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Rat liver acetyl coenzyme A carboxylase was purified about 200-fold and the inhibition of this enzyme by certain hypolipidemic drugs was studied.The inhibition was more pronounced if the drugs were added before rather than after the citrate activation of the enzyme.Kinetic analysis revealed noncompetitive inhibition of the drugs with respect to the substrates acetyl-CoA, ATP, and HCO,-, and competitive inhibition with respect to the activator, citrate.Sucrose density gradient centrifugations showed that the drugs reverse the aggregating effect of citrate to form the active polymeric forms of the enzyme from the inactive monomers.Arrhenius plots and heat-inactivation studies suggest gross conformational changes of the enzyme protein in the presence of the drugs.Relative aflinities of acetyl coenzyme A carboxylase for citrate and the drugs are expressed by the calculated dissociation constant for citrate and the inhibition constants of the drugs.Derangement of fatty acid synthesis in vivo is conceivable by competition of the drugs with the activation of acetyl-CoA carboxylase at low and physiologically possible concentrations of the drugs and citrate.
Maragoudakis et al. (Fri,) studied this question.