Protein Structure and Folding
Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria*

https://doi.org/10.1074/jbc.M115.712612Get rights and content
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Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is one of the targets of first-line antituberculous drugs. This pathway contains a number of potential targets, including some that have been identified only recently and have yet to be explored. One such target, FadD32, is required for activation of the long meromycolic chain and is essential for mycobacterial growth. We report here an in-depth biochemical, biophysical, and structural characterization of four FadD32 orthologs, including the very homologous enzymes from Mycobacterium tuberculosis and Mycobacterium marinum. Determination of the structures of two complexes with alkyl adenylate inhibitors has provided direct information, with unprecedented detail, about the active site of the enzyme and the associated hydrophobic tunnel, shedding new light on structure-function relationships and inhibition mechanisms by alkyl adenylates and diarylated coumarins. This work should pave the way for the rational design of inhibitors of FadD32, a highly promising drug target.

crystal structure
drug design
enzyme inhibitor
mycobacteria
tuberculosis
fatty acyl ACP-synthase
fatty acyl-AMP ligase

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The atomic coordinates and structure factors (codes 5EY8 and 5EY9) have been deposited in the Protein Data Bank (http://wwpdb.org/).

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This work was supported by European Community New Medicines for Tuberculosis Program Grant LSHP-CT-2005-018923. The authors declare that they have no conflicts of interest with the contents of this article.