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Updated: Feb 26, 2026
Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine
Published on: February 16, 2018
Structural evolution-based ancestral sequence reconstruction of medium-chain alcohol dehydrogenase for efficient
Jun Wang1, Songyin Zhao1, Lehang Li1
1Lab of Brewing Microbiology and Applied Enzymology, School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China.
Abstract:
Drug molecules used to treat complex diseases often contain cyclic chiral moieties. Specifically, the synthesis of fused-ring alcohols (e.g., chiral β-tetralol and its derivatives) by chemical methods is challenging. Medium-chain alcohol dehydrogenase (MDR) are widely used in the asymmetric reduction of potential chiral ketones to chiral alcohols, and can be used to synthesize chiral fused-ring alcohols. In this study, we integrated enzyme sequence and structural information in an ancestral sequence reconstruction method. This process identified ancestral medium-chain alcohol dehydrogenase N42, with average conversion and selectivity rates exceeding 98% towards 19 ketone substrates (classified into fused-ring, heterocyclic, and aryl groups), and enhanced thermostability (melting temperature 9.9 °C higher than that of its descendant). Computational analysis explained the origin of the N42 activity and revealed a unique set of functional regulatory sites in the MDR family. This ancestral reconstruction strategy combines sequence and structural information provides novel insights into enzyme discovery and functional regulation, might prove useful for studying enzyme functional evolution in families with deep structural differentiation.
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