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Capturing the key protein and substrate interactions in polyketide synthases using isosteric mimetics

使用等排模拟物捕获聚酮合酶中的关键蛋白质和底物相互作用

基本信息

批准号：
10456293
负责人：
Rebecca N. Re
金额：
$ 3.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456293
关键词：
3-hydroxybutanal Active Sites Acyl Carrier Protein Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antifungal Agents Antineoplastic Agents Attention Biochemistry Biological Biology Carbon Carrier Proteins Chemicals Coenzyme A Complex Crystallization Custom Development Disease Doxorubicin Engineering Enzymes Erythromycin Goals Health Immunosuppressive Agents Isoxazoles Knowledge Lead Learning Length Malonyl Coenzyme A Modeling Modern Medicine Molecular Molecular Machines Natural Products Nature Organism Paper Pharmaceutical Preparations Physical condensation Process Production Proteins Publishing Reaction Research Research Personnel Side Sirolimus Specificity Structure Structure-Activity Relationship Substrate Interaction Synthesis Chemistry System Therapeutic Training Vertebral column Work X-Ray Crystallography actinorhodin analog clay crosslink design diphenyl enzyme activity enzyme pathway enzyme structure falls interdisciplinary approach mimetics novel novel anticancer drug novel therapeutics pharmacophore polyketide synthase prevent protein complex protein crosslink protein protein interaction structural biology success symposium thioether tool

项目摘要

Project Summary. With the majority of therapeutic drugs available on the market being natural products or derivatives of them, understanding how organisms and enzymes function to produce these structurally complex compounds is essential. Polyketides are a class of secondary metabolites that are biosynthesized by polyketide synthases (PKSs) and often serve as antibacterial, antifungal, and anticancer agents. The PKSs are complex biological machineries that involve proteins and substrates interacting with one another with high specificity to assemble polyketides. These unique protein-protein and protein-substrate interactions are the basis for how these synthases are governed and are therefore critical to understand. Common in all three types of PKSs is the iterative elongation of polyketide intermediates by two-carbon units, but how their respective elongation enzymes function and stabilize the substrates while preventing them from undergoing unwanted side reactions continues to remain unknown. In this proposal, we aim to first understand the fit of growing polyketones in the pocket of a carrier protein-guided elongation enzyme by developing isosteric mimetics of polyketide intermediates from a type II PKS model. Here, we will use crosslinking to trap the partner proteins to elucidate the key interactions as the intermediates are elongated. We then plan to apply similar chemical biology tools in our second research aim to define the substrate interactions catalyzed by a CoA-dependent elongation enzyme in a type III PKS system. In this study, we will develop polyketide intermediate mimetics and malonyl-CoA analogs to be able to provide a snapshot of the natural substrate interactions through x-ray crystallography. These studies will allow us to uncover the molecular details that drive the elongation process responsible for building the core carbon backbone of polyketides. Gaining a deeper understanding of these protein and substrate interactions enables their manipulation and redesign to produce novel polyketides with different pharmacophores.

项目总结。市场上的大多数治疗药物都是天然产物或