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Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics

通过跟踪酰基载体蛋白结合和构象动力学进行功能性杂化天然产物合成

基本信息

批准号：
10045624
负责人：
Louise Karine Charkoudian
金额：
$ 29.8万
依托单位：
HAVERFORD COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045624
关键词：
4&apos -phosphopantetheine Actinobacteria class Acyl Carrier Protein Affect Affinity Amino Acid Sequence Amino Acids Anabolism Antibiotics Authorship Behavior Binding Binding Proteins Biological Assay Biology Calorimetry Chemicals Chemistry Collaborations Complex Coupled Coupling Crystallography Engineering Environment Enzyme Interaction Enzymes Escherichia coli Event Fatty Acids Foundations Funding Future Genes Goals Hybrids Hydro-Lyases Lead Length Methodology Methods Modeling Molecular Molecular Conformation Motion Natural Products Outcome Paper Pathway interactions Pharmacologic Substance Play Protein Conformation Proteins Publications Publishing Rattus Research Research Personnel Research Project Grants Role Route Site Specificity Structure Study Subject Training United States National Institutes of Health Work arm base college crosslink design experience experimental study holo-(acyl-carrier-protein) synthase innovation insight microorganism mutant next generation novel polyketide synthase protein protein interaction protein structure function sedimentation velocity small molecule success temporal measurement tool undergraduate research undergraduate student vibration

项目摘要

PROJECT SUMMARY Microorganisms produce structurally diverse molecules, many of which have been successfully repurposed as pharmaceutical agents. These molecules are manufactured by multi-enzyme assemblies, which rely on acyl carrier proteins (ACPs) to modify and transfer chemical intermediates to a team of enzymatic partners. Strategic redesign of natural enzyme assemblies presents an exciting possible route to produce new antibiotics, but the success of any redesign approach hinges on a thorough understanding of what leads to chemically productive ACP-enzyme interactions. The goal of this study is to gain a molecular-level understanding of how ACPs interact with their molecular cargo and enzymatic partners. In the previous funding period, our lab developed new spectrophotometric methodologies that enabled us to unveil the fast and transient interactions between ACPs and their molecular cargo, as well as between ACPs and two enzymatic partners: a ketosynthase (KS) and dehydratase (DH). These studies led to 7 papers with 40 Haverford College undergraduate students earning co-authorship. We now seek to leverage these major advancements to understand the complex interplay between ACP sequence and molecular cargo identity in directing the phenomenon called “chain sequestration,” which is thought to play a critical role in directing biocatalysis. We will also study how chain sequestration effects ACP-KS binding affinity and obtain ACP-KS crosslinked structures for subsequent molecular-level structural characterization. Results from these studies will guide the future biosynthesis of novel small molecules with potential pharmaceutical activity. The work will be executed in the context of independent undergraduate research projects and course-based undergraduate research experiences (CUREs), thereby exposing ~60 undergraduate students to advanced research at the chemistry-biology interface.

项目总结