A malonyl-CoA-dependent switch in the bacterial response to a dysfunction of lipid metabolism

SCHUJMAN, G; ALTABE, SILVIA GRACIELA; DE MENDOZA, D

Mar del Plata

Congreso; XLIII Reunión Anual de la Sociedad Argentina de Investigadores en Bioquímica (SAIB); 2007

SAIB

Bacteria stringently regulate the synthesis of their membrane phospholipids but the responsible regulatory mechanisms are incompletely understood. Bacillus subtilis FabF, the target of the fungal micotoxin cerulenin, catalyzes the condensation of malonyl-ACP with acyl-ACP and is an important determinant of the product distribution of the fatty acid biosynthetic pathway. Here we show that B. subtilis strains containing the fabF1 allele, which codes for the cerulenin-insensitive protein FabF[I108F], overexpressed several genes involved in fatty acid and phospholipid biosynthesis (the fap regulon) and had significantly elevated levels of malonyl-CoA. These results pinpointed FabF[I108F] as the responsible for the increased malonyl-CoA production, which in turn acts as an inducer of the fap regulon by impairing the binding of the FapR repressor to its DNA targets. Analysis of the ACP pool produced by the fatty acid synthase of fabF1 cells showed the accumulation of short- and medium-chain acyl-ACPs. These results support the concept that the acyl-ACP chain-length acceptance of the FabF condensing enzyme is tightly coupled to the transcriptional regulation of membrane lipid synthesis in Gram-positive bacteria. In addition, these data provide a biochemical and physiological framework for understanding antibiotic resistance within these types of condensing enzymes.