Radical SAM enzymes utilize a [4Fe-4S] cluster and S-adenosyl-L-methionine (SAM) to initiate diverse radical-based reactions throughout all kingdoms of life. Despite the limited sequence similarity and vastly divergent reactions catalyzed, the radical SAM enzymes appear to employ a common mechanism for initiation of radical chemistry, in which a reduced [4Fe-4S]+ cluster provides the electron needed for the reductive cleavage of SAM. The amino and carboxylate groups of SAM bind to the unique iron of the catalytic [4Fe-4S] cluster, placing the sulfonium of SAM in close proximity to the cluster. Surprising recent results have shown that the initial enzymatic cleavage of SAM generates an organometallic intermediate prior to liberation of 5’-dAdo•, which initiates radical chemistry on substrate. This organometallic intermediate, denoted , has a 5’-deoxyadenosyl moiety directly bound to the unique iron of the [4Fe-4S] cluster via the 5’-C, giving a structure that is directly analogous to Co-(5’-C) bond of the organometallic cofactor adenosylcobalamin. Our observation that this intermediate  is formed throughout the superfamily suggests that this is a key intermediate in initiating radical SAM reactions, and further indicates that organometallic chemistry is much more broadly relevant in biology than previously thought. We have also discovered novel photochemistry in radical SAM enzymes, wherein photoinduced electron transfer generates SAM-derived radicals, providing new insights into fundamental radical initiation chemistry.








Joan Broderick (Montana State University)