S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases.
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.
CNRS, Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 Route de Narbonne, F-31077 Toulouse, France.
Julien
J
Vaubourgeix
Fabienne
F
Bardou
Fanny
F
Boissier
Sylviane
S
Julien
Patricia
P
Constant
Olivier
O
Ploux
Mamadou
M
Daffé
Annaïk
A
Quémard
Lionel
L
Mourey
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009161:Mycobacterium / Q000201:enzymology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009171:Mycolic Acids / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012435:S-Adenosylhomocysteine / Q000737:chemistry / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000494:pharmacology; D013045:Species Specificity
D004791:Enzyme Inhibitors; D009171:Mycolic Acids; C543722:S-adenosyl-N-decyl-aminoethyl; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008780:Methyltransferases; D000241:Adenosine; C006235:sinefungin