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

Author

Listed:
  • Jahaun Azadmanesh

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Katelyn Slobodnik

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Lucas R. Struble

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • William E. Lutz

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Leighton Coates

    (Oak Ridge National Laboratory)

  • Kevin L. Weiss

    (Oak Ridge National Laboratory)

  • Dean A. A. Myles

    (Oak Ridge National Laboratory)

  • Thomas Kroll

    (SLAC National Accelerator Laboratory)

  • Gloria E. O. Borgstahl

    (Eppley Institute for Research in Cancer and Allied Diseases)

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.

Suggested Citation

  • 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, 2024. "Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50260-w
    DOI: 10.1038/s41467-024-50260-w
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    References listed on IDEAS

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    1. Steven Dajnowicz & Ryne C. Johnston & Jerry M. Parks & Matthew P. Blakeley & David A. Keen & Kevin L. Weiss & Oksana Gerlits & Andrey Kovalevsky & Timothy C. Mueser, 2017. "Direct visualization of critical hydrogen atoms in a pyridoxal 5′-phosphate enzyme," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    2. Lukas Gajdos & Matthew P. Blakeley & Michael Haertlein & V. Trevor Forsyth & Juliette M. Devos & Anne Imberty, 2022. "Neutron crystallography reveals mechanisms used by Pseudomonas aeruginosa for host-cell binding," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
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