Discovery, engineering, and applications of the ketoreductases from Metabacillus lacus in the synthesis of chiral (Hetero)aryl alcohols
Enzymatic reduction of (hetero)aryl ketones is an important reaction for the synthesis of industrially relevant chiral alcohols, but its preparative application remains restricted due to enzyme unavailability and substrate inhibition. Herein, we reported the identification of a ketoreductase and its mutant from Metabacillus lacus ( Ml KREDs) with high activity and wide substrate scope (50 examples) for the reduction of (hetero)aryl ketones by gene mining and protein engineering. During process development, we constructed a deep eutectic solvent (DES)-buffer system to relieve substrate inhibition, achieving the efficient conversion of high-concentration (up to 1.2 M) (hetero)aryl ketones to the corresponding chiral alcohols, some of which are key intermediates for pharmaceuticals. In addition, molecular dynamics simulations provided deeper insights into the substrate inhibition mechanism as well as the DES-induced enzyme activation and stabilization mechanisms. This work provides a green and reliable strategy for the preparative synthesis of pharmaceutical-related chiral (hetero)aryl alcohols.
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