Delgadillo David A, Wu Lin, Wang Caroline, Zhang Yalong, Jha Kunal K, Burch Jessica E, de Moraes Lygia Silva, Rodriguez Isabel Hernandez, Tang Melody J, Bills Gerald F, Tu Benjamin P, Tang Yi, Nelson Hosea M
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
Departments of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California 90095, United States.
J Am Chem Soc. 2025 Jul 30;147(30):26158-26164. doi: 10.1021/jacs.5c01466. Epub 2025 Jun 3.
Nature remains a vast repository of complex and functional metabolites whose structural characterization continues to drive innovations in pharmaceuticals, agrochemicals, and materials science. The cryogenic electron microscopy (cryoEM) method, microcrystal electron diffraction (microED, a 3D ED technique), has emerged as a powerful tool to structurally characterize small molecules. Despite this emerging role in structural chemistry, the cost and throughput of microED have limited its application in the discovery of natural products (NPs). While recent advances in sample preparation (e.g., arrayED) have provided a conceptual framework to address these challenges, they have remained unproven. Herein, we report the arrayED-driven discovery of a structurally unprecedented family of NPs (zopalides A-E), a muurolane-type sesquiterpene glycoside (rhytidoside A), aspergillicin analogs (aspergillicins H and I), and four crystal structures of previously reported fungal metabolites. Lastly, this the first time that the absolute stereo configuration of newly discovered NPs has been determined directly by microED alone without other methods using a small amount of sample.
自然界仍然是复杂且具有功能的代谢物的巨大宝库，其结构表征不断推动着制药、农用化学品和材料科学领域的创新。低温电子显微镜（cryoEM）方法，即微晶电子衍射（microED，一种三维电子衍射技术），已成为对小分子进行结构表征的有力工具。尽管microED在结构化学中发挥着越来越重要的作用，但其成本和通量限制了它在天然产物（NP）发现中的应用。虽然最近在样品制备方面的进展（如阵列电子衍射）提供了应对这些挑战的概念框架，但尚未得到验证。在此，我们报告了通过阵列电子衍射驱动发现的一类结构前所未有的天然产物（佐帕利德A - E）、一种桉叶烷型倍半萜糖苷（皱纹糖苷A）、曲霉霉素类似物（曲霉霉素H和I）以及四种先前报道的真菌代谢物的晶体结构。最后，这是首次仅通过microED直接确定新发现的天然产物的绝对立体构型，而无需使用其他方法且只需少量样品。
