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Structural biology of polyether antibiotic biosynthesis

聚醚抗生素生物合成的结构生物学

基本信息

批准号：
10912964
负责人：
Chu-Young Kim
金额：
$ 31.72万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10912964
关键词：
Acyl Carrier Protein Acyltransferase Anabolism Anti-Bacterial Agents Antibiotics Antifungal Agents Bacteria Binding Biochemical Biogenesis Biological Models Chemicals Complex Cyclic Ethers Cyclization Development Docking Engineering Ensure Enzymes Epoxide hydrolase Epoxy Compounds Family Flavins Foundations Friends Future Gene Cluster Goals Investigation Laboratories Mixed Function Oxygenases Molecular Molecular Conformation Natural Products Nature Organism Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Polyenes Production Property Reaction Research Scheme Solid Streptomyces Structure Subgroup Techniques Testing Therapeutic Time Vertebral column Work Yeasts anti-cancer dimer drug development novel novel therapeutics polyketide synthase polyketides programs protein protein interaction seal structural biology

项目摘要

The overarching goal of our research program is to elucidate how nature produces polyether natural products. Polyethers are a subgroup of polyketide natural products and, as a class, they possess a wide range of useful activities, including antibacterial, antifungal, and anticancer properties. However, polyether drug development is hampered by our inability to quickly and efficiently synthesize natural polyethers and their derivatives for medicinal chemistry and drug optimization studies. This is due to the unusually complex structure of natural polyethers. An attractive solution to this problem is to biosynthesize complex polyethers using engineered laboratory-friendly organisms such as bacteria or yeast. This approach is expected to make countless new polyethers accessible for drug research. In order to create a robust and reliable polyether bioproduction platform, we must first achieve a detailed and comprehensive understanding of how polyethers are produced in living organisms. More than 100 different polyether natural products have been discovered so far, and examination of known polyether biosynthetic gene clusters show that all polyethers are generated via a common three-stage biosynthetic scheme. Stage 1: construction of the polyketide backbone by modular polyketide synthases. Stage 2: stereoselective epoxidation of the polyene intermediate by a monooxygenase. Stage 3: formation of the hallmark cyclic ether groups by one or more epoxide hydrolases. The universal nature of this scheme ensures that investigation of any one particular polyether biosynthesis pathway and its associated enzymes will lead to a general understanding of how nature generates polyethers. In this project, we will study the biosynthetic enzymes from the lasalocid A biosynthesis pathway from Streptomyces lasaliensis. Lasalocid A biosynthesis pathway is an excellent model system for studying how nature produces polyethers because it consists of just nine enzymes, yet it possesses all the hallmark chemical transformations of polyether biosynthesis.

我们研究项目的首要目标是阐明自然界是如何产生聚醚的