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Biosynthesis of medicinal tropane alkaloids in yeast

Author

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  • Prashanth Srinivasan

    (Stanford University)

  • Christina D. Smolke

    (Stanford University
    Chan Zuckerberg Biohub)

Abstract

Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization1,2. Challenges in global supplies have resulted in frequent shortages of these drugs3,4. Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires5 and the COVID-19 pandemic6. Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval7,8 are needed. Here we engineered baker’s yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.

Suggested Citation

  • Prashanth Srinivasan & Christina D. Smolke, 2020. "Biosynthesis of medicinal tropane alkaloids in yeast," Nature, Nature, vol. 585(7826), pages 614-619, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7826:d:10.1038_s41586-020-2650-9
    DOI: 10.1038/s41586-020-2650-9
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    1. Fangyuan Zhang & Fei Qiu & Junlan Zeng & Zhichao Xu & Yueli Tang & Tengfei Zhao & Yuqin Gou & Fei Su & Shiyi Wang & Xiuli Sun & Zheyong Xue & Weixing Wang & Chunxian Yang & Lingjiang Zeng & Xiaozhong , 2023. "Revealing evolution of tropane alkaloid biosynthesis by analyzing two genomes in the Solanaceae family," Nature Communications, Nature, vol. 14(1), pages 1-18, 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. Simon d’Oelsnitz & Daniel J. Diaz & Wantae Kim & Daniel J. Acosta & Tyler L. Dangerfield & Mason W. Schechter & Matthew B. Minus & James R. Howard & Hannah Do & James M. Loy & Hal S. Alper & Y. Jessie, 2024. "Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Sierra M. Brooks & Celeste Marsan & Kevin B. Reed & Shuo-Fu Yuan & Dustin-Dat Nguyen & Adit Trivedi & Gokce Altin-Yavuzarslan & Nathan Ballinger & Alshakim Nelson & Hal S. Alper, 2023. "A tripartite microbial co-culture system for de novo biosynthesis of diverse plant phenylpropanoids," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Tian Tian & Yong-Jiang Wang & Jian-Ping Huang & Jie Li & Bingyan Xu & Yin Chen & Li Wang & Jing Yang & Yijun Yan & Sheng-Xiong Huang, 2022. "Catalytic innovation underlies independent recruitment of polyketide synthases in cocaine and hyoscyamine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    6. 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.
    7. 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.
    8. 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.
    9. Junlan Zeng & Xiaoqiang Liu & Zhaoyue Dong & Fangyuan Zhang & Fei Qiu & Mingyu Zhong & Tengfei Zhao & Chunxian Yang & Lingjiang Zeng & Xiaozhong Lan & Hongbo Zhang & Junhui Zhou & Min Chen & Kexuan Ta, 2024. "Discovering a mitochondrion-localized BAHD acyltransferase involved in calystegine biosynthesis and engineering the production of 3β-tigloyloxytropane," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Gita Naseri, 2023. "A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    11. Jack Chun-Ting Liu & Ricardo De La Peña & Christian Tocol & Elizabeth S. Sattely, 2024. "Reconstitution of early paclitaxel biosynthetic network," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    12. So-Hee Son & Jae-Eung Kim & Gyuri Park & Young-Joon Ko & Bong Hyun Sung & Jongcheol Seo & Seung Soo Oh & Ju Young Lee, 2022. "Metabolite trafficking enables membrane-impermeable-terpene secretion by yeast," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    13. Jiao Yang & Ying Wu & Pan Zhang & Jianxiang Ma & Ying Jun Yao & Yan Lin Ma & Lei Zhang & Yongzhi Yang & Changmin Zhao & Jihua Wu & Xiangwen Fang & Jianquan Liu, 2023. "Multiple independent losses of the biosynthetic pathway for two tropane alkaloids in the Solanaceae family," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. 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.
    15. Wenna Li & Zhao Zhou & Xianglai Li & Lin Ma & Qingyuan Guan & Guojun Zheng & Hao Liang & Yajun Yan & Xiaolin Shen & Jia Wang & Xinxiao Sun & Qipeng Yuan, 2022. "Biosynthesis of plant hemostatic dencichine in Escherichia coli," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    16. Qun Yue & Jie Meng & Yue Qiu & Miaomiao Yin & Liwen Zhang & Weiping Zhou & Zhiqiang An & Zihe Liu & Qipeng Yuan & Wentao Sun & Chun Li & Huimin Zhao & István Molnár & Yuquan Xu & Shuobo Shi, 2023. "A polycistronic system for multiplexed and precalibrated expression of multigene pathways in fungi," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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