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Shimalactone Biosynthesis Involves Spontaneous Double Bicyclo-Ring Formation with 8π-6π Electrocyclization |
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| Authors: | Prof Isao Fujii Dr Makoto Hashimoto Kaori Konishi Akiko Unezawa Haruka Sakuraba Kenta Suzuki Harue Tsushima Miho Iwasaki Satsuki Yoshida Akane Kudo Rina Fujita Aika Hichiwa Koharu Saito Dr Takashi Asano Dr Jun Ishikawa Dr Daigo Wakana Dr Yukihiro Goda Ayumi Watanabe Mamoru Watanabe Yui Masumoto Dr Junichiro Kanazawa Dr Hajime Sato Prof Masanobu Uchiyama |
| Institution: | 1. Division of Natural Product Sciences, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694 Japan;2. Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640 Japan;3. National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kanagawa, 210-9501 Japan
Current address: Department of Organic Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501 Japan;4. National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kanagawa, 210-9501 Japan;5. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan |
| Abstract: | Shimalactones A and B are neuritogenic polyketides possessing characteristic oxabicyclo2.2.1]heptane and bicyclo4.2.0]octadiene ring systems that are produced by the marine fungus Emericella variecolor GF10. We identified a candidate biosynthetic gene cluster and conducted heterologous expression analysis. Expression of ShmA polyketide synthase in Aspergillus oryzae resulted in the production of preshimalactone. Aspergillus oryzae and Saccharomyces cerevisiae transformants expressing ShmA and ShmB produced shimalactones A and B, thus suggesting that the double bicyclo-ring formation reactions proceed non-enzymatically from preshimalactone epoxide. DFT calculations strongly support the idea that oxabicyclo-ring formation and 8π-6π electrocyclization proceed spontaneously after opening of the preshimalactone epoxide ring through protonation. We confirmed the formation of preshimalactone epoxide in vitro, followed by its non-enzymatic conversion to shimalactones in the dark. |
| Keywords: | biosynthesis electrocyclization oxabicyclo rings polyketides shimalactone |