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Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis

Authors

  • Dr. Guangtao Zhang,

    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)
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    • These authors contributed equally to this work.

  • Dr. Wenjun Zhang,

    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)
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    • These authors contributed equally to this work.

  • Dr. Qingbo Zhang,

    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)
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  • Ting Shi,

    1. State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240 (China)
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  • Liang Ma,

    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)
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  • Dr. Yiguang Zhu,

    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)
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  • Dr. Sumei Li,

    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)
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  • Dr. Haibo Zhang,

    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)
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  • Prof. Dr. Yi-Lei Zhao,

    1. State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240 (China)
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  • Prof. Dr. Rong Shi,

    1. Département de biochimie, de microbiologie et de bio-informatique, PROTEO et IBIS, Université Laval, Québec, G1V 0A6 (Canada)
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  • Prof. Dr. Changsheng Zhang

    Corresponding author
    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)
    • 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)===

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  • We thank Prof. Hanjie Ying in Nanjing University of Technology for providing the plasmid pRSF-BmGDH and Prof. Lichuan Gu in Shandong University for providing the strain Thermoplasma acidophilum ATCC 25905. We thank Professors Shuangjun Lin (Shanghai Jiao Tong University) and Ang Li (Shanghai Institute of Organic Chemistry) for helpful discussions. This work is supported in part by the National Natural Science Foundation of China (grant numbers 31125001 and 21377085), the Ministry of Science and Technology of China (grant numbers 2010CB833805 and 2012AA092104), the Chinese Academy of Sciences (grant numberXDA11030403), and the Administration of Ocean and Fisheries of Guangdong Province (grant numbers GD2012-D01-001 and GD2012-D01-002). We are grateful for recording spectroscopic data at SCSIO.

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.

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