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  Biocatalytic Baeyer–Villiger Reactions: Uncovering the Source of Regioselectivity at Each Evolutionary Stage of a Mutant with Scrutiny of Fleeting Chiral Intermediates

Dong, Y., Li, T., Zhang, S., Sanchis, J., Yin, H., Ren, J., et al. (2022). Biocatalytic Baeyer–Villiger Reactions: Uncovering the Source of Regioselectivity at Each Evolutionary Stage of a Mutant with Scrutiny of Fleeting Chiral Intermediates. ACS Catalysis, 12(6), 3669-3680. doi:10.1021/acscatal.2c00415.

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 Creators:
Dong, Yijie1, 2, Author
Li, Tang3, Author
Zhang, Shiqing4, 5, Author
Sanchis, Joaquin6, Author
Yin, Heng3, Author
Ren, Jie1, Author
Sheng, Xiang4, 5, Author
Li, Guangyue1, Author
Reetz, Manfred T.4, 7, Author              
Affiliations:
1State Key Laboratory for Biology of Plant Diseases and Insect Pests/Key Laboratory of Control of Biological Hazard Factors (Plant Origin) for Agri-product Quality and Safety, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China, ou_persistent22              
2Key Laboratory of Agricultural Microbiomics and Precision Application − Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Guangdong Microbial Culture Collection Center (GDMCC), Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, PR China, ou_persistent22              
3Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, PR China, ou_persistent22              
4Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China, ou_persistent22              
5National Center of Technology Innovation for Synthetic Biology, Tianjin 300308, P.R. China, ou_persistent22              
6Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, ou_persistent22              
7Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445588              

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Free keywords: biocatalytic Baeyer-Villiger reaction; regioselectivity; Criegee intermediate; deconvolution; quantum chemical calculations
 Abstract: In this study, we report the discovery of unexpected mechanistic intricacies of Baeyer–Villiger monooxygenases (BVMOs) and provide insights that promise to help in extending their applications in synthetic organic chemistry and biotechnology. The basic mechanism of BVMOs as catalysts in the oxidation of unsymmetrical ketones R1–(C═O)–R2 is well known, which involves the intermediacy of short-lived Criegee intermediates. The tendency of R1 or R2 to migrate preferentially in the breakdown of the Criegee intermediate follows the traditional requirement of an antiperiplanar conformation with maximum stabilization of the incipient positive charge. The challenge of inverting the regioselectivity of group migration with the formation of abnormal products was recently met by the semi-rational directed evolution of TmCHMO with the generation of a quadruple mutant. Although a reasonable model explaining the mutational effect was suggested, the theoretical analysis did not include the calculation of both enantiomeric forms of the fleeting chiral Criegee intermediate in transition states and focused only on the wild-type enzyme and the quadruple mutant. The present investigation utilizes complete mutational deconvolution with the experimental construction of a fitness-pathway landscape comprising 4! = 24 upward climbs. We were confronted by the discovery that the absolute configuration of the Criegee intermediate switches from (R) to (S), depending upon the stage of the evolutionary process. On the basis of X-ray structural data, the physical basis of this phenomenon was illuminated by quantum chemical analyses performed on the enzymes at all evolutionary steps of a selected pathway. The hitherto unexplored role of fleeting chiral intermediates in the mechanism of other enzyme types deserves increased attention.

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Language(s): eng - English
 Dates: 2022-01-232022-03-082022-03-18
 Publication Status: Published online
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acscatal.2c00415
 Degree: -

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Title: ACS Catalysis
  Abbreviation : ACS Catal.
Source Genre: Journal
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Publ. Info: Washington, DC : ACS
Pages: - Volume / Issue: 12 (6) Sequence Number: - Start / End Page: 3669 - 3680 Identifier: ISSN: 2155-5435
CoNE: https://pure.mpg.de/cone/journals/resource/2155-5435