Abstract
Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O2∙−) to molecular oxygen (O2) and hydrogen peroxide (H2O2) 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 pKa 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.
| Original language | English |
|---|---|
| Article number | 1887 |
| Journal | Nature Communications |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2025 |
Funding
This research was supported by the NIH (R01-GM145647) and NASA EPSCoR (NE−80NSSC17M0030 and NE-NNX15AM82A) to G.E.O.B. The UNMC Structural Biology Core Facility was funded by the Fred and Pamela Buffett NCI Cancer Center Support Grant (P30CA036727). The research at Oak Ridge National Laboratory (ORNL) Spallation Neutron Source was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. The Office of Biological and Environmental Research supported research at ORNL Center for Structural Molecular Biology (CSMB) using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Quantum chemical computations were completed using the Holland Computing Center of the University of Nebraska, which receives support from the Nebraska Research Initiative.