Engineering 4-coumaroyl-CoA derived polyketide production in Yarrowia lipolytica through a β-oxidation mediated strategy |
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| Institution: | 1. Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA;2. Department of Biotechnology and Food Microbiology, Wroclaw University of Environmental and Life Sciences, Chelmonskiego 37, 51-630 Wroclaw, Poland;3. These authors contributed equally;1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, PR China;2. Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai, 200237, PR China;1. College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People’s Republic of China;2. Department of Bioengineering and Imperial College Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK;3. School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan Province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, People’s Republic of China;4. Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden;5. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark;1. McKetta Department of Chemical Engineering, The University of Texas at Austin, 200 East Dean Keeton Street, Austin, TX 78712, USA;2. Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2500 Speedway Avenue, Austin, TX 78712, USA;1. The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet 220, 2800 Kgs Lyngby, Denmark;2. Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, SE412 96 Gothenburg, Sweden |
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| Abstract: | Polyketides are a diverse class of molecules sought after for their valuable properties, including as potential pharmaceuticals. Previously, we demonstrated that the oleaginous yeast Yarrowia lipolytica is an optimal host for production of the simple polyketide, triacetic acid lactone (TAL). We here expand the capacities of this host by overcoming previous media challenges and enabling production of more complex polyketides. Specifically, we employ a β-oxidation related strategy to improve polyketide production directly from defined media. Beyond TAL production, we establish biosynthesis of the 4-coumaroyl-CoA derived polyketides: naringenin, resveratrol, and bisdemethoxycurcumin, as well as the diketide intermediate, (E)-5-(4-hydroxyphenyl)-3-oxopent-4-enoic acid. In this background, we enable high-level de novo production of naringenin through import of both a heterologous pathway and a mutant Y. lipolytica allele. In doing so, we generated an averaged maximum titer of 898 mg/L naringenin, the highest titer reported to date in any host. These results demonstrate that Y. lipolytica is an ideal polyketide production host for more complex 4-coumaroyl-CoA derived products. |
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| Keywords: | Naringenin Resveratrol Triacetic acid lactone Curcumin Polyketide synthase Metabolic engineering |
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