Direct detection of coupled proton and electron transfers in human manganese superoxide dismutase

Jahaun Azadmanesh,Gloria E O Borgstahl,Kevin L Weiss,Leighton Coates,William E Lutz

doi:10.1038/s41467-021-22290-1

Jahaun Azadmanesh, Gloria E O Borgstahl + Show 3 more

Open Access

https://doi.org/10.1038/s41467-021-22290-1

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Abstract

Human manganese superoxide dismutase is a critical oxidoreductase found in the mitochondrial matrix. Concerted proton and electron transfers are used by the enzyme to rid the mitochondria of O2•−. The mechanisms of concerted transfer enzymes are typically unknown due to the difficulties in detecting the protonation states of specific residues and solvent molecules at particular redox states. Here, neutron diffraction of two redox-controlled manganese superoxide dismutase crystals reveal the all-atom structures of Mn3+ and Mn2+ enzyme forms. The structures deliver direct data on protonation changes between oxidation states of the metal. Observations include glutamine deprotonation, the involvement of tyrosine and histidine with altered pKas, and four unusual strong-short hydrogen bonds, including a low barrier hydrogen bond. We report a concerted proton and electron transfer mechanism for human manganese superoxide dismutase from the direct visualization of active site protons in Mn3+ and Mn2+ redox states.

Highlights

Human manganese superoxide dismutase is a critical oxidoreductase found in the mitochondrial matrix
Human manganese superoxide dismutase (MnSOD) is a CPETbased oxidoreductase found in the mitochondrial matrix that reduces reactive oxygen species (ROS) levels by eliminating O2− with the unpaired electrons of the active site metal
To visualize the effect of the electronic state of the metal on the active site protons, all-atom, D-labeled neutron structures were obtained for Mn3+SOD and Mn2+SOD to resolutions of 2.20 and 2.30 Å, respectively

Summary

Introduction

Human manganese superoxide dismutase is a critical oxidoreductase found in the mitochondrial matrix. This may be a consequence of Gln[143] deprotonation to the amide anion during the Mn3+ → Mn2+ redox reaction and negative charge stabilization of its Oε1 atom through hydrogen bonding with Trp[123].

Results

Conclusion