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Human Mn-superoxide dismutase inactivation by peroxynitrite: A paradigm of metal-catalyzed tyrosine nitration in vitro and in vivo

Abstract

Human MnSOD is a homotetramer and represents an essential mitochondrial antioxidant enzyme, which catalyzes the dismutation of superoxide radical (O2•−) at near diffusion-controlled rates. Under a variety of disease conditions and in process of aging, nitric oxide (.NO) can outcompete MnSOD and react with O2•− to yield the potent oxidant, peroxynitrite (ONOO-). Then, peroxynitrite can promote the regio-specific nitration of MnSOD at active site tyrosine 34, which turns the enzyme inactive. In this review we assess kinetic aspects of the formation of peroxynitrite in presence of MnSOD and the biochemical mechanisms of peroxynitrite-mediated MnSOD nitration. In particular, the central role of the Mn atom in the reaction of the enzyme with peroxynitrite (k = 1.0 x 105 M-1s-1 per tetramer at pH = 7,4 and T = 37oC) and the catalysis of nitration at the active site are disclosed. Then, we analyze with atomic level of detail how a single oxidative post-translational modification in the enzyme, namely nitration of tyrosine 34, results in enzyme inactivation. Herein, kinetic, molecular, structural biology and computational studies are integrated to rationalize the specificity and impact of peroxynitrite-dependent MnSOD tyrosine nitration in vitro and in vivo from both functional and structural perspectives.

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Publication details

The article was received on 27 Dec 2017, accepted on 16 Apr 2018 and first published on 16 Apr 2018


Article type: Critical Review
DOI: 10.1039/C7MT00348J
Citation: Metallomics, 2018, Accepted Manuscript
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    Human Mn-superoxide dismutase inactivation by peroxynitrite: A paradigm of metal-catalyzed tyrosine nitration in vitro and in vivo

    V. Demicheli, D. Moreno and R. Radi, Metallomics, 2018, Accepted Manuscript , DOI: 10.1039/C7MT00348J

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