Document Detail


S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases.
MedLine Citation:
PMID:  19439410     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Julien Vaubourgeix; Fabienne Bardou; Fanny Boissier; Sylviane Julien; Patricia Constant; Olivier Ploux; Mamadou Daffé; Annaïk Quémard; Lionel Mourey
Publication Detail:
Type:  Journal Article     Date:  2009-05-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-13     Completed Date:  2009-09-25     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19321-30     Citation Subset:  IM    
Affiliation:
CNRS, Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 Route de Narbonne, F-31077 Toulouse, France.
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MeSH Terms
Descriptor/Qualifier:
Adenosine / analogs & derivatives*,  chemistry,  pharmacology
Catalytic Domain
Cell Division / drug effects
Crystallography, X-Ray
Enzyme Inhibitors / chemistry,  pharmacology*
Methyltransferases / antagonists & inhibitors*,  chemistry,  metabolism
Models, Molecular
Molecular Structure
Mycobacterium / enzymology,  metabolism
Mycobacterium tuberculosis / cytology,  enzymology*,  metabolism
Mycolic Acids / chemistry,  metabolism*
Protein Binding
Protein Structure, Tertiary
S-Adenosylhomocysteine / chemistry,  pharmacology
S-Adenosylmethionine / chemistry,  pharmacology
Species Specificity
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Mycolic Acids; 0/S-adenosyl-N-decyl-aminoethyl; 29908-03-0/S-Adenosylmethionine; 58-61-7/Adenosine; 979-92-0/S-Adenosylhomocysteine; EC 2.1.1.-/Methyltransferases; W2U467CIIL/sinefungin
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