Report

A Radically Different Mechanism for S-Adenosylmethionine–Dependent Methyltransferases

See allHide authors and affiliations

Science  17 Mar 2011:
1200877
DOI: 10.1126/science.1200877

Methylation of small molecules and macromolecules is crucial in metabolism, cell signaling, and epigenetic programming, and is most often achieved by S-adenosylmethionine (SAM)–dependent methyltransferases. Most employ an SN2 mechanism to methylate nucleophilic sites on their substrates, but recently, radical SAM (RS) enzymes have been identified that methylate carbon atoms that are not inherently nucleophilic via the intermediacy of a 5′-deoxyadenosyl 5′-radical. We have determined the mechanisms of two such reactions targeting the sp2-hybridized C2 and C8 positions of adenosine 2503 (A2503) in 23S rRNA, catalyzed by RlmN and Cfr, respectively. In neither case is a methyl group transferred directly from SAM to the RNA; rather, both reactions proceed by a ping-pong mechanism involving intermediate methylation of a conserved Cys residue.