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

> **NIH NIH R01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2020 · $301,668

## Abstract

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:** 10283095
- **Project number:** 7R01GM135315-03
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Thomas M Makris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,668
- **Award type:** 7
- **Project period:** 2019-09-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10283095

## Citation

> US National Institutes of Health, RePORTER application 10283095, Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis (7R01GM135315-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10283095. Licensed CC0.

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