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

> **NIH NIH R15** · HAVERFORD COLLEGE · 2020 · $297,992

## Abstract

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.

## Key facts

- **NIH application ID:** 10045624
- **Project number:** 2R15GM120704-02
- **Recipient organization:** HAVERFORD COLLEGE
- **Principal Investigator:** Louise Karine Charkoudian
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $297,992
- **Award type:** 2
- **Project period:** 2016-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045624

## Citation

> US National Institutes of Health, RePORTER application 10045624, Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics (2R15GM120704-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10045624. Licensed CC0.

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