

• Nitric oxide
• MnSOD
• nitroxyl
• peroxynitrite
• tyrosine nitration
• hydrogen peroxide

Notes

^†The authors dedicate this paper to Prof. A. M. Michelson on the occasion of his 80th birthday in 2006.

The authors dedicate this paper to Prof. A. M. Michelson on the occasion of his 80th birthday in 2006.