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Discovery and engineering of colchicine alkaloid biosynthesis

Author

Listed:
  • Ryan S. Nett

    (Stanford University
    Howard Hughes Medical Institute)

  • Warren Lau

    (Stanford University)

  • Elizabeth S. Sattely

    (Stanford University
    Howard Hughes Medical Institute)

Abstract

Few complete pathways have been established for the biosynthesis of medicinal compounds from plants. Accordingly, many plant-derived therapeutics are isolated directly from medicinal plants or plant cell culture1. A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced from Colchicum and Gloriosa species2–5. Here we use a combination of transcriptomics, metabolic logic and pathway reconstitution to elucidate a near-complete biosynthetic pathway to colchicine without prior knowledge of biosynthetic genes, a sequenced genome or genetic tools in the native host. We uncovered eight genes from Gloriosa superba for the biosynthesis of N-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine6. Notably, we identified a non-canonical cytochrome P450 that catalyses the remarkable ring expansion reaction that is required to produce the distinct carbon scaffold of colchicine. We further used the newly identified genes to engineer a biosynthetic pathway (comprising 16 enzymes in total) to N-formyldemecolcine in Nicotiana benthamiana starting from the amino acids phenylalanine and tyrosine. This study establishes a metabolic route to tropolone-containing colchicine alkaloids and provides insights into the unique chemistry that plants use to generate complex, bioactive metabolites from simple amino acids.

Suggested Citation

  • Ryan S. Nett & Warren Lau & Elizabeth S. Sattely, 2020. "Discovery and engineering of colchicine alkaloid biosynthesis," Nature, Nature, vol. 584(7819), pages 148-153, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2546-8
    DOI: 10.1038/s41586-020-2546-8
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    Cited by:

    1. Yue Gao & Fei Li & Zhengshan Luo & Zhiwei Deng & Yan Zhang & Zhenbo Yuan & Changmei Liu & Yijian Rao, 2024. "Modular assembly of an artificially concise biocatalytic cascade for the manufacture of phenethylisoquinoline alkaloids," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Christopher J. Vavricka & Shunsuke Takahashi & Naoki Watanabe & Musashi Takenaka & Mami Matsuda & Takanobu Yoshida & Ryo Suzuki & Hiromasa Kiyota & Jianyong Li & Hiromichi Minami & Jun Ishii & Kenji T, 2022. "Machine learning discovery of missing links that mediate alternative branches to plant alkaloids," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Radin Sadre & Thilani M. Anthony & Josh M. Grabar & Matthew A. Bedewitz & A. Daniel Jones & Cornelius S. Barry, 2022. "Metabolomics-guided discovery of cytochrome P450s involved in pseudotropine-dependent biosynthesis of modified tropane alkaloids," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Yuanwei Gou & Dongfang Li & Minghui Zhao & Mengxin Li & Jiaojiao Zhang & Yilian Zhou & Feng Xiao & Gaofei Liu & Haote Ding & Chenfan Sun & Cuifang Ye & Chang Dong & Jucan Gao & Di Gao & Zehua Bao & Le, 2024. "Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Dong Zheng & Yunlong Zheng & Junjie Tan & Zhenjie Zhang & He Huang & Yao Chen, 2024. "Co-immobilization of whole cells and enzymes by covalent organic framework for biocatalysis process intensification," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    6. Weikai Chen & Xiangfeng Wang & Jie Sun & Xinrui Wang & Zhangsheng Zhu & Dilay Hazal Ayhan & Shu Yi & Ming Yan & Lili Zhang & Tan Meng & Yu Mu & Jun Li & Dian Meng & Jianxin Bian & Ke Wang & Lu Wang & , 2024. "Two telomere-to-telomere gapless genomes reveal insights into Capsicum evolution and capsaicinoid biosynthesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Hao-Tian Wang & Zi-Long Wang & Kuan Chen & Ming-Ju Yao & Meng Zhang & Rong-Shen Wang & Jia-He Zhang & Hans Ågren & Fu-Dong Li & Junhao Li & Xue Qiao & Min Ye, 2023. "Insights into the missing apiosylation step in flavonoid apiosides biosynthesis of Leguminosae plants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Ruiqi Yan & Binghan Xie & Kebo Xie & Qi Liu & Songyang Sui & Shuqi Wang & Dawei Chen & Jimei Liu & Ridao Chen & Jungui Dai & Lin Yang, 2024. "Unravelling and reconstructing the biosynthetic pathway of bergenin," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    9. Xiaofei Yang & Shenghan Gao & Li Guo & Bo Wang & Yanyan Jia & Jian Zhou & Yizhuo Che & Peng Jia & Jiadong Lin & Tun Xu & Jianyong Sun & Kai Ye, 2021. "Three chromosome-scale Papaver genomes reveal punctuated patchwork evolution of the morphinan and noscapine biosynthesis pathway," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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