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.
Angew Chem Int Ed Engl. 2020 Dec 21;59(52):23772-23781. doi: 10.1002/anie.202011171. Epub 2020 Oct 22.
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.
真菌混合萜类化合物是一组结构复杂、具有巨大药物开发潜力的多样化天然产物。在这项工作中，我们评估了真菌混合萜类化合物生物合成途径中早期结构多样性产生步骤的多功能性：由真菌混合萜类化合物环化酶家族催化的多键形成多烯环化。总共使用合成底物化学生物学方法获得了 12 种非天然混合萜类化合物。通过二维 NMR 研究以及基于晶体海绵的 X 射线衍射分析确定了它们的复杂结构。结果表明酶具有高度的多功能性，实验结果结合量子化学计算为深入了解这种新型非典型萜烯环化酶的催化活性提供了依据。所获得的知识为设计和工程基于组合生物合成策略的具有有价值生物活性的第二代混合萜类化合物的人工途径铺平了道路。
