The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis.
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.
Léger
Mathieu
M
Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Département Mécanismes Moléculaires des Infections Mycobactériennes, Toulouse, France.
Gavalda
Sabine
S
Guillet
Valérie
V
van der Rest
Benoît
B
Slama
Nawel
N
Montrozier
Henri
H
Mourey
Lionel
L
Quémard
Annaïk
A
Daffé
Mamadou
M
Marrakchi
Hedia
H
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
D009171:Mycolic Acids; D011994:Recombinant Proteins; D003066:Coenzyme A Ligases