ketone bodies Formation and utilization

• Ketone bodies are water-soluble molecules produced by the liver as an alternative energy source when glucose is scarce, such as during fasting, prolonged exercise, or a low-carbohydrate diet.
• The three main ketone bodies are acetoacetate, beta-hydroxybutyrate (BHB), and acetone.

Formation of ketone bodies (ketogenesis):

• Location: Mitochondria of liver cells
• When glucose levels are low, fatty acids undergo beta-oxidation, producing excess acetyl-CoA. When the capacity of the TCA cycle is exceeded, acetyl-CoA is diverted to ketone body synthesis.

Steps in Ketogenesis:

1. Formation of Acetoacetate:

   • Initial Step: Two acetyl-CoA molecules condense to form acetoacetyl-CoA, catalyzed by thiolase.
   • Intermediate Step: Acetoacetyl-CoA combines with another acetyl-CoA to form HMG-CoA (3-hydroxy-3-methylglutaryl-CoA), catalyzed by HMG-CoA synthase.
   • Final Step: HMG-CoA is cleaved by HMG-CoA lyase to produce acetoacetate and acetyl-CoA.

2. Formation of Beta-Hydroxybutyrate (BHB):

   • Reduction: Acetoacetate is reduced to BHB by beta-hydroxybutyrate dehydrogenase using NADH.

3. Formation of Acetone:

   • Spontaneous Decarboxylation: Acetoacetate can spontaneously decarboxylate to form acetone, which is excreted via breath and urine and is responsible for the fruity odor in ketosis.

Utilization of ketone bodies (ketolysis):

• Location: Extrahepatic tissues (e.g., brain, heart, skeletal muscles)
• Transport: Ketone bodies are transported from the liver through the bloodstream.

Steps in Ketolysis:

1. Conversion of BHB to Acetoacetate:

   • In target tissues, BHB is oxidized back to acetoacetate by beta-hydroxybutyrate dehydrogenase, using NAD+.

2. Activation of Acetoacetate:

   • Acetoacetate is converted to acetoacetyl-CoA by succinyl-CoA:3-ketoacid CoA transferase, transferring CoA from succinyl-CoA.

3. Cleavage to Acetyl-CoA:

   • Acetoacetyl-CoA is cleaved by thiolase into two molecules of acetyl-CoA, which enter the TCA cycle for ATP production.

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