Ketogenesis

Ketogenesis is a metabolic process that generates ketone bodies, offering the body an alternative energy source. Under normal conditions, the body continually produces small quantities of ketone bodies, each capable of generating 22 ATP. This process is primarily regulated by insulin. During ketosis, ketone body production escalates due to reduced carbohydrate intake or increased fatty acid levels. However, an excessive accumulation of ketone bodies can lead to ketoacidosis, a potential risk in cases of uncontrolled diabetes.

1.0Structure of Ketone Bodies

• Ketogenesis breaks down fatty acids to produce acetone, acetoacetate, and beta-hydroxybutyrate. These ketone bodies are water-soluble lipid molecules characterized by two R-groups attached to a carbonyl group (C = O). 
• Their water solubility eliminates the need for lipoproteins for transport. Acetoacetate and beta-hydroxybutyrate are acidic, with pKa values of 3.6 and 4.7, respectively.

2.0Mechanism of Ketogenesis

The liver is the sole organ responsible for producing ketone bodies, a process that takes place in the mitochondria and releases them into the bloodstream. Extrahepatic tissues can then absorb these ketone bodies from the circulating blood and use them as respiratory substrates.

Steps 

1. Formation of Aceto-acetyl-CoA: This is the starting material for ketogenesis. - Two molecules of acetyl-CoA condensed to form aceto-acetylCoA - The thiolase enzyme catalyzes this reaction. 

2. Formation of Acetoacetate: Acetoacetate is the first ketone body to be formed. This can occur in two ways:

(a) By deacylation: Acetoacetate can be formed from aceto-acetyl-CoA by simple deacylation catalyzed by the enzyme aceto-acetyl-CoA deacylase, and this pathway does not seem to be the primary pathway (minor pathway) 

(b) Second pathway (The HMG-CoA pathway): Formation of acetoacetate via intermediate production of "β-hydroxy-β-methyl glutaryl - CoA" (HMG-CoA). Represent the significant route of ketone body formation. 

Steps Involves two steps:

a. Condensation of aceto-acetyl-CoA with another molecule of acetyl-CoA to form β-hydroxy-β methyl glutaryl-CoA (HMG-CoA) catalyzed by the enzyme HMG-CoA synthase (mitochondrial enzyme). 

b. HMG-CoA is then acted upon by another enzyme, HMG-CoA Lyase, also a mitochondrial enzyme, to produce one molecule of "acetoacetate" and one molecule of acetyl-CoA. 

Note : HMG-CoA synthase and HMG-CoA Lyase are mitochondrial and must be available in mitochondria for ketogenesis to occur.

3 . Formation of Acetone: As stated earlier, acetone is formed from acetoacetate by spontaneous decarboxylation (Non-enzymatic).

4. Formation of D-β-hydroxybutyrate: Acetoacetate, once formed, is converted to β-OH-butyric acid; the reaction is catalyzed by the enzyme β-hydroxybutyrate dehydrogenase, which is present in the liver and also found in many other tissues.

3.0Utilisation of Ketone Bodies

1- Extrahepatic tissues utilize ketone bodies as "fuel".

Steps of ketolysis

(a) Activation of Acetoacetate - Two reactions take place in extrahepatic tissues which activate acetoacetate to form aceto-acetyl-CoA, (a) Action of acetoacetate with succinyl-CoA: Major Pathway by which acetoacetate is activated in extrahepatic tissues. Acetoacetate reacts with one molecule of succinyl-CoA (intermediate of TCA cycle), catalyzed by the enzyme CoA transferase (thiophorase), to form acetoacetyl-CoA and succinate.

(b) Second mechanism: Activation of acetoacetate with ATP and CoASH, catalyzed by the enzyme Acetoacetyl-CoA synthetase. This is probably not a major pathway.

Fate of β-hydroxy-Butyrate 

• β-OH-butyrate may be activated directly in extrahepatic tissues by a synthetase. 
• As the reaction is reversible, the β-hydroxy-butyrate can be converted back to "acetoacetate" by the enzyme β-hydroxy-butyrate dehydrogenase and NAD+.
• Regulation of ketogenesis

4.0Regulation of Ketogenesis

Ketogenesis speeds up or slows down depending on three essential factors: 

1. The level of circulating F.F.As: Ketosis does not occur in vivo unless there is a rise in the level of circulating F.F.As that arises from lipolysis of TGs in adipose tissues. Therefore, conditions that affect the mobilization of F.F.As from adipose tissues are essential in controlling ketogenesis. For example, the insulin/glucagon ratio decreases in starvation, causing increased lipolysis in adipose tissues. 

2. Rate of entry of F.F.As into the liver: If F.F.As enter the liver cells in low concentrations, they will nearly all be esterified into TGs and transported out of the liver in very low-density lipoproteins (VLDL). However, when high concentrations of F.F.As enter the liver, such as in starvation, the acetyl CoA carboxylase (gate-keeper enzyme) is inhibited, and malonyl CoA decreases. Decreasing malonyl CoA increases beta-oxidation of fatty acid activation of carnitine palmitoyltransferase I and oxidizes more fatty acyl CoA. 

5.0Imbalancing of Ketone in the Body

Ketonaemia: The rise of ketone bodies in blood above average level is known as ketonaemia. 

Ketonuria: When the blood level of ketone bodies rises above the renal threshold, they are excreted in urine, called ketonuria. 

Ketosis: Accumulation of abnormal amounts of ketone bodies in tissues and body fluids is termed ketosis.

Ketoacidosis: Acetoacetic acid and β-OH-butyric acid are moderately strong acids. They are buffered in blood and tissues, causing loss of buffer cations, progressively depleting the alkali reserve and causing ketoacidosis.