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Coordination of Polyketide Release and Multiple Detoxification Pathways for Tolerable Production of Fungal Mycotoxins |
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| Authors: | Fei Cao Lie-Feng Ma Long-Shuang Hu Chu-Xuan Xu Xuepeng Chen Zha-Jun Zhan Prof. Qing-Wei Zhao Prof. Xu-Ming Mao |
| Affiliation: | 1. Research Center for Clinical Pharmacy, The First Affiliated Hospital & Institute of Pharmaceutical Biotechnology, School of Medicine, Zhejiang University, Hangzhou, 310058 China Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Zhejiang University, Hangzhou, 310058 China These authors contributed equally to this work.;2. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014 China These authors contributed equally to this work.;3. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310006 China;4. Research Center for Clinical Pharmacy, The First Affiliated Hospital & Institute of Pharmaceutical Biotechnology, School of Medicine, Zhejiang University, Hangzhou, 310058 China Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Zhejiang University, Hangzhou, 310058 China;5. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014 China;6. Research Center for Clinical Pharmacy, The First Affiliated Hospital & Institute of Pharmaceutical Biotechnology, School of Medicine, Zhejiang University, Hangzhou, 310058 China |
| Abstract: | Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E ( 1 ) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1 . If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs. |
| Keywords: | Backbone Release Biosynthesis Coordinated Regulation Detoxification Fungal Mycotoxins |