Catalytic Bias in Enzymatic Metal Cofactor‐Based Oxidation–Reduction Catalysis

Abstract

Catalytic bias refers to the relative rate preference of a catalyst for either the forward or reverse direction. In enzymatic metal cofactor‐based oxidation–reduction catalysis, the tuning of catalytic bias plays an underlying role in controlling rates of reactivity. For this, enzymes have evolved complex active sites that can exist in multiple oxidation states with differing reduction potentials in order to achieve challenging multi‐step, oxidation–reduction reactions. Conceivably, the relative stability of the intermediates that contribute to determining the rate‐limiting step of the catalytic cycle could impose catalytic bias, although mechanisms for this concept are just beginning to be realized. As one example, recent work on Clostridium pasteurianum [FeFe]‐hydrogenases which catalyze reversible hydrogen oxidation have shown that the differential stabilization/destabilization of active site oxidation states through either static or dynamic protein interactions can preferentially promote either the hydrogen oxidation or proton reduction direction of the reaction. This revealed how an enzymatic cofactor can impose bias in oxidation–reduction catalysis through various tuning mechanisms by protein scaffold interactions. The hypothesis based on achieving catalytic bias through the modulation of cofactor oxidation states critical for the reaction cycle can be extended more generally to other cofactor‐based oxidation–reductions catalysts. The current understanding of catalytic bias has significant implications for the design of synthetic catalysts used in industrial settings, as well as providing a greater fundamental understanding of the factors that control metabolic processes in all life.