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Tandemly duplicated CYP82Ds catalyze 14-hydroxylation in triptolide biosynthesis and precursor production in Saccharomyces cerevisiae

Author

Listed:
  • Yifeng Zhang

    (Chinese Academy of Chinese Medical Sciences
    Capital Medical University
    Capital Medical University)

  • Jie Gao

    (Chinese Academy of Chinese Medical Sciences
    Capital Medical University)

  • Lin Ma

    (Capital Medical University)

  • Lichan Tu

    (Zhejiang University City College)

  • Tianyuan Hu

    (Hangzhou Normal University)

  • Xiaoyi Wu

    (Capital Medical University)

  • Ping Su

    (Chinese Academy of Chinese Medical Sciences)

  • Yujun Zhao

    (Chinese Academy of Chinese Medical Sciences)

  • Yuan Liu

    (Capital Medical University)

  • Dan Li

    (Capital Medical University)

  • Jiawei Zhou

    (Zhejiang University of Technology)

  • Yan Yin

    (Capital Medical University)

  • Yuru Tong

    (Capital Medical University)

  • Huan Zhao

    (Capital Medical University)

  • Yun Lu

    (Capital Medical University)

  • Jiadian Wang

    (Capital Medical University)

  • Wei Gao

    (Capital Medical University
    Capital Medical University)

  • Luqi Huang

    (Chinese Academy of Chinese Medical Sciences)

Abstract

Triptolide is a valuable multipotent antitumor diterpenoid in Tripterygium wilfordii, and its C-14 hydroxyl group is often selected for modification to enhance both the bioavailability and antitumor efficacy. However, the mechanism for 14-hydroxylation formation remains unknown. Here, we discover 133 kb of tandem duplicated CYP82Ds encoding 11 genes on chromosome 12 and characterize CYP82D274 and CYP82D263 as 14-hydroxylases that catalyze the metabolic grid in triptolide biosynthesis. The two CYP82Ds catalyze the aromatization of miltiradiene, which has been repeatedly reported to be a spontaneous process. In vivo assays and evaluations of the kinetic parameters of CYP82Ds indicate the most significant affinity to dehydroabietic acid among multiple intermediates. The precursor 14-hydroxy-dehydroabietic acid is successfully produced by engineered Saccharomyces cerevisiae. Our study provides genetic elements for further elucidation of the downstream biosynthetic pathways and heterologous production of triptolide and of the currently intractable biosynthesis of other 14-hydroxyl labdane-type secondary metabolites.

Suggested Citation

  • Yifeng Zhang & Jie Gao & Lin Ma & Lichan Tu & Tianyuan Hu & Xiaoyi Wu & Ping Su & Yujun Zhao & Yuan Liu & Dan Li & Jiawei Zhou & Yan Yin & Yuru Tong & Huan Zhao & Yun Lu & Jiadian Wang & Wei Gao & Luq, 2023. "Tandemly duplicated CYP82Ds catalyze 14-hydroxylation in triptolide biosynthesis and precursor production in Saccharomyces cerevisiae," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36353-y
    DOI: 10.1038/s41467-023-36353-y
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    References listed on IDEAS

    as
    1. C. J. Paddon & P. J. Westfall & D. J. Pitera & K. Benjamin & K. Fisher & D. McPhee & M. D. Leavell & A. Tai & A. Main & D. Eng & D. R. Polichuk & K. H. Teoh & D. W. Reed & T. Treynor & J. Lenihan & H., 2013. "High-level semi-synthetic production of the potent antimalarial artemisinin," Nature, Nature, vol. 496(7446), pages 528-532, April.
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    3. Ying Ma & Guanghong Cui & Tong Chen & Xiaohui Ma & Ruishan Wang & Baolong Jin & Jian Yang & Liping Kang & Jinfu Tang & Changjiangsheng Lai & Yanan Wang & Yujun Zhao & Ye Shen & Wen Zeng & Reuben J. Pe, 2021. "Expansion within the CYP71D subfamily drives the heterocyclization of tanshinones synthesis in Salvia miltiorrhiza," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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    5. Nikolaj Lervad Hansen & Louise Kjaerulff & Quinn Kalby Heck & Victor Forman & Dan Staerk & Birger Lindberg Møller & Johan Andersen-Ranberg, 2022. "Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Lichan Tu & Ping Su & Zhongren Zhang & Linhui Gao & Jiadian Wang & Tianyuan Hu & Jiawei Zhou & Yifeng Zhang & Yujun Zhao & Yuan Liu & Yadi Song & Yuru Tong & Yun Lu & Jian Yang & Cao Xu & Meirong Jia , 2020. "Author Correction: Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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