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.

项目总结。在R35 GM118101的竞争更新中，我们建议重点研究和研究