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The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase

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)

  • Jeffrey J. Lovelace

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Erika A. Cone

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Medhanjali Dasgupta

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • William E. Lutz

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Siddhartha Kumar

    (Eppley Institute for Research in Cancer and Allied Diseases)

  • Amarnath Natarajan

    (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) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide ( $${{{{\rm{O}}}}}_{2}^{\bullet -}$$ O 2 ∙ − ) 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.

Suggested Citation

  • Jahaun Azadmanesh & Katelyn Slobodnik & Lucas R. Struble & Jeffrey J. Lovelace & Erika A. Cone & Medhanjali Dasgupta & William E. Lutz & Siddhartha Kumar & Amarnath Natarajan & Leighton Coates & Kevin, 2025. "The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57180-3
    DOI: 10.1038/s41467-025-57180-3
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    1. 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.
    2. Asmit Bhowmick & Rana Hussein & Isabel Bogacz & Philipp S. Simon & Mohamed Ibrahim & Ruchira Chatterjee & Margaret D. Doyle & Mun Hon Cheah & Thomas Fransson & Petko Chernev & In-Sik Kim & Hiroki Maki, 2023. "Structural evidence for intermediates during O2 formation in photosystem II," Nature, Nature, vol. 617(7961), pages 629-636, May.
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