Discovery and Characterization of Natural Product Systems

天然产物系统的发现和表征

• 批准号: 10206351
• 负责人: DAVID H SHERMAN
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206351
• 关键词: Achievement; Antibiotic Resistance; Antibiotics; Area; Bacteria; Biological; Catalytic Domain; Complex; Development; Diels Alder reaction; Enzymes; Gatekeeping; Hydroxylation; Indole Alkaloids; Macrolides; Methods; Molecular Machines; Natural Products; Pathway interactions; Pharmacologic Substance; Process; Publications; Reaction; Reporting; Research; Structure; System; Testing; Therapeutic Agents; Type I Polyketide Synthase; Work; flexibility; glycosylation; human pathogen; microbial; next generation; novel strategies; polyketide synthase; programs

Project Summary. In this competing renewal of R35 GM118101, we propose to focus on investigating and developing biocatalytic systems that generate complex natural products with high potential as therapeutic agents. This program has been highly productive with 34 publications over the past four years. Major progress continues toward studies on the function and structure of modular polyketide synthases (PKSs) from bacteria. A second thematic area involves studies on diverse bacterial and fungal indole alkaloid pathways for which we have reported important achievements on characterizing biosynthetic enzymes that catalyze pericyclic (e. g. Cope, Diels-Alder) reactions. We plan to build on these studies and also expand work on allied tailoring reactions for indole alkaloid structural diversification. Our work in the type I PKS area will focus on function and structure of key catalytic domains that we have identified to be gatekeepers in the catalytic cycle. By employing natural and unnatural advanced polyketide chain elongation intermediates with late stage PKS modules, we plan to develop methods to expand the biocatalytic potential of these remarkable molecular machines for assembly of macrolactone structures. Further glycosylation and late-stage hydroxylation/epoxidation methods will be employed to generate next generation macrolides for testing against a range of antibiotic-resistant human pathogens. Our work in the microbial indole alkaloids will focus on natural products whose core ring systems are derived from biocatalytic pericyclic reactions. Mechanistic understanding of these unusual processes is rapidly emerging, and their apparent flexibility indicates high potential for metabolite structural diversification. These efforts will be augmented by exploring late-stage tailoring enzymes capable of further modifying core indole alkaloid structures to generate a range of biologically active products with significant pharmaceutical potential.

项目摘要。在R35 GM118101的竞争更新中，我们建议专注于调查和 开发生物催化系统，产生具有高治疗潜力的复杂天然产物 探员们。在过去的四年里，这一计划取得了很高的成效，出版了34种出版物。重大进展 继续研究细菌中模块化聚酮合成酶(PKSS)的功能和结构。一个 第二个主题领域涉及不同的细菌和真菌吲哚生物碱途径的研究，我们 已经报道了在表征催化周环的生物合成酶方面的重要成果(例如。 柯普，迪尔斯-阿尔德)反应。我们计划在这些研究的基础上，扩大有关联合剪裁反应的工作 用于吲哚生物碱的结构多样化。 我们在第一类PKS领域的工作将集中在我们拥有的关键催化域的功能和结构上 被确认为催化循环中的看门人。利用天然和非天然高级聚酮链 延长中间体与后期的PKS模块，我们计划开发方法来扩大生物催化 这些非凡的分子机器在组装大内酯结构方面的潜力。进一步糖基化 并将采用后期羟化/环氧化方法生成新一代大环内酯类化合物 对一系列具有抗生素耐药性的人类病原体进行测试。 我们在微生物吲哚生物碱方面的工作将集中在核心环系衍生的天然产物上。 来自生物催化周环反应。对这些不寻常的过程的机械论理解正在迅速形成， 它们明显的灵活性表明代谢物结构多样化的潜力很大。这些努力将是 通过探索能够进一步修饰核心吲哚生物碱结构的后期剪裁酶来增强 生产一系列具有巨大药用潜力的生物活性产品。