S-Adenosyl-N-decyl-aminoethyl, a Potent Bisubstrate Inhibitor ofMycobacterium tuberculosisMycolic Acid Methyltransferases - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Biological Chemistry Année : 2009

S-Adenosyl-N-decyl-aminoethyl, a Potent Bisubstrate Inhibitor ofMycobacterium tuberculosisMycolic Acid Methyltransferases

Résumé

S-Adenosylmethionine-dependent methyltransferases (Ado-Met-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 paralo-gous 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-amin-oethyl, a molecule in which the amino acid moiety of AdoMet is substituted by a lipid chain, inhibited MA-MTs from Mycobac-terium 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.
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Dates et versions

hal-03003382 , version 1 (13-11-2020)

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Julien Vaubourgeix, Fabienne Bardou, Fanny Boissier, Sylviane Julien, Patricia Constant, et al.. S-Adenosyl-N-decyl-aminoethyl, a Potent Bisubstrate Inhibitor ofMycobacterium tuberculosisMycolic Acid Methyltransferases. Journal of Biological Chemistry, 2009, 284, pp.19321 - 19330. ⟨10.1074/jbc.m809599200⟩. ⟨hal-03003382⟩
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