Discovery and Characterization of Natural Product Systems

天然产物系统的发现和表征

• 批准号: 10418743
• 负责人: DAVID H SHERMAN
• 金额: $ 38.11万
• 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/10418743
• 关键词: Achievement; Antibiotic Resistance; Antibiotics; Area; Bacteria; 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，我们建议重点研究和 开发生物催化系统，产生具有高治疗潜力的复杂天然产物 代理。该计划在过去四年中已发表 34 篇出版物，成效显着。主要进展 继续研究细菌模块化聚酮合酶（PKS）的功能和结构。一个 第二个主题领域涉及对多种细菌和真菌吲哚生物碱途径的研究，我们为此 报道了在表征催化周环的生物合成酶（例如 Cope，Diels-Alder）反应。我们计划以这些研究为基础，并扩大联合定制反应的工作 用于吲哚生物碱结构多样化。 我们在 I 型 PKS 领域的工作将重点关注我们拥有的关键催化域的功能和结构 被认为是催化循环中的看门人。采用天然和非天然先进聚酮化合物链 具有后期PKS模块的延伸中间体，我们计划开发方法来扩展生物催化 这些非凡的分子机器在组装大环内酯结构方面的潜力。进一步糖基化 后期羟基化/环氧化方法将用于生成下一代大环内酯类化合物 针对一系列对抗生素具有抗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重点关注其核心环系统衍生的天然产物 来自生物催化周环反应。对这些不寻常过程的机械理解正在迅速出现， 它们明显的灵活性表明代谢物结构多样化的巨大潜力。这些努力将 通过探索能够进一步修饰核心吲哚生物碱结构的后期定制酶来增强 生产一系列具有巨大制药潜力的生物活性产品。