title: The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis.
abstract: Mycolic acids are major and specific lipids of Mycobacterium 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 mycobacterial 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 antimycobacterial agents.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, Toulouse, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Léger
authors.forename: Sabine
authors.initials: S
authors.lastname: Gavalda
authors.forename: Valérie
authors.initials: V
authors.lastname: Guillet
authors.forename: Benoît
authors.initials: B
authors.lastname: van der Rest
authors.forename: Nawel
authors.initials: N
authors.lastname: Slama
authors.forename: Henri
authors.initials: H
authors.lastname: Montrozier
authors.forename: Lionel
authors.initials: L
authors.lastname: Mourey
authors.forename: Annaïk
authors.initials: A
authors.lastname: Quémard
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Hedia
authors.initials: H
authors.lastname: Marrakchi
mesh_terms: D000595:Amino Acid Sequence; D003066:Coenzyme A Ligases / Q000302:isolation & purification / Q000378:metabolism*; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009171:Mycolic Acids / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D009171:Mycolic Acids; D011994:Recombinant Proteins; D003066:Coenzyme A Ligases