Characterization of the transcriptional regulator of mycolic acid biosynthesis in mycobacteria

LARA J, TSAI YT, DIACOVICH L, GAGO G, GRAMAJO H.

Mendoza

Congreso; Reunión Anual N° 48 de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2012

Sociedad Argentina de Bioquimica y Biologia Molecular (SAIB)

Mycolic acids, the dominant feature of the Mycobacterium tuberculosis outer membrane, are essential for the survival, virulence, and antibiotic exclusion of this human pathogen. Mycobacteria, unlike most bacteria, have two fatty acid synthases (FAS-I and II). Both of them are involved in the biosynthesis of mycolic acids. Our research group identified MabR as a new transcriptional regulator that controls the expression of fasII operon genes, by binding specifically to the fasII promoter region. The construction and characterization of a MabR conditional mutant in M. smegmatis, allowed us to demonstrate that this protein modulates the expression of fasII genes in vivo. We also confirmed that MabR is essential to the regulatory network involved in maintenance of lipid homeostasis and that such regulation is modulated by long chain acyl-CoAs or long chain acyl-ACPs that appear to be the signal molecules recognized by this protein. In order to understand the molecular bases of the MabR interaction we set up to obtain the crystal structure of this protein. Laminar crystals were obtained using crystallization kits based on sitting drop vapor diffusion. Currently, we are optimizing the crystallization conditions in order to obtain a suitable crystal for structural function studies. MabR might become an excellent new target for the development of conceptually new antimycobacterium compounds.