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Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide

Author

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  • Nikolaj Lervad Hansen

    (University of Copenhagen)

  • Louise Kjaerulff

    (University of Copenhagen)

  • Quinn Kalby Heck

    (University of Copenhagen)

  • Victor Forman

    (University of Copenhagen)

  • Dan Staerk

    (University of Copenhagen)

  • Birger Lindberg Møller

    (University of Copenhagen)

  • Johan Andersen-Ranberg

    (University of Copenhagen)

Abstract

The diterpenoid triepoxides triptolide and triptonide from Tripterygium wilfordii (thunder god wine) exhibit unique bioactivities with potential uses in disease treatment and as a non-hormonal male contraceptives. Here, we show that cytochrome P450s (CYPs) from the CYP71BE subfamily catalyze an unprecedented 18(4→3) methyl shift required for biosynthesis of the abeo-abietane core structure present in diterpenoid triepoxides and in several other plant diterpenoids. In combination with two CYPs of the CYP82D subfamily, four CYPs from T. wilfordii are shown to constitute the minimal set of biosynthetic genes that enables triptonide biosynthesis using Nicotiana benthamiana and Saccharomyces cerevisiae as heterologous hosts. In addition, co-expression of a specific T. wilfordii cytochrome b5 (Twcytb5-A) increases triptonide output more than 9-fold in S. cerevisiae and affords isolation and structure elucidation by NMR spectroscopic analyses of 18 diterpenoids, providing insights into the biosynthesis of diterpenoid triepoxides. Our findings pave the way for diterpenoid triepoxide production via fermentation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32667-5
    DOI: 10.1038/s41467-022-32667-5
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    1. 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. "Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. 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.
    3. 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.
    4. Zongliang Chang & Weibing Qin & Huili Zheng & Kathleen Schegg & Lu Han & Xiaohua Liu & Yue Wang & Zhuqing Wang & Hayden McSwiggin & Hongying Peng & Shuiqiao Yuan & Jiabao Wu & Yongxia Wang & Shenghui , 2021. "Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. 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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    1. 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.
    2. Abigail E. Bryson & Emily R. Lanier & Kin H. Lau & John P. Hamilton & Brieanne Vaillancourt & Davis Mathieu & Alan E. Yocca & Garret P. Miller & Patrick P. Edger & C. Robin Buell & Björn Hamberger, 2023. "Uncovering a miltiradiene biosynthetic gene cluster in the Lamiaceae reveals a dynamic evolutionary trajectory," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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