# Polynuclear iron complexes as functional mimics of the nitrogenase FeMo-cofactor

> **NIH NIH R01** · HARVARD UNIVERSITY · 2020 · $314,515

## Abstract

Project Summary: Functional models of the polynuclear nitrogen-fixing enzyme cofactors
Nitrogen entry into the biosphere is the rate-limiting step for all biological processes, and therefore, life itself.
Dinitrogen reduction occurs at polynuclear metalloenzymes called nitrogenase. The reaction center of the
Molybdenum-containing enzyme consists of a cysteine ligated MoFe7S7 cofactor (FeMoco) where dinitrogen
fixation takes place. Despite good structural information about the cofactor, many questions regarding substrate
uptake and the overall chemical action of the cofactor during turnover remain. Specifically, the redox flexibility of
Mo point to its likely involvement in substrate activation, which has been vetted by functional model studies.
However, site-mutagenesis studies and theoretical models indicate a polynuclear Fe-face of FeMoco to
participate in substrate activation. Synthetic structural analogues have been fashioned to reproduce the cofactor
composition and elucidate structural details that mimic the cofactor. However, no synthetic models exist that
would permit probing of the interaction between nitrogenase substrates and a polynuclear reaction site
reminiscent of those present in FeMo/FeV/Feco. Using synthetic methodology developed in our laboratories to
reliably synthesize polynuclear clusters, the goal of the proposed research is to both functionally and structurally
model the active site of FeMoco. Polyamide and polyamide/sulfide ligand systems permit the isolation and study
of well-defined tri- and hexanuclear iron complexes. The molecular tri-iron units will allow systematic examination
of the reaction chemistry of nitrogenase substrates with an iron-only reaction site. Furthermore, bimolecular
coupling of tri-iron units will permit the synthesis and characterization of various structural mimics of the cofactor
featuring different interstitial atom components (e.g., C, N, O, S). The proposed research will permit the testing
of several hypotheses concerning interaction of nitrogenase substrates with polynuclear reaction sites prevalent
in the native enzyme: how do substrates bind; how is redox distributed throughout the cluster reaction site; how
do surface hydrides gate dinitrogen or substrate binding; can we authenticate mechanistic proposal for the
enzyme by observation of abiological models? The viability of the synthetic analogues to mimic nitrogenase
activity will be probed by profiling the reactivity of the synthetic clusters towards nitrogenase substrates.

## Key facts

- **NIH application ID:** 9982407
- **Project number:** 5R01GM098395-09
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Theodore A Betley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,515
- **Award type:** 5
- **Project period:** 2011-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982407

## Citation

> US National Institutes of Health, RePORTER application 9982407, Polynuclear iron complexes as functional mimics of the nitrogenase FeMo-cofactor (5R01GM098395-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982407. Licensed CC0.

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