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

Xiang Jiao, Xiaozhi Fu, Qishuang Li, Junling Bu, Xiuyu Liu, Otto Savolainen, Luqi Huang (), Juan Guo (), Jens Nielsen () and Yun Chen ()
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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
Luqi Huang: Dongcheng district
Juan Guo: Dongcheng district
Jens Nielsen: Chalmers University of Technology, Kemivägen 10
Yun Chen: Chalmers University of Technology, Kemivägen 10

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53045-3

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