Microcrystal Electron Diffraction-Guided Discovery of Fungal Metabolites

Area of Science:

• Natural product chemistry
• Structural biology
• Crystallography

Background:

• Nature is a rich source of complex molecules driving innovation in medicine and materials.
• Microcrystal electron diffraction (microED) is a powerful technique for small molecule structure determination.
• Current limitations in cost and throughput hinder microED's application in natural product discovery.

Purpose of the Study:

• To demonstrate the efficacy of arrayED for natural product discovery using microED.
• To overcome the throughput and cost limitations of traditional microED methods.
• To discover and structurally characterize novel natural products.

Main Methods:

• Development and application of arrayED for sample preparation.
• Structure determination of small molecules using microED.
• Analysis of natural products from fungal sources.

Main Results:

• Discovery of a novel family of natural products, zopalides A-E.
• Identification of rhytidoside A, a muurolane-type sesquiterpene glycoside.
• Characterization of aspergillicin analogs (H and I) and four known fungal metabolites.
• First-time direct determination of absolute configurations for new natural products using only microED.

Conclusions:

• ArrayED significantly enhances the throughput and applicability of microED for natural product discovery.
• MicroED alone is sufficient for determining the absolute configurations of novel natural products.
• This work opens new avenues for exploring nature's chemical diversity.