Fig. 7: A suggested mechanism for MnSOD-active site proton transfers that coincide with electron gain or loss at the Mn ion.

Solvent, substrate enters the active site through the His30 and Tyr34 gateway. SOL represents the closest free solvent molecule typically found at the crystallographic site of WAT2 and is replenished from bulk solvent upon enzymatic use. a The five-coordinate oxidized resting state. b Concerted proton-electron transfer (CPET) is initiated by acquisition of an electron by Mn³⁺ that is coupled to both N^δ1(His30) proton gain from solvent and N^ε2(His30) proton sharing to buried Tyr166. c Driven by the new electrostatic environment, a ^–OH molecule binds sixth-coordinate to Mn²⁺. This suppresses the positive charge of Mn²⁺ and polarizes WAT1 to become more negative and instigates proton gain from Gln143 deprotonation. The protonation at WAT1 causes electronegative polarity to instead be localized to the bound ^–OH ligand, denoted OL. OL is subsequently protonated and departs from the active site while Tyr34 becomes protonated to form the five-coordinate reduced resting state. d The five-coordinate reduced resting state. e Electron loss by substrate coincides with the loss of protons at His30 and Tyr34 that are presumed to be acquired by the substrate. Tyr166 and WAT1 donate protons to His30 and Gln143, respectively, as a consequence of the net charge changes to regenerate the state in a. Bracketed panels indicate intermediary catalytic steps between the two resting states. The portrayal of hydrogen bond lengths in 2D are not representative of those seen experimentally in 3D.