Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria
Liyuan Kong,
Gudan Xu,
Xiaoqin Liu,
Jingwen Wang,
Zenglin Tang,
You-Sheng Cai,
Kun Shen,
Weixin Tao,
Yu Zheng,
Zixin Deng,
Neil P.J. Price,
Wenqing Chen
Affiliations
Liyuan Kong
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Gudan Xu
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Xiaoqin Liu
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Jingwen Wang
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Zenglin Tang
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
You-Sheng Cai
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Kun Shen
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Weixin Tao
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Yu Zheng
State Key Laboratory of Food Nutrition and Safety, Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, and College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
Zixin Deng
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
Neil P.J. Price
Agricultural Research Service, US Department of Agriculture, National Center for Agricultural Utilization Research, Peoria, IL, USA
Wenqing Chen
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Corresponding author
Summary: Minimycin (MIN) is a C-nucleoside antibiotic structurally related to pseudouridine, and indigoidine is a naturally occurring blue pigment produced by diverse bacteria. Although MIN and indigoidine have been known for decades, the logic underlying the divergent biosynthesis of these interesting molecules has been obscure. Here, we report the identification of a minimal 5-gene cluster (min) essential for MIN biosynthesis. We demonstrated that a non-ribosomal peptide synthetase (MinA) governs “the switch” for the divergent biosynthesis of MIN and the cryptic indigoidine. We also demonstrated that MinCN (the N-terminal phosphatase domain of MinC), MinD (uracil phosphoribosyltransferase), and MinT (transporter) function together as the safeguard enzymes, which collaboratively constitute an unusual self-resistance system. Finally, we provided evidence that MinD, utilizing an unprecedented substrate-competition strategy for self-resistance of the producer cell, maintains competition advantage over the active molecule MIN-5′-monophosphate by increasing the UMP pool in vivo. These findings greatly expand our knowledge regarding natural product biosynthesis. : Biotechnology; Microbial Biotechnology; Systems Biology Subject Areas: Biotechnology, Microbial Biotechnology, Systems Biology
