# Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis

> **NIH NIH R01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2022 · $192,604

## Abstract

PROJECT SUMMARY
Dinuclear iron enzymes (DIs) utilize a carboxylate- and histidine-coordinated cofactor to
affect synthetically challenging biochemical reactions. The recognized roles for DIs have
recently expanded to include several important natural product biosynthetic pathways,
including the generation of folate in pathogenic bacteria, the modulation of antibiotic
potency via halogen installation, and the synthesis of essential secondary metabolites
through carbon-carbon bond scission. To understand the molecular basis for how a very
similar cofactor and structural core can perform such diverse functions, we propose to
study three newly discovered DIs that contain nearly identical coordination motifs and
overall structural scaffolds but orchestrate chemistry in ways that fundamentally differ
from both each other and from well-studied DIs that instead perform the oxygenation of
substrates. The proposed work will utilize an array of spectroscopic, kinetic, and genetic
tools to identify key sites of the protein, substrate, and cofactor that enable such disparate
activities. An elucidation of the structural basis for DI functional reprogramming will
provide a biochemical template for the synthesis of new pharmacophores and the
molecular basis for pathways that are critical for microbial proliferation and pathogenicity.

## Key facts

- **NIH application ID:** 10581314
- **Project number:** 3R01GM135315-04S1
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Thomas M Makris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,604
- **Award type:** 3
- **Project period:** 2019-09-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581314

## Citation

> US National Institutes of Health, RePORTER application 10581314, Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis (3R01GM135315-04S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10581314. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*