The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis

Mathieu Léger (1) , Sabine Gavalda (1) , Valérie Guillet (1) , Benoît van Der Rest (1) , Nawel Slama (1) , Henri Montrozier (1) , Lionel Mourey (1) , Annaïk Quémard (1) , Mamadou Daffé (1) , Hedia Marrakchi (1)

1 IPBS - Institut de pharmacologie et de biologie structurale

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]

Mathieu Léger, Sabine Gavalda, Valérie Guillet, Benoît van Der Rest, Nawel Slama, et al.. The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis. Chemistry and Biology, 2009, 16, pp.510 - 519. ⟨10.1016/j.chembiol.2009.03.012⟩. ⟨hal-03003389⟩