Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids.,Angewandte Chemie International Edition

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Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids.
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-09-15 , DOI: 10.1002/anie.202011171
Takaaki Mitsuhashi _{1,

2} , Lena Barra ₁ , Zachary Powers ₃ , Volga Kojasoy ₄ , Andrea Cheng ₃ , Feng Yang ₃ , Yoshimasa Taniguchi ₅ , Takashi Kikuchi ₆ , Makoto Fujita _{2,

7} , Dean J Tantillo ₄ , John A Porco ₃ , Ikuro Abe _{1,

8}

Affiliation

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.

中文翻译：

利用类萜环化酶的潜力来扩展真菌类萜的化学空间。

真菌类萜是一组多样化的混合天然产物，具有令人印象深刻的结构复杂性和作为候选药物的巨大潜力。在这项工作中，我们评估了真菌类萜生物合成途径中早期结构多样性生成步骤的混杂性：由目前知之甚少的真菌类萜环化酶家族催化的多键形成多烯环化。使用合成底物通过化学酶法总共获得了 12 种非天然类萜。它们的复杂结构是通过二维核磁共振研究以及基于晶体海绵的 X 射线衍射分析确定的。获得的结果揭示了酶的高度混杂性和实验结果，与量子化学计算一起提供了对这一新的非规范萜烯环化酶家族的催化活性的更深入的了解。所获得的知识为基于组合生物合成策略设计和设计具有有价值的生物活性的第二代类萜的人工途径铺平了道路。

更新日期：2020-09-15

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