Understanding the physiological role of MabR in mycolic acid biosynthesis

TSAI, Y; SALZMAN, V; GAGO, G.; GRAMAJO, H

Canela

Congreso; VII Reunión de la Sociedad Latinoamericana de Tuberculosis y otras Micobacteriosis; 2014

SLAMTB

Background and objectives: Mycobacteria have two fatty acid synthases (FAS-I and FAS-II) that work in a concerted manner for the biosynthesis of mycolic acids. Our research group has identified MabR as a new transcriptional regulator that controls the expression of fasII operon genes, which encode for the enzymes of the FAS-II system, by binding specifically to the fasII promoter region. Our aim is to unequivocally decipher the physiological role of MabR, an important step towards understanding the complex regulatory network involved in maintaining lipid homeostasis in mycobacteria. Methods: Using a two-step homologous recombination strategy we constructed a mabR conditional mutant in M. smegmatis, where expression of mabR is under the control of Pami. This strain was used to analyze the expression of fasII genes by real time PCR and also to study the role of MabR on lipid biosynthesis. Results and discussion: The 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 have also found that long chain acyl-CoAs and acyl-AcpM modulate the affinity of MabR for its DNA binding site, suggesting that these metabolites are sensed in vivo by MabR. Conclusion: The molecular mechanisms used by the two FAS systems to communicate with each other in order to control the balance of fatty acids biosynthesis with that of mycolic is still an open and challenging question. Our studies on the regulation of the fasII operon has opened now a new area of research and raises several important questions that need to be answered around the mechanism used by these microorganisms to maintain lipid homeostasis.