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Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis |
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| Authors: | Dr. Guangtao Zhang Dr. Wenjun Zhang Dr. Qingbo Zhang Ting Shi Liang Ma Dr. Yiguang Zhu Dr. Sumei Li Dr. Haibo Zhang Prof. Dr. Yi‐Lei Zhao Prof. Dr. Rong Shi Prof. Dr. Changsheng Zhang |
| Affiliation: | 1. Key Laboratory of Tropical Marine Bio‐resources and Ecology, RNAM Center for Marine Microbiology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301 (China);2. State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240 (China);3. Département de biochimie, de microbiologie et de bio‐informatique, PROTEO et IBIS, Université Laval, Québec, G1V 0A6 (Canada) |
| Abstract: | Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five‐membered ring in ikarugamycin is reported. A three‐gene‐cassette ikaABC from the marine‐derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five‐membered ring by a Michael addition‐like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs. |
| Keywords: | biosynthesis heterologous expression ikarugamycin polycyclic tetramate macrolactams reductive cyclization |