The Mechanism of the Reaction of Peroxynitrite with Mn-Superoxide Dismutase Investigated by Computer Simulation

DRUSIN, SALVADOR I.; RADI, RAFAEL; ESTRÍN, DARÍO A.; MARTI, MARCELO A.; MORENO, DIEGO M.

Chascomús

Congreso; IV Latin American Meeting on Biological Inorganic Chemistry - V WOQUIBIO; 2014

p { margin-bottom: 0cm; direction: ltr; line-height: 120%; text-align: justify; widows: 2; orphans: 2; }p.western { font-family: "Times",serif; font-size: 12pt; }p.cjk { font-size: 12pt; }p.ctl { font-family: "Times New Roman"; font-size: 12pt; }a:link { color: rgb(0, 0, 255); }a.western:link { }a.cjk:link { }a.ctl:link { font-family: "Times New Roman"; } INTRODUCTION Manganese superoxide dismutase (MnSOD), an antioxidant enzyme present in the mitochondrial matrix of mammalian cells, catalyzes the dismutation of superoxide radicals (O2?-) into oxygen and hydrogen peroxide at diffusion-controlled rates.1 The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinated by H26, H74, H163, D159 and one ?OH ion or H2O molecule (Fig. 1).The catalytic cycle of the enzyme is a ?ping-pong? mechanism involving Mn3+/Mn2+. Tyrosine 34 (Tyr34) has proven to be a key residue in the catalytic process since its mutation to Phe/Val or its oxidative postranslational modification to 3-nitrotyrosine result in inactivation of the enzyme. It has been widely reported that nitration and inactivation of MnSOD is performed by peroxynitrite in vitro and in vivo.4 In particular, the reaction of MnSOD with peroxynitrite leads to the exclusive nitration of the critical Tyr345, in a process that is site-specifically directed by a reaction of the oxidant with the transition metal center. In this work we performed a detailed mechanistic study of the peroxynitrite reaction with MnSOD and the subsequent enzyme nitration by using computer simulations techniques.