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

类黄酮类是一大类天然产品，对人类健康有多种益处。真菌是如何产生类黄酮的尚不清楚，这使得设计结构多样化的类黄酮具有挑战性。本项目将研究一种新的类黄酮类化合物--氯黄素在白曲霉中的生物合成途径。获得的洞察力将被用来设计创造新的类黄酮类化合物的途径。研究生、本科生和高中生将接受培训。将建立一个研究指导计划，目标是代表人数不足的高中生。该项目旨在回答两个基本的科学问题。真菌是如何制造类黄酮的？真菌类黄酮类化合物的生物合成途径能否被设计成产生具有非自然结构特征的新的类似物？将对氯黄素生物合成酶进行表征，并对反应顺序进行调查。将评估卤化酶催化形成卤代黄酮类化合物的潜力。其他剪裁酶将进一步扩大生物催化剂的工具箱，用于类黄酮的修饰。将获得的基础知识将有助于理解真菌中天然产物的组装规则。从大自然中寻找新的结构是耗时和资源密集型的。本研究为扩大黄酮类化合物的化学多样性提供了一条有效途径。新的类黄酮类化合物可能会产生新一代抗菌剂，应用于农业、人类健康、化妆品和制药工业。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.