Rate-limiting function of 3-hydroxy-3-methylglutaryl-coenzyme A synthase in ketogenesis

Abstract

The rate-limiting reaction in the conversion of acetyl-CoA to acetoacetate via the HMG-CoA cycle in rat liver mitochondria was investigated by producing differential effects on the activities of the component enzymes of the sequence and observing consequent reactivity of the overall process. Water-lysed mitochondria were employed to permit measurement of the maximum velocities. Aging at 0°C did not affect acetoacetyl-CoA thiolase or HMG-CoA lyase activities, whereas HMG-CoA synthase activity declined. Acetoacetate production decreased in parallel. Mg 2+ did not affect acetoacetyl-CoA thiolase activity, activated HMG-CoA lyase, and inhibited HMG-CoA synthase. Acetoacetate formation was proportionally depressed. It is concluded that HMG-CoA synthase is the rate-limiting enzyme of the sequence.