Coupling cell growth and biochemical pathway induction in Saccharomyces cerevisiae for production of (+)-valencene and its chemical conversion to (+)-nootkatone |
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| Institution: | 1. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China;2. J1 Biotech Co., Ltd., Wuhan, 430075, China;3. State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China;4. Hubei Engineering Laboratory for Synthetic Microbiology, Wuhan Institute of Biotechnology, Wuhan, 430075, China;1. Departamento de Biotecnología, Universidad Autónoma Metropolitana, P.A. 55-535, 09340 Iztapalapa, México D.F., Mexico;2. Departamento de Química-Bioquímica, Instituto Tecnológico de Durango, Durango, Mexico;1. Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA;2. Member RIFM Expert Panel, Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY, 10032, USA;3. Member RIFM Expert Panel, Malmo University Hospital, Department of Occupational & Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo, SE, 20502, Sweden;4. Member RIFM Expert Panel, School of Natural Resources & Environment, University of Michigan, Dana Building G110, 440 Church St., Ann Arbor, MI, 58109, USA;5. Member RIFM Expert Panel, Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany;6. Member RIFM Expert Panel, University of Sao Paulo, School of Veterinary Medicine and Animal Science, Department of Pathology, Av. Prof. dr. Orlando Marques de Paiva, 87, Sao Paulo, CEP, 05508-900, Brazil;7. Member RIFM Expert Panel, University of Wuerzburg, Department of Toxicology, Versbacher Str. 9, 97078, Würzburg, Germany;8. Member RIFM Expert Panel, Oregon Health Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA;9. Member RIFM Expert Panel, Vanderbilt University School of Medicine, Department of Biochemistry, Center in Molecular Toxicology, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN, 37232-0146, USA;10. Member RIFM Expert Panel, University of Pennsylvania, Perelman School of Medicine, Center of Excellence in Environmental Toxicology, 1316 Biomedical Research Building (BRB) II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-3083, USA;11. Member RIFM Expert Panel, The University of Tennessee, College of Veterinary Medicine, Department of Comparative Medicine, 2407 River Dr., Knoxville, TN, 37996- 4500, USA;12. Member RIFM Expert Panel, Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ, 85724-5050, USA;13. Member RIFM Expert Panel, The Journal of Dermatological Science (JDS), Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan;1. Grupo de Procesos de Transporte y Reacción en Sistemas Multifásicos, Departamento de IPH, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, Mexico;2. Departamento de Biotecnología, Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco 186, Col. Vicentina, 09340, Ciudad de México, Mexico;1. Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China;2. National Technology Innovation Center of Synthetic Biology, Tianjin, 300308, China;3. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China;4. Department of Biology and Biological Engineering, Chalmers University of Technology, SE 412 96, Gothenburg, Sweden |
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| Abstract: | (+)-Nootkatone is a valuable, functional sesquiterpene that is widely used in food, cosmetics, pharmaceutical, agriculture, and other fields. However, only traces of it accumulate in plants, which is insufficient to meet the market demand. Therefore, commercial (+)-nootkatone is currently synthesized from (+)-valencene. Here, we engineered Saccharomyces cerevisiae to achieve high production of (+)-valencene. Employing gene screening, protein engineering and biosynthetic pathway optimization, we achieved 12.4 g/L (+)-valencene production with the mutant strain. This titer was further increased to 16.6 g/L, the highest titer reported to date, by coupling critical factors for cell growth and biochemical pathway induction. Subsequently, (+)-nootkatone was chemically synthesized from bio-fermented (+)-valencene with a yield of 80%. This study achieved efficient microbial synthesis of (+)-valencene, which may be utilized in industrial production and stabilize the supply of (+)-nootkatone. |
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| Keywords: | (+)-Valencene (+)-Nootkatone Metabolic engineering Chemical conversion |
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