Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles

Jun-Kuan Li, Ge Qu, Xu Li, Yuchen Tian, Chengsen Cui, Fa-Guang Zhang, Wuyuan Zhang, Jun-An Ma (), Manfred T. Reetz () and Zhoutong Sun ()
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Jun-Kuan Li: Tianjin University
Ge Qu: Chinese Academy of Sciences
Xu Li: Chinese Academy of Sciences
Yuchen Tian: Tianjin University
Chengsen Cui: Chinese Academy of Sciences
Fa-Guang Zhang: Tianjin University
Wuyuan Zhang: Chinese Academy of Sciences
Jun-An Ma: Tianjin University
Manfred T. Reetz: Chinese Academy of Sciences
Zhoutong Sun: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Chiral heterocyclic compounds are needed for important medicinal applications. We report an in silico strategy for the biocatalytic synthesis of chiral N- and O-heterocycles via Baldwin cyclization modes of hydroxy- and amino-substituted epoxides and oxetanes using the limonene epoxide hydrolase from Rhodococcus erythropolis. This enzyme normally catalyzes hydrolysis with formation of vicinal diols. Firstly, the required shutdown of the undesired natural water-mediated ring-opening is achieved by rational mutagenesis of the active site. In silico enzyme design is then continued with generation of the improved mutants. These variants prove to be versatile catalysts for preparing chiral N- and O-heterocycles with up to 99% conversion, and enantiomeric ratios up to 99:1. Crystal structural data and computational modeling reveal that Baldwin-type cyclizations, catalyzed by the reprogrammed enzyme, are enabled by reshaping the active-site environment that directs the distal RHN and HO-substituents to be intramolecular nucleophiles.

Date: 2022
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DOI: 10.1038/s41467-022-35468-y

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