Redox Out of the Box: Catalytic Versatility Across NAD(P)H-Dependent Oxidoreductases

The asymmetric reduction of double bonds using NAD(P)H-dependent oxidoreductases has proven to be an efficient tool for the synthesis of important chiral molecules in research and on industrial scale. These enzymes are commercially available in screening kits for the reduction of C=O (ketones), C=C (activated alkenes), or C=N bonds (imines). Recent reports, however, indicate that the ability to accommodate multiple reductase activities on distinct C=X bonds occurs in different enzyme classes, either natively or after mutagenesis. This challenges the common perception of highly selective oxidoreductases for one type of electrophilic substrate. Consideration of this underexplored potential in enzyme screenings and protein engineering campaigns may contribute to the identification of complementary biocatalytic processes for the synthesis of chiral compounds. This review will contribute to a global understanding of the promiscuous behavior of NAD(P)H-dependent oxidoreductases on C=X bond reduction and inspire future discoveries with respect to unconventional biocatalytic routes in asymmetric synthesis. NAD(P)H-dependent reductases have been established as chemoselective biocatalysts for the asymmetric reduction of C=O, C=N, and C=C bonds. Serendipity, screening, and engineering unearthed that the ability to convert distinct electrophiles is shared by numerous enzyme families. This review sheds light on this underexplored facet of NAD(P)H-dependent reductases and highlights the catalytic versatility of these enzymes.image