Pathway engineering in yeast for synthesizing the complex polyketide bikaverin

Meng Zhao, Yu Zhao, Mingdong Yao, Hala Iqbal, Qi Hu, Hong Liu, Bin Qiao, Chun Li, Christine A. S. Skovbjerg, Jens Christian Nielsen, Jens Nielsen, Rasmus J. N. Frandsen, Yingjin Yuan and Jef D. Boeke ()
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Meng Zhao: Tianjin University
Yu Zhao: NYU Langone Health
Mingdong Yao: Tianjin University
Hala Iqbal: NYU Langone Health
Qi Hu: Tianjin University
Hong Liu: Tianjin University
Bin Qiao: Tianjin University
Chun Li: Tianjin University
Christine A. S. Skovbjerg: Technical University of Denmark
Jens Christian Nielsen: Chalmers University of Technology
Jens Nielsen: Chalmers University of Technology
Rasmus J. N. Frandsen: Technical University of Denmark
Yingjin Yuan: Tianjin University
Jef D. Boeke: NYU Langone Health

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Fungal polyketides display remarkable structural diversity and bioactivity, and therefore the biosynthesis and engineering of this large class of molecules is therapeutically significant. Here, we successfully recode, construct and characterize the biosynthetic pathway of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We use a green fluorescent protein (GFP) mapping strategy to identify the low expression of Bik1 (polyketide synthase) as a major bottleneck step in the pathway, and a promoter exchange strategy is used to increase expression of Bik1 and bikaverin titer. Then, we use an enzyme-fusion strategy to directly couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to an improved titer of bikaverin at 202.75 mg/L with flask fermentation (273-fold higher than the initial titer). This study demonstrates that the biosynthesis of complex fungal polyketides can be established and efficiently engineered in S. cerevisiae, highlighting the potential for natural product synthesis and large-scale fermentation in yeast.

Date: 2020
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DOI: 10.1038/s41467-020-19984-3

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