Deciphering and engineering an unprecedented fungal biosynthetic pathway for expanded chemical diversity in flavonoids

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Flavonoids are a large family of natural products that provide a variety of human health benefits. How fungi generate flavonoids remains unknown, making it challenging to engineer structurally diverse flavonoids. This project will investigate the biosynthetic pathway for production of a novel flavonoid, chlorflavonin in the fungus Aspergillus candidus. The insight gained will be used to engineer the pathway to create new flavonoids. Graduate, undergraduate and high school students will receive training. A research mentoring program will be established to target underrepresented high school students. This project is designed to answer two fundamental scientific questions. How do fungi make flavonoids? Can fungal flavonoid biosynthetic pathways be engineered to yield novel analogs with unnatural structural features? The chlorflavonin biosynthetic enzymes will be characterized and the sequence of reactions will be investigated. The potential of the halogenase to catalyze the formation of halogenated flavonoids will be evaluated. Other tailoring enzymes will further expand the toolbox of biocatalysts for flavonoid modification. The fundamental knowledge to be gained will facilitate the understanding of the rules of natural product assembly in fungi. Searching for new structures from nature is time-consuming and resource-intensive. This research may provide an effective way to expand the chemical diversity in flavonoids. The novel flavonoids may yield new-generation antimicrobials with applications in agriculture, human health, cosmetics, and the pharmaceutical industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.