Biosynthesis of fatty acids: IV. Studies with inhibitors

Abstract

SUMMARY Tetrolyl-CoA and propiolyl-Coh have been shot{ n to be strong noncompetitive inhibitors of fatty acid synthesis. Acrylyl-CoA and isocrotonyl-Coh also inhibit, but much higher concentrations are required. It is suggested that this inhibition occurs through an interaction between the triple and double bonds of these compounds and enzyme sulfhydryl groups. Palmityl-CoA and free CoA have also been shown to inhibit fatty acid synthesis and to block the condensation of acetyl-CoA with malonyl-CoA, and the reduction of crotonylCoA to butyrate. The reduction of acetoacetyl-Co.4 to the @-hydroxy derivative was not inhibited by these materials, although the complete reduction to butyrate was prevented. The addition of flavin nucleotides also inhibited fatty acid synthesis catalyzed by brain enzyme preparations. The impairment of fatty acid synthesis by several well-recognized inhibitors of sulfhydryl enzymes has been reported previously (1-3). In the course of studies of possible intermediates in fatty acid synthesis, it was discovered that alkyne acyl-CoA analogs are strongly inhibitory. Evidence for the inhibition of several steps in fatty acid biosynthesis is presented. Furthermore, free coenzyme A (CoA), a by-product of fatty acid synthesis, and palmityl-CoA inhibit similarly at concentrations equivalent to optimal substrate levels. The present communication describes experiments dealing with the inhibition of fatty acid synthesis by thesr? and several flavin-containing compounds.