# Radical SAM Enzymes: Radical Mechanisms Central to Biology

> **NIH NIH R35** · MONTANA STATE UNIVERSITY - BOZEMAN · 2024 · $380,336

## Abstract

Summary / Abstract
Radical SAM is the largest enzyme superfamily 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,
including both the radical initiation process common to all enzymes in this large and diverse superfamily,
and mechanisms of individual radical SAM enzymes. Research efforts will focus on freeze-quench trapping
radical intermediates and using time-delay, thermal annealing, and photo-initiation to probe reaction steps
and chemical properties. Trapped intermediates will be characterized by using spectroscopic approaches
such as electron paramagnetic resonance and electron-nuclear double resonance, and structural approaches
such as X-ray crystallography. Systems to be studied will include the pyruvate formate-lyase activating
enzyme, which has proven to be an outstanding prototypical radical SAM enzyme for illuminating
mechanistic details. In addition, we will pursue mechanistic insights into radical SAM enzymes involved
in maturation of RiPPs (ribosomally-encoded, post-translationally modified peptides) and larger protein
substrates undergoing substantial modification. We will further be working to define the biochemical
function of RSAD1, a radical SAM enzyme implicated in Alzheimer’s disease in humans. This project will
provide new insights into the fundamental mechanisms of radical initiation in radical SAM enzymes, and
into the mechanistic and functional details of some of the more complex and interesting reactions catalyzed
by members of this enzyme superfamily.

## Key facts

- **NIH application ID:** 10842817
- **Project number:** 2R35GM131889-06
- **Recipient organization:** MONTANA STATE UNIVERSITY - BOZEMAN
- **Principal Investigator:** Joan B Broderick
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,336
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842817

## Citation

> US National Institutes of Health, RePORTER application 10842817, Radical SAM Enzymes: Radical Mechanisms Central to Biology (2R35GM131889-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10842817. Licensed CC0.

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