Radical SAM enzymes: Nature's choice for radical reactions

2022/10/17 by Joan B. Broderick, Joan Broderick, William E. Broderick +1 · 23 citations
Chemistry · Energy · #Biochemistry #Bond cleavage #CO2 Reduction Techniques and Catalysts #Catalysis #Chemistry #Enzyme #Enzyme catalysis #Homolysis #Metal-Catalyzed Oxygenation Mechanisms #Metalloenzymes and iron-sulfur proteins #Organic chemistry #Radical #Radical ion #Reactivity (psychology) #Regioselectivity #Stereochemistry

paper · doi:10.1002/1873-3468.14519

openalex publication_date 2022/10/17 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

Enzymes that use a [4Fe‐4S] 1+ cluster plus S ‐adenosyl‐ l ‐methionine (SAM) to initiate radical reactions (radical SAM) form the largest enzyme superfamily, with over half a million members across the tree of life. This review summarizes recent work revealing the radical SAM reaction pathway, which ultimately liberates the 5′‐deoxyadenosyl (5′‐dAdo•) radical to perform extremely diverse, highly regio‐ and stereo‐specific, transformations. Most surprising was the discovery of an organometallic intermediate Ω exhibiting an Fe‐C5′‐adenosyl bond. Ω liberates 5′‐dAdo• through homolysis of the Fe–C5′ bond, in analogy to Co–C5′ bond homolysis in B 12 , previously viewed as biology's paradigmatic radical generator. The 5′‐dAdo• has been trapped and characterized in radical SAM enzymes via a recently discovered photoreactivity of the [4Fe‐4S] + /SAM complex, and has been confirmed as a catalytically active intermediate in enzyme catalysis. The regioselective SAM S–C bond cleavage to produce 5′‐dAdo• originates in the Jahn–Teller effect. The simplicity of SAM as a radical precursor, and the exquisite control of 5′‐dAdo• reactivity in radical SAM enzymes, may be why radical SAM enzymes pervade the tree of life, while B 12 enzymes are only a few.

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• Computational Description of Alkylated Iron-Sulfur Organometallic Clusters. [europepmc]
• ENDOR Spectroscopy Reveals the "Free" 5'-Deoxyadenosyl Radical in a Radical SAM Enzyme Active Site Actually is Chaperoned by Close Interaction with the Methionine-Bound [4Fe-4S] 2+ Cluster. [europepmc]
• Direct Detection of the α-Carbon Radical Intermediate Formed by OspD: Mechanistic Insights into Radical S -Adenosyl-l-methionine Peptide Epimerization. [europepmc]
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• Aromatic side-chain crosslinking in RiPP biosynthesis. [europepmc]
• Rewiring Escherichia coli to transform formate into methyl groups. [europepmc]
• Deciphering the influence of the [4Fe-4S] cluster of tRNA thiolation enzymes on tRNA binding. [europepmc]
• Posttranslational Regulation of Mammalian Sulfur Amino Acid Metabolism. [europepmc]
• Sulfide regulation and catabolism in health and disease. [europepmc]
• Diverse thioether macrocyclized peptides through a radical SAM maturase. [europepmc]
• Inhibition of Clostridioides difficile -Specific DNA Adenine Methyltransferase CamA by Analogs of S ‑Adenosyl‑l‑methionine. [europepmc]
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