2FK7

Crystal structure of Hma (MmaA4) from Mycobacterium tuberculosis, apo-form

Summary for 2FK7

• Entry DOI: 10.2210/pdb2fk7/pdb
• Related: 1KP9 1KPG 1KPH 1KPI 1L1E 1TPY 2FK8
• Descriptor: methoxy mycolic acid synthase 4 (2 entities in total)
• Functional Keywords: s-adenosylmethionine-dependent methyltransferase fold, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 36521.31

Authors

Boissier, F.,Guillet, V.,Mourey, L. (deposition date: 2006-01-04, release date: 2006-01-17, Last modification date: 2023-08-30)

Primary citation

Boissier, F.,Bardou, F.,Guillet, V.,Uttenweiler-Joseph, S.,Daffe, M.,Quemard, A.,Mourey, L.
Further insight into S-adenosylmethionine-dependent methyltransferases: structural characterization of Hma, an enzyme essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis.
J.Biol.Chem., 281:4434-4445, 2006

PubMed Abstract: 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.

PubMed: 16356931
DOI: 10.1074/jbc.M510250200

Experimental method

X-RAY DIFFRACTION (2.1 Å)