Dissecting the regulatory network of lipid homeostasis in mycobacteria

SALZMAN, VALENTINA; MONDINO, SONIA; GAGO, G; GRAMAJO, H

VANCOUVER

Congreso; Keystone Symposia: “Mycobacteria: Physiology, Metabolism and Pathogenesis - Back to the Basics; 2011

KEYSTONE

Mycolic acids are major components of the cell envelope of mycobacteria and play an important role in its architecture and interaction with the environment. Synthesis of mycolic acids is carried out by two fatty acid synthases working in concert: FASI, capable of de novo synthesis of medium-chain fatty acids, and FASII, responsible for their elongation. MabR is a novel transcriptional regulator, whose binding to the FASII promoter region (pfasII) was demonstrated in vitro and in vivo. Under mabR over expression conditions in M. smegmatis, down-regulation of fasII and fas transcription was observed and further correlated with a deficiency in mycolic acids and in de novo FA biosynthesis. Furthermore, MabR increased concentrations resulted in accumulation of C24 fatty acids probably reflecting an alteration in the crosstalk between FASI and FASII. In order to understand the coordinate regulation of the FAS systems we used a series of biochemical and spectroscopic techniques to analyze the effect of acyl-CoA and acyl-ACP molecules on MabR-DNA binding. In addition, using lacZ fusions we identified new cis elements in FasII operon that might also be involved in the coordinated transcriptional regulation of this pathway. These results represent an important step toward understanding the complex regulatory network involved in maintaining lipid homeostasis in mycobacteria.