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Neutron Structure of Peroxide-Soaked Tyr34Phe MnSOD
Structural highlights
DiseaseSODM_HUMAN Genetic variation in SOD2 is associated with susceptibility to microvascular complications of diabetes type 6 (MVCD6) [MIM:612634. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. FunctionSODM_HUMAN Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.[1] Publication Abstract from PubMedHuman manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide ( O2â- ) to molecular oxygen (O(2)) and hydrogen peroxide (H(2)O(2)) with proton-coupled electron transfers (PCETs). A key catalytic residue, Tyr34, determines the activity of human MnSOD and also becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. Tyr34 has an unusual pK(a) due to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. Neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations in oxidized, reduced and product inhibited enzymatic states shed light on the role of Tyr34 in MnSOD catalysis. The data identify the contributions of Tyr34 in MnSOD activity that support mitochondrial function and give a thorough characterization of how a single tyrosine modulates PCET catalysis. Product inhibition occurs by an associative displacement mechanism. The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase.,Azadmanesh J, Slobodnik K, Struble LR, Lovelace JJ, Cone EA, Dasgupta M, Lutz WE, Kumar S, Natarajan A, Coates L, Weiss KL, Myles DAA, Kroll T, Borgstahl GEO Nat Commun. 2025 Feb 22;16(1):1887. doi: 10.1038/s41467-025-57180-3. PMID:39987263[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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