# Modeling the Organometallic Chemistry of Radical S-adenosylmethionine Enzymes

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $292,612

## Abstract

Project Summary/Abstract
Iron-sulfur enzymes perform some of the most challenging transformations in biology. Of these, [Fe4S4]
enzymes are the most ubiquitous and catalyze dozens of known transformations (and likely many more) that
play direct and indirect roles in human health and disease. This proposal concerns the mechanisms of the >
100,000 members of the radical S-adenosyl-L-methionine (SAM) superfamily of enzymes. Understanding their
reaction mechanisms on a molecular level is critical for identifying disease targets and designing mechanism-
based inhibitors. An emerging theme in mechanistic studies of these enzymes is the intermediacy of species
containing Fe–alkyl bonds whereby generation of the reactive 5’-deoxyadenosyl radical may proceed by
homolytic Fe–C bond cleavage. However, the exact electronic and geometric structure of this intermediate, its
function in catalysis, the strength of its Fe–C bond, and the mechanisms by which these steps might occur are
not clear, and there is no precedent in synthetic Fe–S clusters for this structure type or reactivity. We therefore
propose to address these questions using structurally and functionally faithful synthetic [Fe4S4]–alkyl
complexes. We will prepare [Fe4S4]–alkyl complexes with rationally tunable properties and formulate and test
hypotheses concerning the geometric and electronic structure requirements for achieving Fe–C bond
homolysis. These requirements will be elucidated through systematic kinetic and spectroscopic studies.
Overall, this work will reveal the role of organometallic chemistry in catalysis by radical SAM enzymes and
yield insights into how Nature utilizes reactive Fe–C bonds in human health and disease.

## Key facts

- **NIH application ID:** 10372003
- **Project number:** 5R01GM136882-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Daniel Leif Migdow Suess
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $292,612
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372003

## Citation

> US National Institutes of Health, RePORTER application 10372003, Modeling the Organometallic Chemistry of Radical S-adenosylmethionine Enzymes (5R01GM136882-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372003. Licensed CC0.

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