IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v584y2020i7819d10.1038_s41586-020-2546-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2546-8
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-2546-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2546-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.