Regulation of lipid biosynthesis in Gram positive bacteria

SCHUJMAN, GE; DE MENDOZA, D

Rosario

Simposio; XLII Reunión Anual de la Sociedad Argentina de Investigadores en Bioquímica (SAIB),; 2006

SAIB

Fatty acids and their derivatives play essential roles in all living organisms as components of membranes and energy sources. Biosynthesis of these compounds is carried out by a single multifunctional polypeptide (type I system) in higher eukaryotes and by dissociable enzymes (type II system) 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 each cellular type. 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.