Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily

Radical S-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5′-deoxyadenosyl (5′-dAdo•) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe–C5′-adenosyl bond. Regioselective reductive cleavage of the SAM S–C5′ bond produces 5′-dAdo• to form Ω, with the regioselectivity originating in the Jahn–Teller effect. Ω liberates the free 5′-dAdo• as the catalytically active intermediate through homolysis of the Fe–C5′ bond, in analogy to Co–C5′ bond homolysis in B12, which was once viewed as biology's choice of radical generator.