Catalytic promiscuity enabled by photoredox catalysis in nicotinamide-dependent oxidoreductases

Strategies that provide enzymes with the ability to catalyse non-natural reactions are of considerable synthetic value. Photoredox catalysis has proved adept at expanding the synthetic repertoire of existing catalytic platforms, yet, in the realm of biocatalysis it has primarily been used for cofactor regeneration. Here we show that photoredox catalysts can be used to enable new catalytic function in nicotinamide-dependent enzymes. Under visible-light irradiation, xanthene-based photocatalysts enable a double-bond reductase to catalyse an enantioselective deacetoxylation. Mechanistic experiments support the intermediacy of an alpha-acyl radical, formed after the elimination of acetate. Isotopic labelling experiments support nicotinamide as the source of the hydrogen atom. Preliminary calculations and mechanistic experiments suggest that binding to the protein attenuates the reduction potential of the starting material, an important feature for localizing radical formation to the enzyme active site. The generality of this approach is highlighted with the radical dehalogenation of alpha-bromoamides catalysed by ketoreductases with Eosin Y as a photocatalyst.