A Radically Different Mechanism for S-Adenosylmethionine—Dependent Methyltransferases

• Published in: Science (American Association for the Advancement of Science) 2011-04, Vol.332 (6029), p.604-607
• Main Authors: Grove, Tyler L., Benner, Jack S., Radle, Matthew I., Ahlum, Jessica H., Landgraf, Bradley J., Krebs, Carsten, Booker, Squire J.
• Format: Article
• Language: English
• Subjects: Acoustic microscopes; Adenosine - chemistry; Adenosine - metabolism; Amino acids; Analytical, structural and metabolic biochemistry; Atoms; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biocatalysis; Biochemistry; Biological and medical sciences; Carbon; Carbon - chemistry; Chemical Phenomena; Cysteine - chemistry; Cysteine - metabolism; Deuterium; Enzymes; Enzymes and enzyme inhibitors; Escherichia coli - enzymology; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Hydrogen; Hydrogen - chemistry; Mass spectra; Metabolism; Methylation; Methyltransferases - chemistry; Methyltransferases - genetics; Methyltransferases - metabolism; Nucleotides; Programming; Radicals; Residues; Ribonucleic acids; RNA; RNA, Bacterial - metabolism; RNA, Ribosomal, 23S - metabolism; S-Adenosylmethionine - metabolism; Staphylococcus aureus - enzymology; Transferases
• ISSN: 0036-8075; 1095-9203
• 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 S N 2 mechanism to methylate nucleophilic sites on their substrates, but recently, radical SAM 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 carbons at positions 2 and 8 of adenosine 2503 in 23S ribosomal RNA, 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 cysteine residue.