RadicalSAM

RadicalSAM refers to a large superfamily of enzymes that catalyze radical-based transformations using S-adenosylmethionine (SAM) as a co-substrate. The defining feature is a CxxxCxxC motif that coordinates a [4Fe-4S] cluster. In a reductive step, the cluster donates an electron to SAM, cleaving it to methionine and a 5'-deoxyadenosyl radical. The radical abstracts a hydrogen atom from the substrate or initiates other radical chemistry, generating a substrate radical that undergoes diverse transformations. The reaction cycle is completed as the product is formed and the iron-sulfur cluster is re-reduced.

The radical SAM core is often supplemented by additional domains or auxiliary iron-sulfur clusters, enabling more complex chemistry. While the CxxxCxxC motif marks the family, the surrounding protein context dictates substrate binding and reaction type. Some enzymes also require external electron donors such as ferredoxins or flavodoxins to maintain the reduced state of the cluster.

The radical SAM family executes a broad range of reactions, including sulfur insertion into unactivated substrates, rearrangements and isomerizations, and methylthiolation. Notable examples include biotin synthase (BioB), which inserts sulfur to form biotin; lipoyl synthase (LipA), which creates lipoic acid; MiaB, a tRNA methylthiotransferase; and RimO, which methylthiolates ribosomal protein S12. Other members participate in cofactor biosynthesis or in post-transcriptional and post-translational modifications.

RadicalSAM enzymes are widespread in bacteria and archaea and occur in some eukaryotes. Their activity is essential for certain biosynthetic pathways and for the maturation of RNA and protein cofactors, reflecting their important role in cellular metabolism.