ArticleThe Journal of biological chemistry2009
S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Ensemble learning-guided discovery of anti-tuberculosis phytochemicals: computational prediction and mechanistic insights.Journal of computer-aided molecular design · 2026Article
- The Biosynthetic Pathway of Mycolic Acids: Dual-Function Targets for Tuberculosis Therapeutics and Green Steroid Drugs Biomanufacturing.Pharmaceutics · 2025Review
- In Silico Investigation of TATA-Binding Protein as a Therapeutic Target for Chagas Disease: Insights into FDA Drug Repositioning.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Crystal structure of the S-adenosylmethionine-dependent mycolic acid synthase UmaA from Mycobacterium tuberculosis.Acta crystallographica. Section F, Structural biology communications · 2025Article
- Review
- Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) fromPharmaceuticals (Basel, Switzerland) · 2021Article
- Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents.Molecular diversity · 2021Article
- Discovery of a novel dehydratase of the fatty acid synthase type II critical for ketomycolic acid biosynthesis and virulence of Mycobacterium tuberculosis.Scientific reports · 2020Article
- HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness.Scientific reports · 2018Article
- Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Frontiers in cellular and infection microbiology · 2018Review
- SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases.ACS chemical biology · 2016Review
- New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics.Current pharmaceutical design · 2014Review
- Mycobacterium tuberculosis lacking all mycolic acid cyclopropanation is viable but highly attenuated and hyperinflammatory in mice.Infection and immunity · 2012Article
- Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis cyclopropanation of oxygenated mycolates.Journal of bacteriology · 2010Article
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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