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A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

Author

Listed:
  • Michael E. Pyne

    (Concordia University
    Concordia University)

  • Kaspar Kevvai

    (Concordia University
    Concordia University)

  • Parbir S. Grewal

    (University of California, Berkeley)

  • Lauren Narcross

    (Concordia University
    Concordia University)

  • Brian Choi

    (University of California, Berkeley)

  • Leanne Bourgeois

    (Concordia University
    Concordia University)

  • John E. Dueber

    (University of California, Berkeley
    Lawrence Berkeley National Laboratory)

  • Vincent J. J. Martin

    (Concordia University
    Concordia University)

Abstract

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L−1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.

Suggested Citation

  • Michael E. Pyne & Kaspar Kevvai & Parbir S. Grewal & Lauren Narcross & Brian Choi & Leanne Bourgeois & John E. Dueber & Vincent J. J. Martin, 2020. "A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17172-x
    DOI: 10.1038/s41467-020-17172-x
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    Cited by:

    1. Xiang Jiao & Xiaozhi Fu & Qishuang Li & Junling Bu & Xiuyu Liu & Otto Savolainen & Luqi Huang & Juan Guo & Jens Nielsen & Yun Chen, 2024. "De novo production of protoberberine and benzophenanthridine alkaloids through metabolic engineering of yeast," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. 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.
    3. 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.
    4. Quanli Liu & Yi Liu & Gang Li & Otto Savolainen & Yun Chen & Jens Nielsen, 2021. "De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Michael E. Pyne & James A. Bagley & Lauren Narcross & Kaspar Kevvai & Kealan Exley & Meghan Davies & Qingzhao Wang & Malcolm Whiteway & Vincent J. J. Martin, 2023. "Screening non-conventional yeasts for acid tolerance and engineering Pichia occidentalis for production of muconic acid," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. 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.
    7. Meirong Gao & Yuxin Zhao & Zhanyi Yao & Qianhe Su & Payton Van Beek & Zengyi Shao, 2023. "Xylose and shikimate transporters facilitates microbial consortium as a chassis for benzylisoquinoline alkaloid production," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. Björn D. M. Bean & Colleen J. Mulvihill & Riddhiman K. Garge & Daniel R. Boutz & Olivier Rousseau & Brendan M. Floyd & William Cheney & Elizabeth C. Gardner & Andrew D. Ellington & Edward M. Marcotte , 2022. "Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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