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Title: De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae
Abstract

Berberine is an extensively used pharmaceutical benzylisoquinoline alkaloid (BIA) derived from plants. Microbial manufacturing has emerged as a promising approach to source valuable BIAs. Here, we demonstrated the complete biosynthesis of berberine inSaccharomyces cerevisiaeby engineering 19 genes including 12 heterologous genes from plants and bacteria. Overexpressing bottleneck enzymes, fermentation scale-up, and heating treatment after fermentation increased berberine titer by 643-fold to 1.08 mg L-1. This pathway also showed high efficiency to incorporate halogenated tyrosine for the synthesis of unnatural BIA derivatives that have higher therapeutical potentials. We firstly demonstrate the in vivo biosynthesis of 11-fluoro-tetrahydrocolumbamine via nine enzymatic reactions. The efficiency and promiscuity of our pathway also allow for the simultaneous incorporation of two fluorine-substituted tyrosine derivatives to 8, 3’-di-fluoro-coclaurine. This work highlights the potential of yeast as a versatile microbial biosynthetic platform to strengthen current pharmaceutical supply chain and to advance drug development.

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NSF-PAR ID:
10396263
Author(s) / Creator(s):
;
Publisher / Repository:
Nature Publishing Group
Date Published:
Journal Name:
Communications Chemistry
Volume:
6
Issue:
1
ISSN:
2399-3669
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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