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.
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Authors | Mathieu Léger, Sabine Gavalda, Valérie Guillet, Benoît van der Rest, Nawel Slama, Henri Montrozier, Lionel Mourey, Annaïk Quémard, Mamadou Daffé, Hedia Marrakchi |
Journal | Chemistry & biology
(Chem Biol)
Vol. 16
Issue 5
Pg. 510-9
(May 29 2009)
ISSN: 1879-1301 [Electronic] United States |
PMID | 19477415
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Mycolic Acids
- Recombinant Proteins
- Coenzyme A Ligases
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Topics |
- Amino Acid Sequence
- Coenzyme A Ligases
(isolation & purification, metabolism)
- Molecular Sequence Data
- Mycobacterium tuberculosis
(enzymology)
- Mycolic Acids
(chemistry, metabolism)
- Recombinant Proteins
(isolation & purification, metabolism)
- Sequence Alignment
- Sequence Homology, Amino Acid
- Substrate Specificity
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