|
|||||
|
|
Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids |
|
| Authors: | Dr. Takaaki Mitsuhashi Dr. Lena Barra Zachary Powers Volga Kojasoy Andrea Cheng Feng Yang Dr. Yoshimasa Taniguchi Dr. Takashi Kikuchi Prof. Dr. Makoto Fujita Prof. Dr. Dean J. Tantillo Prof. Dr. John A. Porco Jr Prof. Dr. Ikuro Abe |
| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan Division of Advanced Molecular Science, Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, 444-8787 Japan These authors contributed equally to this work.;2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan These authors contributed equally to this work.;3. Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, 02215 USA These authors contributed equally to this work.;4. Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California, 95616 USA These authors contributed equally to this work.;5. Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts, 02215 USA;6. Central Laboratories for Key Technologies, Kirin Holdings Co. Ltd., 1-13-5, Fukuura Kana-zawa-ku, Yokohama-shi, Kanagawa, 236-0004 Japan;7. Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima-shi, Tokyo, 196-8666 Japan;8. Division of Advanced Molecular Science, Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, 444-8787 Japan Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656 Japan;9. Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California, 95616 USA;10. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan |
| Abstract: | Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies. |
| Keywords: | chemoenzymatic synthesis combinatorial biosynthesis crystalline-sponge x-ray diffraction meroterpenoid cyclase meroterpenoids |