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bioRxiv · 10.1101/2024.01.26.577433

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

Azadmanesh, J.·Slobodnik, K.·Struble, L.·Lutz, W. E.·Coates, L.·Weiss, K. L.·Myles, D. A. A.·Kroll, T.·Borgstahl, G. E.
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Abstract

Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting O2[bullet]- to O2 and H2O2 with proton-coupled electron transfers (PCETs). Since changes in mitochondrial H2O2 concentrations are capable of stimulating apoptotic signaling pathways, human MnSOD has evolutionarily gained the ability to be highly inhibited by its own product, H2O2. A separate set of PCETs is thought to regulate product inhibition, though mechanisms of PCETs are typically unknown 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 underlying mechanism, we combined neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states to reveal the all-atom structures and electronic configuration of the metal. The data identifies the product-inhibited complex for the first time and a PCET mechanism of inhibition is constructed.

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Azadmanesh, J., Slobodnik, K., Struble, L., Lutz, W. E., Coates, L., Weiss, K. L., Myles, D. A. A., Kroll, T., Borgstahl, G. E.. 2024-01-27. Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition. https://doi.org/10.1101/2024.01.26.577433

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