Further Insight into S-Adenosylmethionine-dependent Methyltransferases: STRUCTURAL CHARACTERIZATION OF Hma, AN ENZYME ESSENTIAL FOR THE BIOSYNTHESIS OF OXYGENATED MYCOLIC ACIDS IN MYCOBACTERIUM TUBERCULOSIS

Fanny Boissier (1) , Fabienne Bardou (1) , Valérie Guillet (1) , Sandrine Uttenweiler-Joseph (1) , Mamadou Daffé (1) , Annaïk Quémard (1) , Lionel Mourey (1)

1 IPBS - Institut de pharmacologie et de biologie structurale

Mycolic acids are major and specific components of the cell envelope of Mycobacteria that include Mycobacterium tuberculosis, the causative agent of tuberculosis. Their metabolism is the target of the most efficient antitubercular drug currently used in therapy, and the enzymes that are involved in the production of mycolic acids represent important targets for the development of new drugs effective against multidrug-resistant strains. Among these are the S-adenosylmethionine-dependent methyltransferases (SAM-MTs) that catalyze the introduction of key chemical modifications in defined positions of mycolic acids. Some of these subtle structural variations are known to be crucial for both the virulence of the tubercle bacillus and the permeability of the mycobacterial cell envelope. We report here the structural characterization of the enzyme Hma (MmaA4), a SAM-MT that is unique in catalyzing the introduction of a methyl branch together with an adjacent hydroxyl group essential for the formation of both keto- and methoxymycolates in M. tuberculosis. Despite the high propensity of Hma to proteolytic degradation, the enzyme was produced and crystallized, and its three-dimensional structure in the apoform and in complex with S-adenosylmethionine was solved to about 2 A. Thestructuresshowtheimportantroleplayedbythemodificationsfound within mycolic acid SAM-MTs, especially thealpha2-alpha3 motif and the chemical environment of the active site. Essential information with respect to cofactor and substrate binding, selectivity and specificity, and about the mechanism of catalytic reaction were derived.

Domaines: Sciences du Vivant [q-bio]

Fanny Boissier, Fabienne Bardou, Valérie Guillet, Sandrine Uttenweiler-Joseph, Mamadou Daffé, et al.. Further Insight into S-Adenosylmethionine-dependent Methyltransferases: STRUCTURAL CHARACTERIZATION OF Hma, AN ENZYME ESSENTIAL FOR THE BIOSYNTHESIS OF OXYGENATED MYCOLIC ACIDS IN MYCOBACTERIUM TUBERCULOSIS. Journal of Biological Chemistry, 2006, 281 (7), pp.4434-4445. ⟨10.1074/jbc.M510250200⟩. ⟨hal-03003456⟩