Regulation of thiolases from pig heart. Control of fatty acid oxidation in heart.
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 severly inhibited by acetyl-CoA than was acetoacetyl-CoA thiolase. 3-Oxoacyl-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 (Ki = 125 microM) 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 (Ki = 3.9 microM). 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.
D000105:Acetyl Coenzyme A / Q000494:pharmacology; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism*; D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D013552:Swine
D005227:Fatty Acids; D000105:Acetyl Coenzyme A; D000217:Acyltransferases; D000123:Acetyltransferases; D000102:Acetyl-CoA C-Acyltransferase; D000101:Acetyl-CoA C-Acetyltransferase; D008274:Magnesium