Ketogenesis is the synthesis of ketone bodies. Three are 3 ketone bodies namely, acetoacetate, β-hydroxybutyrate, and acetone. Normally in our body, a very less amount of ketone bodies are present in our blood as the starting material for ketogenesis is acetyl-CoA which enters the TCA cycle. When there is the excess formation of acetyl CoA from β-oxidation, It undergoes ketogenesis in the mitochondria of the liver. There are 2 conditions that generate more ketone bodies by excessive lipolysis which are prolonged starvation and uncontrolled diabetes mellitus. Our body completely depends upon ketone bodies for energy during these 2 conditions. The first step of ketogenesis is a condensation of two molecules of acetyl CoA to form acetoacetyl CoA, catalyzed by an enzyme thiolase. In the second step of the ketogenesis pathway, another molecule of acetyl CoA reacts with the acetoacetyl CoA to form 3-Hydroxy-3-methyl glutaryl CoA (HMGCoA). This reaction is catalyzed by the HMG-CoA synthase enzyme that is the rate-limiting enzyme. The HMG-CoA converted to acetoacetate by the action of the enzyme HMG-CoA lyase. The acetoacetate is spontaneously decarboxylated to acetone. Acetoacetate also can be reversibly converted to β-hydroxybutyrate by a β-hydroxybutyrate dehydrogenase enzyme.
Utilization of ketone bodies
Ketone body catabolism, also referred to as ketolysis, involves the breakdown and utilization of ketone bodies as an alternative fuel source when glucose availability is limited. Ketone bodies, specifically beta-hydroxybutyrate (BHB), acetoacetate, and acetone, are produced in the liver during periods of prolonged fasting, low carbohydrate intake, or in individuals with certain metabolic conditions like diabetes.
The process of ketone body catabolism occurs primarily in extrahepatic tissues such as the brain, heart, and skeletal muscle. Here’s a brief overview of the steps involved in ketone body catabolism:
- Conversion of ketone bodies to acetyl-CoA: In peripheral tissues, ketone bodies are transported out of the liver via the bloodstream. In target tissues, such as the brain or muscle cells, ketone bodies are taken up and converted back into acetyl-CoA through a series of enzymatic reactions.
- Entry into the citric acid cycle: Acetyl-CoA generated from ketone bodies enters the citric acid cycle (also known as the Krebs cycle or TCA cycle) within the mitochondria. Acetyl-CoA combines with oxaloacetate to form citrate, initiating the cycle.
- Energy production: The citric acid cycle proceeds, generating reduced coenzymes (NADH and FADH2) that carry high-energy electrons. These electrons are transferred to the electron transport chain (ETC) located in the inner mitochondrial membrane.
- ATP synthesis: As electrons flow through the ETC, the energy is used to pump protons (H+) across the inner mitochondrial membrane, creating a proton gradient. The flow of protons back through ATP synthase drives the synthesis of ATP, the cell’s main energy currency.
- Generation of ketone bodies: Ketone bodies are continuously produced and utilized in response to metabolic demands. When glucose availability is restored or insulin levels increase, the production of ketone bodies decreases, and glucose becomes the primary energy source.
The utilization of ketone bodies provides an efficient energy supply to tissues, especially the brain, during times of fasting or carbohydrate restriction. Ketone bodies can cross the blood-brain barrier and provide an alternative fuel source to glucose for brain cells. Skeletal muscle and the heart can also utilize ketone bodies as an energy source, sparing glucose for other organs.
It’s worth noting that excessive production and accumulation of ketone bodies beyond the body’s capacity to utilize them can lead to a condition called ketoacidosis, which can be potentially life-threatening. However, under normal physiological conditions, the controlled catabolism and utilization of ketone bodies serve as an essential adaptive mechanism to maintain energy homeostasis during periods of metabolic stress.