The Atypical Cobalamin-Dependent S-Adenosyl-l-Methionine Nonradical Methylase TsrM and Its Radical Counterparts

J Am Chem Soc. 2022 Apr 6;144(13):5673-5684. doi: 10.1021/jacs.1c12064. Epub 2022 Mar 28.


Cobalamin (Cbl)-dependent S-adenosyl-l-methionine (AdoMet) radical methylases are known for their use of a dual cofactor system to perform challenging radical methylation reactions at unactivated carbon and phosphorus centers. These enzymes are part of a larger subgroup of Cbl-dependent AdoMet radical enzymes that also perform difficult ring contractions and radical rearrangements. This subgroup is a largely untapped reservoir of diverse chemistry that requires steady efforts in biochemical and structural characterization to reveal its complexity. In this Perspective, we highlight the significant efforts over many years to elucidate the function, mechanism, and structure of TsrM, an unexpected nonradical methylase in this subgroup. We also discuss recent achievements in characterizing radical methylase subgroup members that exemplify how key tools in mechanistic enzymology are valuable time and again. Finally, we identify recent enzyme activity studies that have made use of bioinformatic analyses to expand our definition of the subgroup. Additional breakthroughs in radical (and nonradical) enzymatic chemistry and challenging transformations from the unexplored space of this subgroup are undoubtedly on the horizon.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Methionine
  • Methylation
  • Methyltransferases / metabolism
  • S-Adenosylmethionine* / metabolism
  • Vitamin B 12* / chemistry


  • S-Adenosylmethionine
  • Methionine
  • Methyltransferases
  • Vitamin B 12