Ketone bodies | Anatomy2Medicine
ketone bodies

Ketone bodies

 

  • Ketone body synthesis and utilization

 

      • Synthesis of ketone bodies
        • occurs in liver mitochondria
        • occurs when fatty acids are in high concentration in the blood (during fasting, starvation, or as a result of a high-fat diet).
        • How is Acetyl CoA accumulated during starvation
          • beta-Oxidation produces NADH and ATP and results in the accumulation of acetyl coenzyme A (CoA), owing to allosteric inhibition of tricarboxylic acid (TCA) cycle enzymes.
          • The liver is also producing glucose using oxaloacetate (OAA), so there is decreased condensation of acetyl CoA with OAA to form citrate.
        • Two molecules of acetyl CoA condense to produce acetoacetyl CoA.
          • Enzyme : thiolase
        • Acetoacetyl CoA and acetyl CoA form hydroxymethylglutaryl CoA (HMG-CoA)
          • Enzyme : HMG-CoA synthase.
        • HMG-CoA is cleaved to form acetyl CoA and acetoacetate.

 

  • Enzyme : HMG-CoA lyase

 

        • Acetoacetate can be reduced  to 3-hydroxybutyrate (also known as beta-hydroxybutyrate).
          • Enzyme : NAD-requiring dehydrogenase (3-hydroxybutyrate dehydrogenase)
          • This is a reversible reaction.
        • Acetoacetate is also spontaneously decarboxylated in a nonenzymatic reaction, forming acetone
        • Acetone causes odor on the breath of ketotic diabetic patients
        • The liver lacks the enzyme needed to metabolize ketone bodies (succinyl CoA-acetoacetate- CoA transferase, a thiotransferase), so it cannot use the ketone bodies it produces. (MCQ)
        • Therefore, acetoacetate and 3-hydroxybutyrate are released into the blood by the liver.
      • Utilization of ketone bodies
        • When ketone bodies are released from the liver into the blood, they are taken up by peripheral tissues such as muscle and kidney, where they are oxidized for energy.
        • During starvation, ketone bodies in the blood increase to a level that permits entry into brain cells, where they are oxidized.

 

  • Acetoacetate can enter cells directly,
  • Acetoacetate can be produced from the oxidation of Beta-hydroxybutyrate
  • Enzyme : 3-hydroxybutyrate dehydrogenase.

 

          • NADH is produced by this reaction and can generate ATP
        • Acetoacetate is activated by reacting with succinyl CoA to form acetoacetyl CoA and succinate.
          • Enzyme : succinyl CoA-acetoacetate-CoA transferase (a thiotransferase).
        • Acetoacetyl CoA is cleaved to form two molecules of acetyl CoA, which enter the TCA cycle and are oxidized to molecules of CO2.
          • Enzyme : thiolase
      • Energy Calculations on ATP produced during  oxidation of ketone bodies.

 

  • One acetoacetate produces two acetyl CoA, each of which can generate about 10 ATP, or a total of about 20 ATP via the TCA cycle.

 

        • Why does activation of acetoacetate results in the generation of one less ATP ?
          • Because guanosine triphosphate (GTP), the equivalent of ATP, is not produced when succinyl CoA is used to activate acetoacetate.
          • Whereas ,in the TCA cycle, when succinyl CoA forms succinate, GTP is generated

 

  • Therefore, the oxidation of acetoacetate produces a net yield of only 19 ATP
  • When 3-hydroxybutyrate is oxidized, 2.5 additional ATP are formed because the oxidation of 3-hydroxybutyrate to acetoacetate produces NADH.