Characterizing CmodAA-Containing Biosynthetic Pathways of Nonribosomal Peptides

表征非核糖体肽的含 CmodAA 生物合成途径

• 批准号: 2310177
• 负责人: Bo Li
• 金额: $ 57.77万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2310177&HistoricalAwards=false
• 关键词: Characterizing; CmodAA; Containing; Biosynthetic; Pathways

With the support of the Chemistry in Life Processes program in the Division of Chemistry, Bo Li of the University of North Carolina at Chapel Hill is studying the formation of dehydroamino acids in the biosynthesis of nonribosomal peptides. Nonribosomal peptides are a major class of biologically and industrially important natural products and they are synthesized by microorganisms using enzyme assembly lines known as nonribosomal peptide synthetases (NRPSs). Dehydroamino acids are critical for the biological activities of the natural products that contain them; however, how NRPSs incorporate these amino acids had not been experimentally studied until recently. The PI will study how NRPSs integrate dehydroamino acids into diverse natural products using biochemical, structural, and bioinformatic approaches. The work is expected to advance understanding of the molecular details of the biosynthesis of natural products, particularly the novel biofilm-forming natural products under study here. The proposed study will allow graduate students to acquire specialize training in biological and natural product chemistry and provide summer research opportunities to undergraduates. This research project seeks to understand the biosynthesis of α,β-dehydroamino acids in natural products, which is catalyzed by a unique subgroup of NRPS condensation domains (CmodAA). The research will focus on bicyclic alkaloids, including pyrrolizidines and cyclocarbamates that exhibit diverse bioactivities. In the biosynthesis of these natural products, the function of CmodAA domains and flavin-dependent monooxygenases will be characterized. An uncharacterized CmodAA-containing biosynthetic gene cluster will be investigated to identify potentially novel natural products. This project will use a combination of approaches in biochemistry, structural biology, synthetic chemistry, and bioinformatics. As an important scientific broader impact, this research is expected to enable the incorporation of dehydroamino acids into nonribosomal peptides for engineered biosynthesis and synthetic biology, in general.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.

在化学过程中的化学过程中的支持下，北卡罗来纳大学教堂山分校的Bo li正在研究非透射式胡椒体的生物合成中的脱氢氨基酸的形成。非核糖体辣椒是一类重要的生物学和工业重要天然产物，它们是由使用酶组装系（称为非核糖体辣椒合成酶（NRPS））合成的。脱氢氨基酸对于含有它们的天然产物的生物学活性至关重要。但是，直到最近才对NRPS结合这些氨基酸。 PI将研究NRPS如何使用生化，结构和生物信息学方法将脱氢氨基酸整合到潜水的天然产物中。预计这项工作将提高对天然产物生物合成的分子细节的理解，尤其是在此处研究的新型生物膜形成的天然产物。拟议的研究将允许研究生获得专门的生物和天然产品化学培训，并为本科生提供夏季研究机会。该研究项目旨在了解天然产物中α，β-脱水瘤的生物合成，这是由独特的NRPS冷凝域（CMODAA）催化的。该研究将重点放在生物学生物碱上，包括存在于潜水生物活性的吡咯烷和环氨基烷。在这些天然产物的生物合成中，将表征Cmodaa结构域和黄素依赖性单加氧酶的功能。将研究一个未表征的含Cmodaa的生物合成基因簇，以鉴定潜在的新型天然产物。该项目将使用生物化学，结构生物学，合成化学和生物信息学方面的方法组合。作为重要的科学广播影响，这项研究有望使脱氢氨基酸纳入非侧质辣椒中，以进行工程生物合成和合成生物学，一般而言。这项奖项反映了NSF的法定任务，并通过使用基金会的知识优点和广泛影响来评估NSF的法定任务。