Regulation of Thiolases from Pig Heart. Control of Fatty Acid Oxidation in Heart

Abstract

The effects of various mitochondrial coenzymes and metabolities on the activities of 3‐oxoacyl‐CoA thiolase (EC 2.3.1.16) and acetoacetyl‐CoA thiolase (EC 2.3.1.9) from pig heart were investigated with the aim of elucidating the possible regulation of these two enzymes. Of the compounds tested, acetyl‐CoA was the most effective inhibitor of both thiolases. However, 3‐oxoacyl‐CoA thiolase was more severely inhibited by acetyl‐CoA than was acetoacetyl‐CoA thiolase. 3‐Oxo‐acyl‐CoA thiolase was also significantly inhibited by decanoyl‐CoA while acetoacetyl‐CoA thiolase was inhibited by 3‐hydroxybutyryl‐CoA as strongly as it was by acetyl‐CoA. All other compounds either did not affect the thiolase activities or only at unphysiologically high concentrations. The inhibition of acetoacetyl‐CoA thiolase by acetyl‐CoA was linear and apparently noncompetitive with respect to CoASH (K_i= 125 μM) whereas that of 3‐oxoacyl‐CoA thiolase was nonlinear. However at low concentrations of acetyl‐CoA the inhibition of 3‐oxoacyl‐CoA thiolase was linear competitive with respect to CoASH (K_i= 3.9 μM). It is concluded that 3‐oxoacyl‐CoA thiolase, but not acetoacetyl‐CoA thiolase, will be completely inhibited by acetyl‐CoA at concentrations of CoASH and acetyl‐CoA which are assumed to exist intramitochondrially at state‐4 respiration. It is suggested that fatty acid oxidation in heart muscle at sufficiently high concentrations of plasma free fatty acids is controlled via the regulation of 3‐oxoacyl‐CoA thiolase by the acetyl‐CoA/CoASH ratio which is determined by the rate of the citric acid cycle and consequently by the energy demand of the tissue.