Tackling lipid biosynthesis of Mycobacteria

Rajesh Gokhale’s group has recently published the results of their study on how a recently discovered family of mycobacterial enzymes differs from their well known cousins found across all genera. The study demonstrates their importance as novel drug targets. They demonstrate how a subtle change in the amino acid sequence of the enzyme could determine the final outcome of catalysis by modifying rearrangements within the enzyme. In pathogenic mycobacteria, this large family of enzymes termed fatty acyl AMP ligases (FAALs) participate in the synthesis of complex lipids. These enzymes activate fatty acids to fatty acyl-AMP by coupling with a molecule of ATP, the cellular energy currency. The omnipresent FACLs, in contrast, extend this reaction by replacing AMP with a molecule of Coenzyme A. This seemingly minor difference in the reaction determines the ultimate fate of the activated fatty acid. Whereas FACL derived acyl-CoA caters for the routine metabolic needs like energy production by β-oxidation and phospholipid synthesis, FAAL derived acyl-AMP is channeled into complex lipids that confer virulent properties to this organism.

By employing a systems-based approach, the investigators have demonstrated how this enzyme family could be used as anti-mycobacterial targets. Simultaneous inhibition of many enzymes alters the delicate balance of lipids. Lack of these complex lipids alters the ultra-structure of mycobacteria rendering them vulnerable to environmental factors. From the point of view of drug discovery, this approach has immense potential, as a single compound simultaneously targets many pathways, most of which are essential for the mycobacterial virulence. With the emergence of multi-drug resistant strains and increased incidence of tuberculosis in patients suffering from AIDS, this discovery highlights a promising therapeutic strategy.