# Radical SAM Enzymes: Molecular Mechanisms of Radical Initiation

> **NIH NIH R35** · MONTANA STATE UNIVERSITY - BOZEMAN · 2022 · $355,468

## Abstract

Radical SAM is one of the largest enzyme superfamilies known, with its members catalyzing a
remarkable diversity of reactions in all domains of life. Radical SAM enzymes are involved in the
synthesis of essential cofactors and antibiotics, repair of DNA damage, and the assembly of complex
biological metal clusters, among many other reactions. The presence of radical SAM enzymes in humans
as well as in both beneficial and pathogenic microbes lends high significance to understanding their
fundamental properties and mechanisms. The proposed research will develop a critical understanding of
radical SAM mechanisms, in particular the radical initiation process common to all enzymes in this large
and diverse superfamily. Research efforts will focus on trapping radical intermediates using rapid freeze-
quench, cryoreduction, annealing, and photolysis approaches. These intermediates will then be
characterized by using spectroscopic approaches such as electron paramagnetic resonance and electron-
nuclear double resonance, and structural approaches such as X-ray crystallography. Computational
studies will provide insights into stability/reactivity and reaction pathways. Much of the work will build
on the recent discovery of a novel organometallic intermediate containing a direct bond between an iron
of the iron-sulfur cluster and a carbon of an adenosyl moiety, a structure reminiscent of coenzyme B12.
The results will provide an understanding of this fundamental and ubiquitous reaction in biology, and its
surprising involvement of organometallic chemistry.

## Key facts

- **NIH application ID:** 10370355
- **Project number:** 5R35GM131889-04
- **Recipient organization:** MONTANA STATE UNIVERSITY - BOZEMAN
- **Principal Investigator:** Joan B Broderick
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $355,468
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370355

## Citation

> US National Institutes of Health, RePORTER application 10370355, Radical SAM Enzymes: Molecular Mechanisms of Radical Initiation (5R35GM131889-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370355. Licensed CC0.

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