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

Author

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  • Jun-Kuan Li

    (Tianjin University
    Chinese Academy of Sciences)

  • Ge Qu

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Xu Li

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Yuchen Tian

    (Tianjin University)

  • Chengsen Cui

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Fa-Guang Zhang

    (Tianjin University)

  • Wuyuan Zhang

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

  • Jun-An Ma

    (Tianjin University)

  • Manfred T. Reetz

    (Chinese Academy of Sciences
    Max-Planck-Institut für Kohlenforschung)

  • Zhoutong Sun

    (Chinese Academy of Sciences
    National Technology Innovation Center of Synthetic Biology)

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.

Suggested Citation

  • Jun-Kuan Li & Ge Qu & Xu Li & Yuchen Tian & Chengsen Cui & Fa-Guang Zhang & Wuyuan Zhang & Jun-An Ma & Manfred T. Reetz & Zhoutong Sun, 2022. "Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35468-y
    DOI: 10.1038/s41467-022-35468-y
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    1. Kinya Hotta & Xi Chen & Robert S. Paton & Atsushi Minami & Hao Li & Kunchithapadam Swaminathan & Irimpan I. Mathews & Kenji Watanabe & Hideaki Oikawa & Kendall N. Houk & Chu-Young Kim, 2012. "Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis," Nature, Nature, vol. 483(7389), pages 355-358, March.
    2. Sarah L. Lovelock & Rebecca Crawshaw & Sophie Basler & Colin Levy & David Baker & Donald Hilvert & Anthony P. Green, 2022. "The road to fully programmable protein catalysis," Nature, Nature, vol. 606(7912), pages 49-58, June.
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    1. Lucien F. Krapp & Fernando A. Meireles & Luciano A. Abriata & Jean Devillard & Sarah Vacle & Maria J. Marcaida & Matteo Dal Peraro, 2024. "Context-aware geometric deep learning for protein sequence design," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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