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De novo production of protoberberine and benzophenanthridine alkaloids through metabolic engineering of yeast

Author

Listed:
  • Xiang Jiao

    (Chalmers University of Technology, Kemivägen 10)

  • Xiaozhi Fu

    (Chalmers University of Technology, Kemivägen 10)

  • Qishuang Li

    (Dongcheng district)

  • Junling Bu

    (Dongcheng district)

  • Xiuyu Liu

    (Dongcheng district)

  • Otto Savolainen

    (Chalmers University of Technology, Kemivägen 10
    Kemivägen 10)

  • Luqi Huang

    (Dongcheng district)

  • Juan Guo

    (Dongcheng district)

  • Jens Nielsen

    (Chalmers University of Technology, Kemivägen 10
    BioInnovation Institute)

  • Yun Chen

    (Chalmers University of Technology, Kemivägen 10)

Abstract

Protoberberine alkaloids and benzophenanthridine alkaloids (BZDAs) are subgroups of benzylisoquinoline alkaloids (BIAs), which represent a diverse class of plant-specialized natural metabolites with many pharmacological properties. Microbial biosynthesis has been allowed for accessibility and scalable production of high-value BIAs. Here, we engineer Saccharomyces cerevisiae to de novo produce a series of protoberberines and BZDAs, including palmatine, berberine, chelerythrine, sanguinarine and chelirubine. An ER compartmentalization strategy is developed to improve vacuole protein berberine bridge enzyme (BBE) activity, resulting in >200% increase on the production of the key intermediate (S)-scoulerine. Another promiscuous vacuole protein dihydrobenzophenanthridine oxidase (DBOX) has been identified to catalyze two-electron oxidation on various tetrahydroprotoberberines at N7-C8 position and dihydrobenzophenanthridine alkaloids. Furthermore, cytosolically expressed DBOX can alleviate the limitation on BBE. This study highlights the potential of microbial cell factories for the biosynthesis of a diverse group of BIAs through engineering of heterologous plant enzymes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53045-3
    DOI: 10.1038/s41467-024-53045-3
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    References listed on IDEAS

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    Cited by:

    1. Ling-Tong Cheng & Zi-Long Wang & Qian-Hao Zhu & Min Ye & Chu-Yu Ye, 2025. "A long road ahead to reliable and complete medicinal plant genomes," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    2. Fei Li & Zhenbo Yuan & Yue Gao & Zhiwei Deng & Yan Zhang & Zhengshan Luo & Yijian Rao, 2025. "A concise enzyme cascade enables the manufacture of natural and halogenated protoberberine alkaloids," Nature Communications, Nature, vol. 16(1), pages 1-13, December.

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