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
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.
Formation of Beta-Hydroxybutyrate (BHB)
Reduction: Acetoacetate is reduced to BHB by beta-hydroxybutyrate dehydrogenase using NADH.
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
Conversion of BHB to Acetoacetate
In target tissues, BHB is oxidized back to acetoacetate by beta-hydroxybutyrate dehydrogenase, using NAD+.
Activation of Acetoacetate
Acetoacetate is converted to acetoacetyl-CoA by succinyl-CoA:3-ketoacid CoA transferase, transferring CoA from succinyl-CoA.
Cleavage to Acetyl-CoA
Acetoacetyl-CoA is cleaved by thiolase into two molecules of acetyl-CoA, which enter the TCA cycle for ATP production.