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Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol

Author

Listed:
  • Chengshuai Yang

    (Chinese Academy of Sciences)

  • Yan Wang

    (Chinese Academy of Sciences)

  • Zhen Su

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Lunyi Xiong

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Pingping Wang

    (Chinese Academy of Sciences)

  • Wen Lei

    (Shanghai Research Institute of Chemical Industry)

  • Xing Yan

    (Chinese Academy of Sciences)

  • Dawei Ma

    (Chinese Academy of Sciences)

  • Guoping Zhao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Zhihua Zhou

    (Chinese Academy of Sciences)

Abstract

Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1β-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol.

Suggested Citation

  • Chengshuai Yang & Yan Wang & Zhen Su & Lunyi Xiong & Pingping Wang & Wen Lei & Xing Yan & Dawei Ma & Guoping Zhao & Zhihua Zhou, 2024. "Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46583-3
    DOI: 10.1038/s41467-024-46583-3
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    References listed on IDEAS

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    1. Jianhua Li & Ishmael Mutanda & Kaibo Wang & Lei Yang & Jiawei Wang & Yong Wang, 2019. "Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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