Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition

Jahaun Azadmanesh; Katelyn Slobodnik; Lucas R. Struble; William E. Lutz; Leighton Coates; Kevin L. Weiss; Dean A.A. Myles; Thomas Kroll; Gloria E.O. Borgstahl

doi:10.1038/s41467-024-50260-w

Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition

Jahaun Azadmanesh, Katelyn Slobodnik, Lucas R. Struble, William E. Lutz, Leighton Coates, Kevin L. Weiss, Dean A.A. Myles, Thomas Kroll, Gloria E.O. Borgstahl

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Abstract

Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting superoxide (O₂^●−) to molecular oxygen (O₂) and hydrogen peroxide (H₂O₂) with proton-coupled electron transfers (PCETs). Human MnSOD has evolved to be highly product inhibited to limit the formation of H₂O₂, a freely diffusible oxidant and signaling molecule. The product-inhibited complex is thought to be composed of a peroxide (O₂²⁻) or hydroperoxide (HO₂⁻) species bound to Mn ion and formed from an unknown PCET mechanism. PCET mechanisms of proteins are typically not known due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the mechanism, we combine neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states of the enzyme to reveal the positions of all the atoms, including hydrogen, and the electronic configuration of the metal ion. The data identifies the product-inhibited complex, and a PCET mechanism of inhibition is constructed.

Original language	English
Article number	5973
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-50260-w
State	Published - Dec 2024

Funding

This research was supported by the NIH (R01-GM145647) and NASA EPSCoR (NE\u221280NSSC17M0030 and NE-NNX15AM82A) grants awarded 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.

Funders	Funder number
Basic Energy Sciences
Biological and Environmental Research
Oak Ridge National Laboratory
University of Nebraska-Lincoln
SLAC National Accelerator Laboratory
U.S. Department of Energy
Scientific User Facilities Division
NASA EPSCoR	80NSSC17M0030, NE-NNX15AM82A
Fred and Pamela Buffett NCI	P30CA036727
National Institutes of Health	R01-GM145647
National Institute of General Medical Sciences	P30GM133894
Office of Science	DE-AC02-76SF00515

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title = "Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition",

abstract = "Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting superoxide (O2●−) to molecular oxygen (O2) and hydrogen peroxide (H2O2) with proton-coupled electron transfers (PCETs). Human MnSOD has evolved to be highly product inhibited to limit the formation of H2O2, a freely diffusible oxidant and signaling molecule. The product-inhibited complex is thought to be composed of a peroxide (O22−) or hydroperoxide (HO2−) species bound to Mn ion and formed from an unknown PCET mechanism. PCET mechanisms of proteins are typically not known due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the mechanism, we combine neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states of the enzyme to reveal the positions of all the atoms, including hydrogen, and the electronic configuration of the metal ion. The data identifies the product-inhibited complex, and a PCET mechanism of inhibition is constructed.",

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AU - Borgstahl, Gloria E.O.

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Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition

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