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

土壤细菌会产生各种化合物。有些还具有药用价值。其中一类值得注意的分子被称为蒽环类药物(ACS)。蒽环类药物可以治疗几种癌症。本项目的目的是了解空调生产的规律。相关的酶和途径将被“混合和匹配”，以产生具有潜在的新的抗肿瘤特性的新型ACS。该项目将由本科生在首席调查员的指导下进行。预计让本科生参与研究将有效地培训他们在生物制造经济中的职业生涯。结果将通过播客与公众交流。总体目标是表征糖基化ACS的生物合成。这些都是聚酮类天然产物，具有精致的糖链，饰以一种或多种氨基糖和硝基糖基。在聚酮类化合物中很少观察到硝化糖。负责它们的生物发生和附着的酶知之甚少。各种途径将结合在一起，产生新的AC。中心假设是，较高的蒽环类途径具有共同的进化和酶起源。这将通过比较生物信息学进行检查，为路径建设提供信息。这一假设将在两个目标上进行功能验证：(1)放线菌中两个更高的蒽环类药物途径将被完全重构；(2)教授和他的学生将利用组合生物合成来合成新的具有抗癌和抗菌活性的AC类似物。该奖项反映了NSF的法定使命，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。

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.