Signaling mechanisms controlling membrane lipid homeostasis in bacteria

SCHUJMAN, GE

Noordwijkerhout

Conferencia; FEBS Special Meeting - European Lipidomics Initiative; 2006

FEBS - European Lipidomics Initiative

Fatty acids and their derivatives play essential roles in all living organisms as components of membranes and source of metabolic energy. Biosynthesis of these compounds involve repeated cycles of condensation, reduction and dehydration of carbon-carbon linkages, which are carried out by a single multifunctional polypeptide (type I systems) in higher eukaryotes and by dissociable enzymes (type II systems) in bacterial cells, plant chloroplasts and malaria parasites. Yet despite the complexity of these biosynthetic pathways, biological membranes maintain stable compositions that are characteristic for different organisms, tissues and intracellular organelles. Nevertheless, the precise homeostatic mechanisms maintaining the concentration of lipids at particular levels are largely unknown. Here we report a novel role for malonyl-CoA, a universal intermediate in fatty acid biosynthesis, as a negative effector of the global transcriptional repressor FapR that regulates the expression of several genes encoding fatty acid and phospholipid biosynthetic enzymes in Bacillus subtilis. Crystallographic and binding studies demonstrate that malonyl-CoA specifically binds to the thioesterase-like effector domain of FapR, inducing a conformational rearrangement that dissociates the FapR-DNA complex or prevents its formation. Furthermore, mutations disrupting the FapR-malonyl-CoA interaction result in a lethal phenotype, suggesting that this homeostatic signaling pathway is a target for novel chemotherapeutic agents against Gram-positive pathogens.