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Catalytic innovation underlies independent recruitment of polyketide synthases in cocaine and hyoscyamine biosynthesis

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  • Tian Tian

    (Chinese Academy of Sciences
    Shaanxi Normal University
    University of Chinese Academy of Sciences)

  • Yong-Jiang Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jian-Ping Huang

    (Chinese Academy of Sciences
    Chengdu University of Traditional Chinese Medicine)

  • Jie Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bingyan Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yin Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Li Wang

    (Chengdu University of Traditional Chinese Medicine)

  • Jing Yang

    (Chinese Academy of Sciences)

  • Yijun Yan

    (Chinese Academy of Sciences)

  • Sheng-Xiong Huang

    (Chinese Academy of Sciences)

Abstract

Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32776-1
    DOI: 10.1038/s41467-022-32776-1
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    References listed on IDEAS

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    1. Prashanth Srinivasan & Christina D. Smolke, 2020. "Biosynthesis of medicinal tropane alkaloids in yeast," Nature, Nature, vol. 585(7826), pages 614-619, September.
    2. Jian-Ping Huang & Chengli Fang & Xiaoyan Ma & Li Wang & Jing Yang & Jianying Luo & Yijun Yan & Yu Zhang & Sheng-Xiong Huang, 2019. "Tropane alkaloids biosynthesis involves an unusual type III polyketide synthase and non-enzymatic condensation," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    3. 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.
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    1. 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.
    2. 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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