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

Fei Li, Zhenbo Yuan, Yue Gao, Zhiwei Deng, Yan Zhang, Zhengshan Luo and Yijian Rao ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57280-0

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