InterPro domain: IPR007197

Radical SAM proteins are found in all three domains of life and share an unusual Fe-S cluster associated with generation of a free radical by reductive cleavage of SAM and often provide an anaerobic or oxygen-independent mechanism that is found as an aerobic reaction in other proteins. Radical SAM proteins catalyse diverse reactions, including unusual methylations, isomerization, sulphur insertion, ring formation, anaerobic oxidation and protein radical formation. These proteins function in DNA precursor, vitamin, cofactor, antibiotic and herbicide biosynthesis and in biodegradation pathways [ 1 , 2 ].

Radical SAM proteins share several common features, notably three strictly conserved cysteine residues generally included in the CxxxCxxC motif. These critical cysteines coordinate the unusual [4Fe-4S]2+/1+ cluster, while SAM serves as ligand for the fourth iron atom and acts as a cofactor or a cosubstrate [ 3 ]. The radical SAM enzymes biochemically characterised to date have in common the cleavage of the [4Fe-4S]1+-SAM complex to [4Fe-4S]2+-Met and the 5'-deoxyadenosyl radical, which abstracts a hydrogen atom from the substrate to initiate a radical mechanism [ 3 , 4 ].

The Radical SAM domain is organised in a fold related to the beta-barrel or TIM barrel, in which beta-strands are arranged in a barrel-like array, with peripheral helices intervening between beta-strands. The [4Fe–4S] clusters and substrates are bound within the barrels, as is typical of TIM barrel enzymes [ 5 , 6 ].

1. Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods. Nucleic Acids Res. 29, 1097-106
2. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc. Natl. Acad. Sci. U.S.A. 101, 12870-5
3. Structural insights into recognition and repair of UV-DNA damage by Spore Photoproduct Lyase, a radical SAM enzyme. Nucleic Acids Res. 40, 9308-18
4. The Radical SAM Superfamily. Crit Rev Biochem Mol Biol 43, 63-88
5. Structures of the peptide-modifying radical SAM enzyme SuiB elucidate the basis of substrate recognition. Proc Natl Acad Sci U S A 114, 10420-10425
6. Structural diversity in the AdoMet radical enzyme superfamily. Biochim Biophys Acta 1824, 1178-95