亚胺
还原胺化
化学
对映体过量
工业生物技术
胺化
组合化学
酶
有机化学
对映选择合成
催化作用
生物技术
生物
作者
Markus Schöber,Chris MacDermaid,Anne A. Ollis,Sandy Chang,Diluar Khan,Joseph Hosford,Jonathan Latham,Leigh Anne F. Ihnken,Murray J. B. Brown,Douglas E. Fuerst,Mahesh J. Sanganee,Gheorghe‐Doru Roiban
出处
期刊:Nature Catalysis
[Springer Nature]
日期:2019-09-16
卷期号:2 (10): 909-915
被引量:129
标识
DOI:10.1038/s41929-019-0341-4
摘要
Imine reductases catalyse the reductive amination of aldehydes or ketones with amines to produce chiral amines—a key transformation in the preparation of fine chemicals and active pharmaceutical ingredients. Although significant progress has been recently made in the field, their industrial application has not been demonstrated. Herein, we describe a wild-type imine reductase that was engineered to perform reductive amination with concomitant substrate amine resolution to give a commercially relevant manufacturing process to lysine-specific demethylase-1 inhibitor GSK2879552. Three rounds of evolution resulted in an enzyme variant showing a >38,000-fold improvement over wild type. The engineering of a more stable and active enzyme variant enabled process optimization to an economic, high quality and sustainable operating space. Using the evolved enzyme, kilogram quantities of a key intermediate to GSK2879552 were produced in 84% yield, at 99.9% purity and >99.7% enantiomeric excess, with improved process mass intensity. Imine reductases have been regarded as one of the most promising enzymes by the pharmaceutical industry—but their industrial application is still lacking. This work reports the successful industrial application of an imine reductase, enabled by directed evolution.
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