A malonyl-CoA-dependent switch in the bacterial response to a dysfunction of lipid metabolism.
Bacteria stringently regulate the synthesis of their membrane phospholipids, but the responsible regulatory mechanisms are incompletely understood. Bacillus subtilis FabF, the target of the mycotoxin cerulenin, catalyses the condensation of malonyl-ACP with acyl-ACP to extend the growing acyl chain by two carbons. 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 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. Synthesis of acyl-ACPs by a cell-free fatty acid system prepared from fabF1 cells showed the accumulation of short- and medium-chain acyl-ACPs. These results indicate that the acyl-ACP chain length acceptance of FabF[I108F] is biased towards shorter acyl-ACPs. We also provide evidence that upregulation of FabF[I108F] is essential for survival and for resistance to cerulenin of fabF1 cells. These findings indicate that malonyl-CoA is a key molecule to monitor lipid metabolism functioning and trigger appropriate genetic and biochemical adjustments to relieve dysfunctions of this essential metabolic pathway.
Schujman
Gustavo E
GE
Instituto de Biología Molecular y Celular de Rosario, and Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Altabe
Silvia
S
de Mendoza
Diego
D
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001412:Bacillus subtilis / Q000201:enzymology* / Q000235:genetics; D002569:Cerulenin / Q000494:pharmacology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D050356:Lipid Metabolism / Q000235:genetics*; D008316:Malonyl Coenzyme A / Q000235:genetics* / Q000378:metabolism; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D018085:Regulon; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D010743:Phospholipids; D012097:Repressor Proteins; D002569:Cerulenin; D008316:Malonyl Coenzyme A; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase