Ketogenesis

Ketone body formation occurs as an alternative energy source during times of prolonged stress e.g. starvation. It occurs in the liver from an initial substrate of:

• long chain fatty acids; the fatty acids undergo beta-oxidation by their normal pathway within mitochondria until acetyl-CoA is produced, or
• ketogenic amino acids; amino acids such as leucine and lysine, released at times of energy depletion, are interconverted only to acetyl-CoA

Then, three molecules of acetyl-CoA are effectively joined together in three enzyme steps sequentially catalyzed by:

• acetyl CoA acetyltransferase
• HMG-CoA transferase
• HMG-CoA lyase

Coenzyme A is regenerated and the ketone body acetoacetate is formed. Finally, acetoacetate is reduced to another ketone body, D-3-hydroxybutyrate, in a reaction catalyzed by 3-hydroxybutyrate dehydrogenase. This requires NADH. The oxidate state of the liver is such that the forward reaction is generally favoured; this results in more hydroxybutyrate being formed than acetoacetate.

There are 3 products - acetoacetate, 3 hydroxybutyrate and acetone.

The significance is that acetoacetate is tested via urine keto stix and 3 hydroxybutyrate is tested by blood ketone monitors. Acetone is smelt on the breath.

Reference

1. Pranita Ghimire; Amit S. Dhamoon. Ketoacidosis. Treasure Island (FL): StatPearls Publishing. 2024 Jan