Structural analysis of inhibitors of the Mycobacterium tuberculosis biotin-protein ligase BirA.

Biotin is an essential cofactor that is necessary for the synthesis of essential membrane phospholipids, cell-wall mycolic acids, and important virulence factors in Mycobacterium tuberculosis (Mtb). The first committed step of fatty acid biosynthesis is catalyzed by Acetyl-Coenzyme A Carboxylase, a multimeric complex that requires the covalent ligation of biotin to the Biotin Carboxyl Carrier Protein (BCCP) domain in order to become functionally active. In Mtb, this step is catalyzed by the biotin protein ligase BirA. Biotinylation proceeds through a two-step reaction wherein biotin is first activated to 5'-biotinyl-AMP before transfer to the e-amino group of a target lysine residue of the BCCP domain. BirA is the only biotin protein ligase detected in the Mtb genome and has been shown to be essential for fatty acid biosynthesis in Mycobacterium smegmatis. Inhibitors of BirA are under investigation as potential novel antibacterial agents for the treatment of tuberculosis and other pathogenic microorganisms