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Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization

Author

Listed:
  • Matthew A. Bedewitz

    (Michigan State University)

  • A. Daniel Jones

    (Michigan State University
    Michigan State University)

  • John C. D’Auria

    (Texas Tech University)

  • Cornelius S. Barry

    (Michigan State University)

Abstract

Tropinone is the first intermediate in the biosynthesis of the pharmacologically important tropane alkaloids that possesses the 8-azabicyclo[3.2.1]octane core bicyclic structure that defines this alkaloid class. Chemical synthesis of tropinone was achieved in 1901 but the mechanism of tropinone biosynthesis has remained elusive. In this study, we identify a root-expressed type III polyketide synthase from Atropa belladonna (AbPYKS) that catalyzes the formation of 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid. This catalysis proceeds through a non-canonical mechanism that directly utilizes an unconjugated N-methyl-Δ1-pyrrolinium cation as the starter substrate for two rounds of malonyl-Coenzyme A mediated decarboxylative condensation. Subsequent formation of tropinone from 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid is achieved through cytochrome P450-mediated catalysis by AbCYP82M3. Silencing of AbPYKS and AbCYP82M3 reduces tropane levels in A. belladonna. This study reveals the mechanism of tropinone biosynthesis, explains the in planta co-occurrence of pyrrolidines and tropanes, and demonstrates the feasibility of tropane engineering in a non-tropane producing plant.

Suggested Citation

  • Matthew A. Bedewitz & A. Daniel Jones & John C. D’Auria & Cornelius S. Barry, 2018. "Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07671-3
    DOI: 10.1038/s41467-018-07671-3
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    Cited by:

    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. 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.
    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. 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.
    5. 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.

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