The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis
Résumé
Mycolic acids are major and specific lipids of Myco-bacterium tuberculosis cell envelope. Their synthesis requires the condensation by Pks13 of a C 22-C 26 fatty acid with the C 50-C 60 meromycolic acid activated by FadD32, a fatty acyl-AMP ligase essential for myco-bacterial growth. A combination of biochemical and enzymatic approaches demonstrated that FadD32 exhibits substrate specificity for relatively long-chain fatty acids. More importantly, FadD32 catalyzes the transfer of the synthesized acyl-adenylate onto specific thioester acceptors, thus revealing the protein acyl-ACP ligase function. Therefore, FadD32 might be the prototype of a group of M. tuberculosis polyketide-synthase-associated adenylation enzymes possessing such activity. A substrate analog of FadD32 inhibited not only the enzyme activity but also mycolic acid synthesis and mycobacterial growth, opening an avenue for the development of novel antimycobac-terial agents.
Domaines
Sciences du Vivant [q-bio]
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