Ketone bodies

Which enzymes catalyze the sequential reactions of ketogenesis?

The sequential reactions of ketone body synthesis occur in the mitochondrial matrix of hepatocytes and are catalyzed by the following enzymes:

• Thiolase catalyzes the condensation of 2 molecules of acetyl-CoA to form acetoacetyl-CoA; HS-CoA is released.
• HMG-CoA synthase catalyzes the formation of HMG-CoA from acetoacetyl-CoA, acetyl-CoA, and H₂O; this is the key enzyme of ketogenesis and the rate-limiting step enzyme.
• HMG-CoA lyase catalyzes the lysis of HMG-CoA to form acetoacetate and acetyl-CoA.

Subsequently, acetoacetate can be reduced to β-hydroxybutyrate or, at high concentrations, undergo spontaneous non-enzymatic decarboxylation to acetone.

Which hormones stimulate and inhibit the synthesis of ketone bodies?

Ketone body synthesis is enhanced during low insulin levels and under the action of hormones that activate lipolysis and increase the influx of fatty acids into the liver.

• Glucagon activates lipolysis during starvation, enhances the influx of fatty acids into the liver, and has a ketogenic effect; it also stimulates gluconeogenesis, which is associated with the drainage of oxaloacetate and inhibition of the TCA cycle.
• Adrenaline activates fat mobilization during physical exertion, which increases the flow of fatty acids to the liver and promotes enhanced ketogenesis.
• Cortisol is a counter-regulatory hormone; its excess, along with glucagon and adrenaline, is noted as a factor in ketoacidosis in diabetes mellitus.
• Insulin inhibits lipolysis in adipose tissue; in insulin deficiency, this inhibition is lifted, the release of free fatty acids into the blood increases, and ketogenesis is enhanced.

How many ATP molecules are formed during the complete oxidation of one molecule of beta-hydroxybutyrate to CO2 and H2O?

During the complete oxidation of one molecule of $\beta$-hydroxybutyrate to $CO_2$ and $H_2O$, 21.5 or 22.5 molecules of ATP are formed (or 26 ATP according to older coefficients).

The energy balance consists of the following stages:

• Oxidation of $\beta$-hydroxybutyrate to acetoacetate yields 1 NADH, which is equivalent to 2.5 ATP.
• Cleavage of acetoacetyl-CoA yields 2 molecules of Acetyl-CoA, whose oxidation in the Krebs cycle produces 20 ATP ($2 \times 10$).
• At the acetoacetate activation stage, the energy of the high-energy bond of succinyl-CoA is consumed, meaning 1 GTP (equivalent to 1 ATP) is not formed in the Krebs cycle. Subtracting this loss, the final yield is 21.5 ATP.

What is the difference between physiological ketosis and diabetic ketoacidosis?

The sources of adaptive utilization of ketone bodies and diabetic ketoacidosis can be contrasted as follows:

What enzymes are involved in the utilization (oxidation) of ketone bodies in peripheral tissues?

The utilization of ketone bodies occurs in the mitochondria of peripheral tissues (brain, skeletal muscle, myocardium) involving three main enzymes.

• $\beta$-Hydroxybutyrate dehydrogenase oxidizes $\beta$-hydroxybutyrate to acetoacetate, reducing the $NAD^+$ coenzyme.
• Succinyl-CoA:3-ketoacid-CoA transferase (also known as thiophorase) activates acetoacetate by transferring Coenzyme A from succinyl-CoA to form acetoacetyl-CoA. This enzyme is absent in the liver.
• Thiolase performs the thiolytic cleavage of acetoacetyl-CoA into two molecules of Acetyl-CoA, which then enter the tricarboxylic acid cycle to generate energy.