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, Jef D. Boeke

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Article number6197
    JournalNature communications
    Volume11
    Issue number1
    DOIs
    StatePublished - Dec 2020

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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