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Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration



Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration



Archives of Biochemistry and Biophysics 507(2): 304-309



Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O₂(.)⁻) into H₂O₂ and O₂. 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. The catalytic cycle of the enzyme is a "ping-pong" mechanism involving Mn³+/Mn²+. It is known that nitration of Y34 is responsible for enzyme inactivation, and that this protein oxidative modification is found in tissues undergoing inflammatory and degenerative processes. However, the molecular basis about MnSOD tyrosine nitration affects the protein catalytic function is mostly unknown. In this work we strongly suggest, using computer simulation tools, that Y34 nitration affects protein function by restricting ligand access to the active site. In particular, deprotonation of 3-nitrotyrosine increases drastically the energetic barrier for ligand entry due to the absence of the proton. Our results for the WT and selected mutant proteins confirm that the phenolic moiety of Y34 plays a key role in assisting superoxide migration.

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Accession: 053142157

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PMID: 21167124

DOI: 10.1016/j.abb.2010.12.011


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