Mycolic acid biosynthesis: definition and targeting of the Claisen condensation step

Through the use of 2,2-[ 2H]palmitic acid pulse labeling of the whole cells of C. matruchotti and analysis by gas chromatography-mass spectrometry of the non-labeled and [ 2H]-labeled corynomycolates, we established a new mechanism for palmitate condensation devoid of the postulated carboxylation st...

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Bibliographic Details
Published in:	Biochimica et biophysica acta 1997-06, Vol.1346 (3), p.275-284
Main Authors:	Lee, Richard E, Armour, Jason W, Takayama, Kuni, Brennan, Patrick J, Besra, Gurdyal S
Format:	Article
Language:	eng
Subjects:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Biosynthesis Claisen condensation Corynebacterium - drug effects Corynebacterium - growth & development Corynebacterium - metabolism Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Fatty Acid Synthases - antagonists & inhibitors Fatty Acid Synthases - metabolism Gas Chromatography-Mass Spectrometry Magnetic Resonance Spectroscopy Molecular Structure Mycobacteria Mycobacterium tuberculosis Mycobacterium tuberculosis - chemistry Mycolic acid Mycolic Acids - metabolism Mycolic Acids - pharmacology Palmitates - chemistry Palmitates - pharmacology Palmitic Acid - metabolism
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Summary:	Through the use of 2,2-[ 2H]palmitic acid pulse labeling of the whole cells of C. matruchotti and analysis by gas chromatography-mass spectrometry of the non-labeled and [ 2H]-labeled corynomycolates, we established a new mechanism for palmitate condensation devoid of the postulated carboxylation step. This evidence allowed the design and synthesis of several structurally related antagonists against the condensation reactions which were shown to possess potent in vivo activity against C. matruchotti with complete inhibition of growth on solid media at concentrations between 1–10 μg/ml. In addition, a cell-free in vitro assay of corynomycolate synthesis was developed to allow the screening of these and other antagonists.
ISSN:	0005-2760 0006-3002 1879-145X 1878-2434