Ketone bodies are water-soluble molecules produced by the liver when glucose availability is low, such as during fasting, prolonged exercise, or a low-carbohydrate diet.
They serve as an alternative energy source for tissues, particularly the brain.
The three main ketone bodies are acetoacetate, beta-hydroxybutyrate (BHB), and acetone.
Formation of ketone bodies (ketogenesis):
Ketogenesis occurs primarily in the mitochondria of liver cells.
When the body experiences low glucose levels, it breaks down fatty acids through beta-oxidation, resulting in an increased production of acetyl-CoA.
When the rate of acetyl-CoA production exceeds the capacity of the TCA cycle, the liver diverts the excess acetyl-CoA towards ketone body synthesis.
Steps in Ketogenesis:
1. Formation of Acetoacetate:
Initial Step: Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, catalyzed by the enzyme thiolase.
Intermediate Step: Acetoacetyl-CoA reacts with another molecule of acetyl-CoA to form HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) in a reaction catalyzed by HMG-CoA synthase.
Final Step: HMG-CoA is subsequently cleaved by HMG-CoA lyase to yield acetoacetate and acetyl-CoA.
2. Formation of Beta-Hydroxybutyrate:
Reduction Reaction: Acetoacetate can be reduced to beta-hydroxybutyrate by the enzyme beta-hydroxybutyrate dehydrogenase, using NADH as a cofactor.
3. Formation of Acetone:
Spontaneous Decarboxylation: Acetoacetate can spontaneously decarboxylate to form acetone, which is the least abundant and least utilized ketone body. Acetone is excreted through the breath and urine and is responsible for the characteristic fruity odor on the breath of individuals in ketosis.
Utilization of ketone bodies (ketolysis):
Location:
Extrahepatic tissues, such as the brain, heart, and skeletal muscles, utilize ketone bodies as an energy source when glucose is scarce.
Transport:
Ketone bodies are transported from the liver to peripheral tissues through the bloodstream.
Steps in Ketolysis:
Conversion of Beta-Hydroxybutyrate to Acetoacetate (Initial Step):
In the target tissues, beta-hydroxybutyrate is converted back to acetoacetate by beta-hydroxybutyrate dehydrogenase, using NAD+ as a cofactor.
Conversion of Acetoacetate to Acetoacetyl-CoA (Intermediate Step):
Acetoacetate is activated to acetoacetyl-CoA by the enzyme succinyl-CoA:3-ketoacid CoA transferase, which transfers a CoA molecule from succinyl-CoA to acetoacetate.
Cleavage of Acetoacetyl-CoA to Acetyl-CoA (Final Step):
Acetoacetyl-CoA is cleaved by thiolase into two molecules of acetyl-CoA, which can then enter the TCA cycle for ATP production.
