RUI: BIOPOLYMER - BIObricks POLYketide Metabolic EngineeRing platform for unraveling the biosynthesis of higher anthracyclines

土壤细菌产生多种化合物。有些具有药用价值。这些分子中有一类被称为蒽环类（ACs）。蒽环类药物治疗几种癌症。这个项目的目的是了解空调生产的规律。相关的酶和途径将“混合和匹配”，以产生具有潜在的新型抗肿瘤特性的新型ACs。该项目将由本科生完成，由首席研究员指导。预计让本科生参与研究将有效地培养他们在生物制造经济中的职业。结果将通过播客与公众沟通。总体目标是表征糖基化ac的生物合成。这是一种聚酮类天然产物，具有复杂的糖链，由一个或多个氨基糖和硝基糖部分修饰。在聚酮上很少观察到硝基糖。负责它们的生物形成和附着的酶很少被了解。这些途径将聚集在一起产生新的ac。中心假设是高级蒽环类途径具有共同的进化和酶的起源。这将通过比较生物信息学来检查，以告知途径建设。这一假设将在两个目标上进行功能测试：(1)两个更高的蒽环类药物途径将在放线菌中完全重构；(2)利用组合生物合成技术合成具有抗癌和抗菌活性的新型AC类似物。最终目标是开发合成“自然新”药物的设计能力。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。

Soil bacteria produce a variety of compounds. Some have medicinal value. A notable class of these molecules are referred to as anthracyclines (ACs). Anthracyclines treat several types of cancer. The objective of this project is to understand the regulation of AC production. Related enzymes and pathways will be "mixed and matched" to produce novel ACs with potentially novel anti-tumor properties. The project will be performed by undergraduates, directed by the principal investigator. It is expected that involving undergraduates in research will be effective in training them for careers in the biomanufacturing economy. Results will be communicated with the public through podcasts. The overall objective is to characterize the biosynthesis of glycosylated ACs. These are polyketide natural products with elaborate saccharide chains adorned with one or more amino-sugar and nitro-sugar moieties. Nitro-sugars are rarely observed on polyketides. The enzymes responsible for their biogenesis and attachment are poorly understood. Pathways will be brought together to yield new ACs. The central hypothesis is that the higher anthracycline pathways have shared evolution and enzymatic origins. This will be examined via comparative bioinformatics to inform pathway construction. This hypothesis will be functionally tested in two objectives: (1) two higher anthracycline pathways will be fully refactored in actinomycetes; and (2) the professor and his students will use combinatorial biosynthesis to synthesize new AC analogs expected to have anticancer and antibacterial activities. The ultimate goal is to develop design capabilities for synthesizing “new to nature” pharmaceuticals.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.