Inhibition of fatty acid synthesis by the antibiotic cerulenin. Specific inactivation of beta-ketoacyl-acyl carrier protein synthetase.

Abstract Cerulenin, (2S) (3R)2,3-epoxy-4-oxo-7,10-dodecadienoylamide, an antibiotic isolated from the culture filtrate of Cephalosporium caerulens, inhibits the fatty acid synthetase of Escherichia coli by specifically inhibiting β-ketoacyl-acyl carrier protein synthetase, the enzyme which catalyzes the condensation reaction of fatty acid biosynthesis. Although cerulenin and tetrahydrocerulenin inhibited both β-ketoacyl-acyl carrier protein synthetase and fatty acid synthetase, neither dihydrocerulenin nor hexahydrocerulenin, analogs which lack the epoxide ring, inhibited these enzyme systems. Both β-ketoacyl-acyl carrier protein synthetase and fatty acid synthetase were protected to the same extent against inhibition by cerulenin by prior incubation with acetyl-acyi carrier protein. The acyl group of this thioester is bound at the fatty acyi site of β-ketoacyl-acyl carrier protein synthetase. Detailed studies with homogeneous β-ketoacyl-acyl carrier protein synthetase indicated that cerulenin inhibited model reactions representing both the fatty acyl transacylase and the malonyl-acyl carrier protein decarboxylase components of the β-ketoacyl-acyl carrier protein synthetase reaction. Inhibition of β-ketoacyl-acyl carrier protein synthetase by cerulenin was irreversible, and it was associated with the binding of approximately 1 mole of inhibitor per mole of enzyme when inhibition approached 100 %.