Radical SAM enzymes: Nature's choice for radical reactions

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 B₁₂ , 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 B₁₂ enzymes are only a few.