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Human Mn-superoxide dismutase inactivation by peroxynitrite: a paradigm of metal-catalyzed tyrosine nitration in vitro and in vivo
Metallomics ( IF 3.4 ) Pub Date : 2018-04-16 00:00:00 , DOI: 10.1039/c7mt00348j
Verónica Demicheli 1, 2, 3, 4, 5 , Diego M. Moreno 6, 7, 8, 9, 10 , Rafael Radi 1, 2, 3, 4, 5
Affiliation  

Human MnSOD is a homotetramer and represents an essential mitochondrial antioxidant enzyme, which catalyzes the dismutation of superoxide radicals (O2˙) at near diffusion-controlled rates. Under a variety of disease conditions and in the 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 the kinetic aspects of the formation of peroxynitrite in the 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 × 105 M−1 s−1 per tetramer at pH = 7.4 and T = 37 °C) and the catalysis of nitration at the active site are disclosed. Then, we analyze at the atomic level of detail how a single oxidative post-translational modification in the enzyme, namely the 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.

中文翻译:

过氧亚硝酸盐使人锰超氧化物歧化酶失活:金属催化酪氨酸硝化的体外体内范例

人类的MnSOD是同源四聚体,并代表一个基本线粒体抗氧化酶,其催化超氧化物自由基的歧化(O 2 ˙ - )在接近扩散控制的速率。在各种疾病状况和在老化的过程中,一氧化氮(NO)可胜出的MnSOD和反应带O 2 ˙ - ,得到有效的氧化剂过氧化亚硝酸盐(ONOO -)。然后,过氧亚硝酸盐可在活性位点酪氨酸34上促进MnSOD的区域特异性硝化,从而使酶失活。在这篇综述中,我们评估了在存在MnSOD时过氧亚硝酸盐形成的动力学方面以及过氧亚硝酸盐介导的MnSOD硝化的生物化学机理。尤其是,Mn原子在酶与过氧亚硝酸盐(k = 1.0×10 5 M -1 s -1每个四聚体,pH = 7.4和T= 37℃)并公开了在活性位点的硝化催化作用。然后,我们在原子的详细水平上分析了酶中的单个氧化后翻译修饰(即酪氨酸34的硝化)如何导致酶失活。在这里,动力学,分子,结构生物学和计算研究相结合,以从功能和结构的角度合理化体外体内过氧亚硝酸盐依赖性的MnSOD酪氨酸硝化的特异性和影响。
更新日期:2018-04-16
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