Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for as...

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Published in:Nature communications 2023-01, Vol.14 (1), p.353-353, Article 353
Main Authors: Hou, Xiaodong, Xu, Huibin, Yuan, Zhenbo, Deng, Zhiwei, Fu, Kai, Gao, Yue, Liu, Changmei, Zhang, Yan, Rao, Yijian
Format: Article
Language:English
Subjects:
631/92/173
631/92/603
639/638/92/613
Alcohol
Alcohols
Alcohols - chemistry
Asymmetry
Crystal structure
Emodin
Enantiomers
Humanities and Social Sciences
Hydrogen bonds
Ketones
Ketones - chemistry
multidisciplinary
Oxidoreductases
Reductase
Reductases
Reduction
Science
Science (multidisciplinary)
Stereoisomerism
Stereoselectivity
Structural analysis
Substrates
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Summary:Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α -haloacetophenones to optically pure (2 S , 3 S )-ketols and ( R )-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols. Asymmetric reduction of prochiral ketones is challenging. Here, the authors identify and solve the structure of anthrol reductase CbAR, whose variant H162F can convert 1,3-cyclodiketones and α-haloacetophenones to the corresponding chiral alcohols.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-36064-4