Engineering of Candida glabrata Ketoreductase 1 for Asymmetric Reduction of α-Halo Ketones
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Abstract
Enantiopure halohydrins, which are important building blocks for pharmaceutical agents, could be synthesized by biocatalytic reduction of α-halo ketones using ketoreductases. In this study, Candida glabrata ketoreductase 1 (CgKR1) variants with >99% stereoselectivity toward α-halo ketones, such as 2-chloroacetophenone, 2-chloro-4′-fluoroacetophenone, and 2-bromoacetophenone, were obtained through engineering of CgKR1 at residues Phe92 and Tyr208. Interestingly, asymmetric reduction of these α-halo ketones by all the variants of CgKR1 followed anti-Prelog's rule, which is rarely found in natural ketoreductases. Moreover, the biocatalytic processes for reduction of these aromatic α-halo ketones with high substrate loading were achieved by coexpression of glucose dehydrogenase (GDH) for NADPH regeneration, indicating the potential of practical applications of these variants.
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