Studies on the Mechanism of Fatty Acid Synthesis

Abstract

Kinetic studies of the pigeon liver fatty acid synthetase have revealed that the enzyme is sensitive to inhibition by malonyl coenzyme A, one of the substrates of fatty acid synthesis.The inhibition is of the mixed type with respect to acetyl-CoA, and is competitive with respect to TPNH.Malonyl-CoA most markedly affects the K, for TPNH, increasing it 19-fold over a malonyl-CoA concentration range of 10 to 37.5 PM.The inhibition by malonyl-CoA can be reversed by fructose 1,6-diphosphate, and this reversal is reflected in a progressive decrease in the K, for TPNH with increasing fructose 1,6diphosphate concentrations.Fructose 1,6-diphosphate does not markedly affect the K, values for either acetyl-CoA or malonyl-CoA.Some of the kinetic patterns obtained, such as nonlinear reciprocal coordinate plots for the rate of fatty acid synthesis against malonyl-CoA concentration and nonlinear Dixon plots for the malonyl-CoA inhibition, suggest that the substrate inhibition seen in this study may be due to substrate binding at a regulatory site rather than to the classically invoked interaction of substrate molecules at an active site.The biosynthesis of long chain fatty acids de novo from acetyl coenayme A is catalyzed by two enzymic systems, acetyl-CoA carboxylase (acetyl-CoA: COZ ligase (ADP), EC 6.4.1.2) and fatty acid synthetase (2, 3).The over-all reactions catalyzed by these enzymes are as follows.