Bioinformatic Guided Discovery and Characterization of New RiPP Natural Products

新 RiPP 天然产物的生物信息引导发现和表征

• 批准号: 10667603
• 负责人: Jonathan Rodi Chekan
• 金额: $ 34.82万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667603
• 关键词: Antibiotics; Artemisinins; Biochemical; Bioinformatics; Complement; Development; Elements; Engineering; Enzymes; Family; Future; Gene Cluster; Genome; Health; Human; Lead; Life; Link; Logic; Methodology; Mining; Modern Medicine; Natural Products; Nature; Organism; Pathway interactions; Penicillins; Peptides; Pharmaceutical Preparations; Postdoctoral Fellow; Process; Ribosomes; Scientist; Techniques; Training; Trees; bioactive natural products; graduate student; guided inquiry; in silico; insight; interdisciplinary approach; next generation; novel therapeutics; peptide natural products; secondary metabolite

PROJECT SUMMARY Ranging from penicillin to artemisinin, natural products have been essential in the discovery and development of new drugs. To complement the traditional activity-guided isolation approaches, genome mining techniques can enable an efficient and high throughput discovery pipeline by specifically targeting promising organisms and gene clusters for detailed study. However, detailed understanding of a biosynthetic pathway is typically needed, significantly constraining the search process. Therefore, alternative bioinformatic approaches combined with detailed biochemical characterization and bioactivity studies will help expand our collective understanding of bioactive secondary metabolites in nature and their value for human health. The overall focus of the Chekan lab is to utilize enzyme-independent genome mining as a guide to enable the discovery and detailed study of new types of bioactive natural products and biosynthetic pathways. This proposal focuses on the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. RiPPs are a ubiquitous family of natural products found across all domains of life and possess a wide range of bioactivities, with antibiotic activity being particularly well represented. These natural products all share a consistent biosynthetic logic, but can be generated from a wide variety of biosynthetic enzymes. In order to discover completely new classes of RiPPs, we propose to exploit conserved biosynthetic and structural features instead of specific enzymatic transformations. This will allow for rapid in silico identification of promising biosynthetic gene clusters that generate never before isolated molecules. To fully study and characterize these new pathways, a combination of biochemical and structural approaches will be employed. These results will give important insights into the new biosynthetic enzymes, reveal their mechanisms, and assess their applicability for engineering. Finally, this first project will reveal the bioactivity of the newly discovered natural products and their mechanism of action. To complement this discovery element, a second project will seek to link peptidic natural product families, for which no biosynthetic information is available, to their biosynthetic enzymes. This proposal will also enable the training of both graduate students and postdocs, the next generation of scientists responsible for advancing human health. Overall, the results of this proposal will not only lead to the discovery of new natural products and enzymes, but will inform future genome mining based discovery studies and pathway engineering efforts to identify promising drug leads.

项目摘要 从青霉素到青蒿素，天然产物在发现和 开发新药。为了补充传统的活动导向分离方法，基因组挖掘 这些技术可以通过专门针对有希望的发现流水线来实现高效和高吞吐量的发现流水线 生物和基因簇进行详细研究。然而，对生物合成途径的详细了解是 这通常是必需的，极大地限制了搜索过程。因此，替代生物信息学方法 结合详细的生物化学表征和生物活性研究将有助于扩大我们的集体 了解自然界中具有生物活性的次级代谢产物及其对人类健康的价值。 Chekan实验室的总体重点是利用酶独立基因组挖掘作为指导， 发现和详细研究新型生物活性天然产物和生物合成途径。这 该提案的重点是核糖体合成和后修饰肽（RiPP）家族， 天然产品。RIPP是一种无处不在的天然产物家族，在生活的各个领域都有发现， 具有广泛的生物活性，其中抗生素活性特别突出。这些天然产品 它们都具有一致的生物合成逻辑，但可以由多种生物合成酶产生。在 为了发现全新的RIPPs，我们建议利用保守的生物合成和结构 特征而不是特定的酶促转化。这将允许快速在计算机上识别有希望的 生物合成基因簇产生了以前从未分离过的分子。为了充分研究和描述这些 新的途径，生物化学和结构方法的组合将被采用。这些结果将使 新的生物合成酶的重要见解，揭示其机制，并评估其适用性， 工程.最后，这第一个项目将揭示新发现的天然产物的生物活性及其 作用机制。为了补充这一发现元素，第二个项目将寻求将肽天然 没有生物合成信息可用的产品系列，其生物合成酶。这项建议 还将使研究生和博士后的培训，下一代科学家负责 促进人类健康。总的来说，这项建议的结果不仅会导致新的自然发现， 产品和酶，但将告知未来的基因组挖掘为基础的发现研究和途径工程 努力确定有希望的药物线索。

项目成果

A Widely Distributed Biosynthetic Cassette Is Responsible for Diverse Plant Side Chain Cross-Linked Cyclopeptides.

• DOI: 10.1002/anie.202218082
• 发表时间: 2023-02-06
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Lima, Stella T.;Ampolini, Brigitte G.;Underwood, Ethan B.;Graf, Tyler N.;Earp, Cody E.;Khedi, Imani C.;Pasquale, Michael A.;Chekan, Jonathan R.
• 通讯作者: Chekan, Jonathan R.