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A concise enzyme cascade enables the manufacture of natural and halogenated protoberberine alkaloids

Author

Listed:
  • Fei Li

    (Jiangnan University)

  • Zhenbo Yuan

    (Jiangnan University)

  • Yue Gao

    (Jiangnan University)

  • Zhiwei Deng

    (Jiangnan University)

  • Yan Zhang

    (Jiangnan University)

  • Zhengshan Luo

    (Jiangnan University)

  • Yijian Rao

    (Jiangnan University)

Abstract

The application and drug development of plant-derived natural products are often limited by their low abundance in medicinal plants and the lack of structural complexity and diversity. Herein, we design a concise enzyme cascade to efficiently produce natural and unnatural protoberberine alkaloids from cost-effective, readily available substrates. Through enzyme discovery and engineering, along with systematic optimization of the berberine bridge enzyme to address remaining manufacturing challenges in protoberberine alkaloid biosynthesis, the high production of drug Rotundine is achieved at an impressive gram-scale titer, demonstrating its industrial potential. More importantly, this cascade also enables the efficient biosynthesis of various unnatural halogenated protoberberine alkaloids. Thus, this work not only unlocks the potential of enzyme cascades in overcoming longstanding challenges in the efficient biosynthesis of plant-derived alkaloids, but also opens avenues to introduce structural complexity and diversity into alkaloids through synthetic biology, offering significant potential for drug development.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57280-0
    DOI: 10.1038/s41467-025-57280-0
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