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

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $39,633

## Abstract

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.

## Key facts

- **NIH application ID:** 10456293
- **Project number:** 5F31GM139327-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Rebecca N. Re
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,633
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456293

## Citation

> US National Institutes of Health, RePORTER application 10456293, Capturing the key protein and substrate interactions in polyketide synthases using isosteric mimetics (5F31GM139327-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10456293. Licensed CC0.

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