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 hydroxymethylgluaryl‐CoA synthase. The enzyme has an apparent Km for acetoacetyl‐CoA (0.35μM) which is more than an order of magnitude lower than the K(6‐10μM) 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 μM 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 acetoaetyl‐CoA levels are increased by aaat least tenfold when compared to controls. Elevated acetoacetyl‐CoA levels may serve to inhibit fatty acid utilization y the heart. Thus, a consideration of the multiple interactions of acetoacetyl‐CoA with the enzymes involved in ketone ody production and utilization may be useful in evaluating the metabolic significance of this intermediate.