What is it about?

Many enzymes use radical chemistry to build essential molecules, but radicals are highly reactive and can easily cause damage if not tightly controlled. Our study reveals how a radical-generating enzyme, MoaA, from the radical S-adenosyl-L-methionine (SAM) superfamily, senses when its correct substrate is bound and safely triggers the radical reaction. Using a combination of nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy, computational modeling, and biochemical experiments, we show how this mechanism prevents unwanted side reactions and provides insight into a human metabolic disease caused by related mutations.

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Why is it important?

Enzymes often use radical chemistry to carry out biologically essential but chemically challenging reactions that would otherwise be impossible. Yet radicals are inherently risky, because if uncontrolled, they can damage the enzyme itself or surrounding biomolecules. Radical SAM enzymes form one of the largest enzyme superfamilies, with more than 700,000 members across all forms of life. Our study is the first to reveal how a radical SAM enzyme, MoaA, senses its substrate and safely triggers radical chemistry, providing a detailed mechanistic explanation of substrate-controlled radical initiation. Similar mechanisms likely exist in many radical SAM enzymes, offering a new framework for understanding their chemistry. The findings also explain why certain human mutations cause molybdenum cofactor (Moco) deficiency, a rare and severe metabolic disease.

Perspectives

This work provides the first detailed view of how substrate binding directly controls radical initiation in a radical SAM enzyme. Although the flexible C-terminal tail is unique to MoaA, the substrate-induced interaction with the methionine portion of SAM may represent a more general strategy shared across this large enzyme family. I believe this study offers a new paradigm for thinking about how radical SAM enzymes trigger their chemistry, in connection with the fundamental chemical mechanism of SAM cleavage and the role of the organometallic intermediate (Ω). This project was a true team effort that brought together expertise in NMR (Prof. Pei Zhou), EPR (Prof. Alexey Silakov), and DFT computation (Prof. Weitao Yang). I am deeply grateful for their collaboration and for the opportunity to integrate such diverse approaches to solve this challenging mechanistic problem.

Kenichi Yokoyama
Duke University

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This page is a summary of: Mechanism of controlled radical initiation in radical SAM GTP 3’,8-cyclase, Proceedings of the National Academy of Sciences, November 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2502098122.
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