IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Molecular mechanism of lipid biosynthesis regulation by FapR in Staphylococcus aureus
Autor/es:
DANIELA ALBANESI, GEORGINA REH, FRANCIS SCHAEFFER, GUSTAVO E. SCHUJMAN, DIEGO DE MENDOZA, AND PEDRO ALZARI
Lugar:
San Diego, CA USA
Reunión:
Congreso; V Conference on Functional Genomics of Gram-Positive Microorganisms. 15th International Conference on Bacilli; 2009
Resumen:
FapR is a transcription factor that negatively controls the expression of several genes of the fatty acid and phospholipid biosynthesis in Bacillus subtilis (the fap regulon). It is the first global regulator of lipid synthesis discovered in bacteria and is largely conserved in Gram positive organisms, including human pathogens as Bacillus anthracis, Listeria monocytogenes and Staphylococcus aureus. FapR recognizes a consensus palindromic 17 bp sequence located in, or close to, the core promoter elements of all the transcriptional units that are members of the fap regulon and, upon binding, it protects approximately a 40 bp DNA region, which includes the 17 pb palindromic sequence. Malonyl-CoA acts as a negative effector of FapR promoting its release from DNA and the concomitant induction of the regulated promoters. It has been show that specific mutations disrupting the FapR-malonyl-CoA interaction result in a lethal phenotype in B. subtilis suggesting that this homeostatic signaling pathway could be a target for novel chemotherapeutic agents against Gram-positive pathogens. Here we show through biochemical, biophysical and structural results that the function of FapR is conserved in S. aureus. Moreover, we have determined the 3D structures of FapR from S. aureus alone or in complex with malonyl-CoA and DNA which shed light into the molecular mechanisms by which malonyl-CoA modulates the DNA-binding activity of FapR. The detailed understanding of this modulation mechanism not only provides unique opportunities to learn how Gram-positive bacteria monitor the status of fatty acid biosynthesis and adjust the lipid synthesis accordingly but also constitutes the basis for the development of novel antibacterial compounds with potential therapeutic applications.