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

类黄酮是一大类天然产品，对人体健康有多种益处。真菌如何产生类黄酮仍然未知，这使得设计结构多样化的类黄酮具有挑战性。本课题将研究真菌假丝曲霉（Aspergillus candius）生产新型类黄酮氯黄酮的生物合成途径。所获得的见解将用于设计制造新的类黄酮的途径。研究生、本科生和高中生将接受培训。将设立一个研究指导计划，针对代表性不足的高中生。这个项目旨在回答两个基本的科学问题。真菌是如何产生类黄酮的？真菌类黄酮生物合成途径能否被设计成具有非自然结构特征的新型类似物？对氯黄酮生物合成酶进行了表征，并对其反应顺序进行了研究。并对该卤化酶催化生成卤化黄酮类化合物的潜力进行了评价。其他裁剪酶将进一步扩大类黄酮修饰生物催化剂的工具箱。所获得的基本知识将有助于理解真菌中天然产物组装的规则。从自然界中寻找新的结构是耗时和资源密集的。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。该新型类黄酮可用于生产新一代抗菌剂，在农业、人体健康、化妆品和制药等领域具有广泛的应用前景。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.