Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast

Yuanwei Gou, Dongfang Li, Minghui Zhao, Mengxin Li, Jiaojiao Zhang, Yilian Zhou, Feng Xiao, Gaofei Liu, Haote Ding, Chenfan Sun, Cuifang Ye, Chang Dong, Jucan Gao, Di Gao, Zehua Bao, Lei Huang, Zhinan Xu and Jiazhang Lian ()
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Yuanwei Gou: Zhejiang University
Dongfang Li: Zhejiang University
Minghui Zhao: Zhejiang University
Mengxin Li: Zhejiang University
Jiaojiao Zhang: Zhejiang University
Yilian Zhou: Zhejiang University
Feng Xiao: Zhejiang University
Gaofei Liu: Zhejiang University
Haote Ding: Zhejiang University
Chenfan Sun: Zhejiang University
Cuifang Ye: Zhejiang University
Chang Dong: Zhejiang University
Jucan Gao: Zhejiang University
Di Gao: Zhejiang University
Zehua Bao: Zhejiang University
Lei Huang: Zhejiang University
Zhinan Xu: Zhejiang University
Jiazhang Lian: Zhejiang University

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

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49554-w

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