NAD(P)H-Dependent Reductases: Research Advances in the Biocatalytic Asymmetric Reduction of Multiple C=O/C=N/C=C Bonds

Asymmetric reduction by enzymatic action leads the way in green biocatalysis as a viable path toward chiral drug precursors. This article summarizes the research progress of three pivotal NADPH-dependent reductases, including amine dehydrogenases (AmDHs), imine reductases (IREDs), and ene reductases (EREDs), in asymmetric reductive amination, imine reduction, and asymmetric olefin reduction, and highlights the catalytic mechanisms, substrate scopes, stereoselectivities, as well as enzyme engineering modification strategies for the above key reactions. Advances in directed evolution, rational design, and system optimization (including cofactor regeneration and photoenzyme catalysis) have significantly alleviated traditional bottlenecks (e.g., low enzyme activity, coenzyme instability, and poor stereoselectivity), yielding biocatalysts with enhanced stability and performance and greater industrial applicability. In addition, this article summarizes successful applications of these enzymes in the synthesis of key chiral building blocks for various drugs. It discusses their future directions for development in sustainable chemical synthesis and industrial scale-up.