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

RUI：BIOPOLYMER - BIObricks 聚酮化合物代谢工程平台，用于揭示高级蒽环类药物的生物合成

• 批准号: 2321976
• 负责人: Stephen Nybo
• 金额: $ 36.97万
• 依托单位: Ferris State University (Inc.)
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321976&HistoricalAwards=false
• 关键词: RUI; BIOPOLYMER; BIObricks; POLYketide; Metabolic

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.

土壤细菌产生多种化合物，其中一些具有药用价值，被称为蒽环类药物（AC），该项目的目的是了解蒽环类药物产生的相关调节。酶和途径将被“混合和匹配”，以产生具有潜在新颖抗肿瘤特性的新型AC。该项目将由本科生在首席研究员的指导下进行，预计参与培训的本科生将是有效的。研究结果将通过播客与公众交流，其总体目标是表征糖基化 AC 的生物合成。这些是具有复杂糖链的聚酮天然产物，其上装饰有一种或多种氨基糖和硝基糖。硝基糖在聚酮化合物上很少被观察到，而负责其生物发生和附着的酶却很少被了解。 ACs。中心假设是高级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，以告知途径构建该假设将在两个目标中进行功能测试：（1）两个高级蒽环类途径将得到充分的验证。在放线菌中重构；（2）教授和他的学生将利用组合生物合成来合成有望具有抗癌和抗菌活性的新AC类似物。目标是开发合成“新自然”药物的设计能力。该奖项反映了 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。