Ketogenesis

Ketone bodies are molecules used as a source of preferential energy by some tissues such as muscle tissue and in a secondary form by others such as nervous tissue in low glucose for example. There are three bodies that participate in ketogenesis: Acetone, Acetoacetate and Beta OH Butyrate, however the first is eliminated in the breath due to its very volatile characteristic. This group of molecules is formed from Acetyl CoA in the hepatocyte mainly, in the mitochondrial matrix.

Ketogenesis:

For the process to take place, two steps are important. In the first, 2 acetyl-CoA molecules give rise to the acetoacetyl-CoA molecule. This reaction is catalyzed by the thiolase. It is worth mentioning that this reaction in the opposite direction is the same found in beta oxidation. Acetyl-CoA accumulation occurs and this reaction will go towards synthesis. The second step occurs between the acetoacetyl-CoA molecule with a third acetyl-CoA molecule. The compound HMG-CoA is formed, a reaction catalyzed by HMG-CoA Synthase. Subsequently, the cleavage of this compound occurs by HMG-CoA Liase, forming acetoacetate and acetyl-CoA. Acetoacetate may or may not be converted to beta hydroxybutyrate, by the action of the beta OH butyrate dehydrogenase enzyme. It can also undergo spontaneous decarboxylation and give rise to acetone.

Use of Ketone Bodies by Tissues:

Mainly muscle tissue uses this source of energy. It has the beta enzyme acetoacyl-CoA transferase that catalyzes the transfer reaction of CoA from a succinyl-CoA molecule to acetoacetate. In this way, the acetoacetyl-CoA and succinate compounds are formed. Acetoacetyl-CoA through the thiolase releases acetyl-CoA that will be used in the Krebs Cycle . Beta-hydroxybutyrate can be used when it has been previously converted to acetoacetate. This reaction occurs through the enzyme beta-hydroxybutyrate dehydrogenase.

In situations where the production of ketone bodies is high, such as prolonged fasting and decompensated diabetes, the brain can also use it as an energy source. The high concentration of these compounds activates the enzyme monocarboxylate trasnlocase, which allows these bodies to enter nervous tissue. It is important to understand that the production of ketone bodies is abnormally high when lipolysis is not accompanied by carbohydrate degradation.

In drastic situations such as those already mentioned, oxalacetate decreases. This is because there is no more pyruvate from the glycolytic pathway and in the hepatic tissue the gluconeogenesis pathway consumes this oxalacetate even more. The low concentration of oxalacetate causes the oxidation pathway of acetyl-CoA to decrease dramatically. Thus, acetyl-CoA accumulates and condenses to form ketone bodies. When production is very high, it can lead to ketosis with ketonemia and ketonuria present. Another feature is the elimination of excess acetone, which leads to breath with a characteristic odor. The most damaging consequence is the formation of ketoacidosis, which can lead to death. This is what often happens in patients with decompensated diabetes.

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