Azadmanesh Jahaun, Slobodnik Katelyn, Struble Lucas R, Lovelace Jeffrey J, Cone Erika A, Dasgupta Medhanjali, Lutz William E, Kumar Siddhartha, Natarajan Amarnath, Coates Leighton, Weiss Kevin L, Myles Dean A A, Kroll Thomas, Borgstahl Gloria E O
Eppley Institute for Research in Cancer and Allied Diseases, 986805 Nebraska Medical Center, Omaha, NE, USA.
Second Target Station, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN, USA.
Nat Commun. 2025 Feb 22;16(1):1887. doi: 10.1038/s41467-025-57180-3.
Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide ( ) to molecular oxygen (O) and hydrogen peroxide (HO) 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 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.
人类锰超氧化物歧化酶（MnSOD）通过质子耦合电子转移（PCET）将超氧化物（ ）转化为分子氧（O）和过氧化氢（HO），在控制活性氧（ROS）水平方面发挥着关键作用。一个关键的催化残基Tyr34决定了人类MnSOD的活性，并且在与线粒体功能障碍相关的各种疾病中会因硝化作用而发生翻译后失活。Tyr34由于靠近锰金属而具有不寻常的pK，并且经历循环去质子化和质子化事件以促进MnSOD的电子转移。在氧化、还原和产物抑制的酶状态下进行的中子衍射、X射线光谱和量子化学计算揭示了Tyr34在MnSOD催化中的作用。这些数据确定了Tyr34在支持线粒体功能的MnSOD活性中的贡献，并全面表征了单个酪氨酸如何调节PCET催化。产物抑制通过缔合取代机制发生。
