# Protein-Protein Interactions in Natural Product Biosynthesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $482,157

## Abstract

7. Project Summary.
This program investigates the role of protein'protein interactions in carrier protein-dependent biosynthesis,
including fatty acid synthase, polyketide synthase, and non-ribosomal peptide synthetase pathways. The
natural products associated with these pathways serve as therapeutics including antibiotics, antifungals, and
anticancer agents. The ability to direct the biosynthesis of these pathways for the production of untried
bioactive compounds is of critical importance for new and improved therapies. In prior years, we demonstrated
how protein'protein interactions between carrier proteins and partner protein domains direct reactivity and
guide processivity. Moreover, we developed a suite of chemical biology tools to stabilize and interrogate these
interactions at atomic resolution through innovative crosslinker development and structural biology. We now
propose to expand these tools with new, caged crosslinkers designed to capture transient partner proteins.
With this comprehensive library of crosslinkers, we will evaluate carrier protein interactions with partner
proteins that include ketoreductases, enoyl reductases, and thioesterases from fatty acid and polyketide
synthases, ketosynthase/chain-length factors and acyltransferases from polyketide synthases, and
condensation domains, halogenases, and oxidases from non-ribosomal peptide synthetases. Once captured,
these crosslinked species will be studied by solution-phase NMR, kinetic and thermodynamic assays, X-ray
crystallography, and molecular dynamics simulations to more fully elucidate mechanism and specificity
conferred by carrier protein-substrate/intermediate/produ interactions. Finally, we will use data collected in this
program as an informatic platform to enable synthetic biological production of new natural product hybrids.

## Key facts

- **NIH application ID:** 9972685
- **Project number:** 2R01GM095970-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael D. Burkart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,157
- **Award type:** 2
- **Project period:** 2012-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972685

## Citation

> US National Institutes of Health, RePORTER application 9972685, Protein-Protein Interactions in Natural Product Biosynthesis (2R01GM095970-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972685. Licensed CC0.

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