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

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 L. Weiss; Dean A.A. Myles; Thomas Kroll; Gloria E.O. Borgstahl

doi:10.1038/s41467-025-57180-3

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

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 L. Weiss, Dean A.A. Myles, Thomas Kroll, Gloria E.O. Borgstahl

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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 pK_a 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 (US)
Article number	1887
Journal	Nature communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-57180-3
State	Published - Dec 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Azadmanesh, J., Slobodnik, K., Struble, L. R., Lovelace, J. J., Cone, E. A., Dasgupta, M., Lutz, W. E., Kumar, S., Natarajan, A., Coates, L., Weiss, K. L., Myles, D. A. A., Kroll, T., & Borgstahl, G. E. O. (2025). The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase. Nature communications, 16(1), Article 1887. https://doi.org/10.1038/s41467-025-57180-3

Azadmanesh, J, Slobodnik, K, Struble, LR, Lovelace, JJ, Cone, EA, Dasgupta, M, Lutz, WE, Kumar, S, Natarajan, A, Coates, L, Weiss, KL, Myles, DAA, Kroll, T & Borgstahl, GEO 2025, 'The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase', Nature communications, vol. 16, no. 1, 1887. https://doi.org/10.1038/s41467-025-57180-3

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title = "The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase",

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.",

author = "Jahaun Azadmanesh and Katelyn Slobodnik and Struble, {Lucas R.} and Lovelace, {Jeffrey J.} and Cone, {Erika A.} and Medhanjali Dasgupta and Lutz, {William E.} and Siddhartha Kumar and Amarnath Natarajan and Leighton Coates and Weiss, {Kevin L.} and Myles, {Dean A.A.} and Thomas Kroll and Borgstahl, {Gloria E.O.}",

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doi = "10.1038/s41467-025-57180-3",

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AU - Cone, Erika A.

AU - Dasgupta, Medhanjali

AU - Lutz, William E.

AU - Kumar, Siddhartha

AU - Natarajan, Amarnath

AU - Coates, Leighton

AU - Weiss, Kevin L.

AU - Myles, Dean A.A.

AU - Kroll, Thomas

AU - Borgstahl, Gloria E.O.

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N2 - 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.

AB - 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.

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

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