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。有些具有医疗价值。这些分子一类称为蒽环类分子（ACS）。蒽环类药物治疗几种类型的癌症。该项目的目的是了解AC生产的调节。相关的酶和途径将“混合和匹配”，以产生具有潜在新型抗肿瘤特性的新型AC。该项目将由主要研究人员指导的大学生进行。预计参与研究的大学生将有效地培训他们从事生物制造经济的职业。结果将通过播客与公众传达。总体目标是表征糖基化AC的生物合成。这些是带有一个或多个氨基糖和硝基糖中的精美糖链的聚酮化合物天然产物。在聚酮化合物上很少观察到硝基糖。负责其生物发生和附着的酶的理解很少。途径将聚集在一起，以产生新的AC。中心假设是，较高的蒽环类途径具有共同的进化和酶促的起源。这将通过比较生物信息学对此进行检查，以告知途径构建。该假设将在两个目标中进行功能测试：（1）在放线菌中将完全重构邻苯二甲林的途径； （2）教授和他的学生将使用组合生物合成来综合预计将具有抗癌和抗菌活动的新AC类似物。最终目标是开发综合“新的自然”制药的设计能力。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响评估标准，认为通过评估来获得珍贵的支持。