S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases. Academic Article uri icon



  • S-Adenosylmethionine-dependent methyltransferases (AdoMet-MTs) constitute a large family of enzymes specifically transferring a methyl group to a range of biologically active molecules. Mycobacterium tuberculosis produces a set of paralogous AdoMet-MTs responsible for introducing key chemical modifications at defined positions of mycolic acids, which are essential and specific components of the mycobacterial cell envelope. We investigated the inhibition of these mycolic acid methyltransferases (MA-MTs) by structural analogs of the AdoMet cofactor. We found that S-adenosyl-N-decyl-aminoethyl, a molecule in which the amino acid moiety of AdoMet is substituted by a lipid chain, inhibited MA-MTs from Mycobacterium smegmatis and M. tuberculosis strains, both in vitro and in vivo, with IC(50) values in the submicromolar range. By contrast, S-adenosylhomocysteine, the demethylated reaction product, and sinefungin, a general AdoMet-MT inhibitor, did not inhibit MA-MTs. The interaction between Hma (MmaA4), which is strictly required for the biosynthesis of oxygenated mycolic acids in M. tuberculosis, and the three cofactor analogs was investigated by x-ray crystallography. The high resolution crystal structures obtained illustrate the bisubstrate nature of S-adenosyl-N-decyl-aminoethyl and provide insight into its mode of action in the inhibition of MA-MTs. This study has potential implications for the design of new drugs effective against multidrug-resistant and persistent tubercle bacilli.


  • Vaubourgeix, Julien
  • Bardou, Fabienne
  • Boissier, Fanny
  • Julien, Sylviane
  • Constant, Patricia
  • Ploux, Olivier
  • Daffé, Mamadou
  • Quémard, Annaïk
  • Mourey, Lionel

publication date

  • May 13, 2009



  • Adenosine
  • Enzyme Inhibitors
  • Methyltransferases
  • Mycobacterium tuberculosis
  • Mycolic Acids


PubMed Central ID

  • PMC2740557

Scopus Document Identifier

  • 67749120736

Digital Object Identifier (DOI)

  • 10.1074/jbc.M809599200

PubMed ID

  • 19439410

Additional Document Info


  • 284


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