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- Title
Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast.
- Authors
Gou, Yuanwei; Li, Dongfang; Zhao, Minghui; Li, Mengxin; Zhang, Jiaojiao; Zhou, Yilian; Xiao, Feng; Liu, Gaofei; Ding, Haote; Sun, Chenfan; Ye, Cuifang; Dong, Chang; Gao, Jucan; Gao, Di; Bao, Zehua; Huang, Lei; Xu, Zhinan; Lian, Jiazhang
- Abstract
While sanguinarine has gained recognition for antimicrobial and antineoplastic activities, its complex conjugated structure and low abundance in plants impede broad applications. Here, we demonstrate the complete biosynthesis of sanguinarine and halogenated derivatives using highly engineered yeast strains. To overcome sanguinarine cytotoxicity, we establish a splicing intein-mediated temperature-responsive gene expression system (SIMTeGES), a simple strategy that decouples cell growth from product synthesis without sacrificing protein activity. To debottleneck sanguinarine biosynthesis, we identify two reticuline oxidases and facilitated functional expression of flavoproteins and cytochrome P450 enzymes via protein molecular engineering. After comprehensive metabolic engineering, we report the production of sanguinarine at a titer of 448.64 mg L−1. Additionally, our engineered strain enables the biosynthesis of fluorinated sanguinarine, showcasing the biotransformation of halogenated derivatives through more than 15 biocatalytic steps. This work serves as a blueprint for utilizing yeast as a scalable platform for biomanufacturing diverse benzylisoquinoline alkaloids and derivatives. Sanguinarine is a plant-derived benzylisoquinoline alkaloid that exhibits diverse pharmacological activities. Here, the authors report the complete biosynthesis of sanguinarine and halogenated derivatives using engineered yeast strains through a temperature-responsive dynamic control strategy.
- Subjects
SANGUINARINE; TEMPERATURE control; BIOSYNTHESIS; YEAST; CYTOCHROME P-450; CYTOCHROME oxidase; HUMAN activity recognition; RNA splicing; ISOQUINOLINE alkaloids
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49554-w