Pathway engineering in yeast for synthesizing the complex polyketide bikaverin
Pathway engineering in yeast for synthesizing the complex polyketide bikaverin
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 recoded, constructed and characterized the biosynthetic pathway of the formation of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We used a green fluorescent protein (GFP) tagging strategy to identify the low expression of Bik1 (polyketide synthase) as the bottleneck step in the pathway, and a promoter exchange strategy to increase expression of Bik1 and bikaverin yield. To further increase product yield, we used an enzyme-fusion strategy to couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to a dramatic improvement of Bikaverin yield of nearly 60-fold. This study demonstrates that the biosynthesis of complex polyketides biosynthesis can be established and efficiently engineered in S. cerevisiae, highlighting the great potential for natural product synthesis and large-scale fermentation in yeast.
Frandsen Rasmus J.N.、Zhao Yu、Zhao Meng、Iqbal Hala、Yao Mingdong、Li Chun、Boeke Jef D.、Nielsen Jens B.、Qiao Bin、Skovbjerg Christine A. S.、Nielsen Jens Christian、Hu Qi、Liu Hong、Yuan Yingjin
Section for Synthetic Biology, Department of Biotechnology and Biomedicine, Technical University of DenmarkInstitute for Systems Genetics and Department of Biochemistry and Molecular PharmacologyFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University||Institute for Systems Genetics and Department of Biochemistry and Molecular PharmacologyInstitute for Systems Genetics and Department of Biochemistry and Molecular PharmacologyFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin UniversityFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin UniversityInstitute for Systems Genetics and Department of Biochemistry and Molecular PharmacologyDepartment of Biology and Biological Engineering, Chalmers University of Technology||Novo Nordisk Foundation Center for Biosustainability, Technical University of DenmarkFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin UniversitySection for Synthetic Biology, Department of Biotechnology and Biomedicine, Technical University of DenmarkDepartment of Biology and Biological Engineering, Chalmers University of TechnologyFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin UniversityFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin UniversityFrontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University||SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University
生物工程学生物化学药学
Frandsen Rasmus J.N.,Zhao Yu,Zhao Meng,Iqbal Hala,Yao Mingdong,Li Chun,Boeke Jef D.,Nielsen Jens B.,Qiao Bin,Skovbjerg Christine A. S.,Nielsen Jens Christian,Hu Qi,Liu Hong,Yuan Yingjin.Pathway engineering in yeast for synthesizing the complex polyketide bikaverin[EB/OL].(2025-03-28)[2025-08-03].https://www.biorxiv.org/content/10.1101/783365.点此复制
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