Interrelationships between 3-hydroxy-3-methylglutaryl-CoA synthase, acetoacetyl-CoA and ketogenesis.
Kinetic and physical approaches have been employed to investigate the binding of acetoacetyl-CoA to hydroxymethylglutaryl-CoA synthase. The enzyme has an apparent Km for acetoacetyl-CoA (0.35 microM) which is more than an order of magnitude lower than the Ki (6--10 microM) measured for substrate inhibition by this metabolite. Hepatic acetoacetyl-CoA concentration, as measured by a sensitive and highly specific radioactive assay appears to be in the 1--10 microM range; the concentration decreases during diabetic ketoacidosis. Total hepatic activity of hydroxymethylglutaryl-CoA synthase and levels of mitochondrial enzyme protein, determined by radioimmunoassay, are not appreciably different in livers from control or ketoacidotic animals. In contrast to the decrease in hepatic acetoacetyl-CoA concentration observed during ketoacidosis, myocardial acetoacetyl-CoA levels are increased by at least tenfold when compared to controls. Elevated acetoacetyl-CoA levels may serve to inhibit fatty acid utilization by the heart. Thus, a consideration of the multiple interactions of acetoacetyl-CoA with the enzymes involved in ketone body production and utilization may be useful in evaluating the metabolic significance of this intermediate.
D000105:Acetyl Coenzyme A / Q000031:analogs & derivatives* / Q000378:metabolism; D000214:Acyl Coenzyme A; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D016883:Diabetic Ketoacidosis / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D007328:Insulin / Q000627:therapeutic use; D007657:Ketone Bodies / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D007652:Oxo-Acid-Lyases / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D001786:Blood Glucose; D007328:Insulin; D007657:Ketone Bodies; C010667:acetoacetyl CoA; D000105:Acetyl Coenzyme A; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases