Question

1. Under what conditions are ketone bodies formed and what are their uses in the body?

2. Mammals are unable to use fatty acids in gluconeogenesis (synthesis of glucose from noncarbohydrate sources) because they lack an enzyme to convert acetyl- CoA to pyruvate. However, recent experimental evidence indicates that certain unusual fatty acids that have odd-numbered carbon chains can be converted to small quantities of glucose. As the odd-carbon chain fatty acid undergoes oxidation, one molecule of propionyl-CoA (3 carbons) is produced during the last cycle. What is the fate of this molecule?

Answer 1

1. Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids. The latter cannot be obtained from the blood, because they cannot pass through the blood–brain barrier.

Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not including fatty acids).They are therefore always released into the blood by the liver together with newly produced glucose, after the liver glycogenstores have been depleted. (These glycogen stores are depleted after only 24 hours of fasting.)

Acetoacetate consists of two acetyl-CoA molecules (without their -CoAs, or coenzyme A) combined in tandem. Beta-hydroxybutyrate is a reduced form of acetoacetate, in which the ketone group is converted into an alcohol (or hydroxyl) group (see illustration on the right). Both are 4-carbon molecules, that can readily be converted back into acetyl-CoA by most tissues of the body, with the notable exception of the liver. Acetone is the decarboxylated form of acetoacetate which cannot be converted back into acetyl-CoA except via detoxification in the liver where it is converted into lactic acid, which can, in turn, be oxidized into pyruvic acid, and only then into acetyl-CoA.

Ketone bodies have a characteristic smell, which can easily be detected in the breath of persons in ketosis and ketoacidosis. It is often described as fruityor like nail polish remover (which usually contains acetone or ethyl acetate).

Apart from the three endogenous ketone bodies, acetone, acetoacetic acid, and beta-hydroxybutyric acid, other ketone bodies like beta-ketopentanoateand beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides, such as triheptanoin.

Ketone bodies can be used for energy. Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle. Ketone bodies cannot be used by the liver for energy, because the liver lacks the enzyme β-ketoacyl-CoA transferase, also called thiophorase. Acetone in low concentrations is taken up by the liver and undergoes detoxification through the methylglyoxal pathway which ends with lactate. Acetone in high concentrations due to prolonged fasting or a ketogenic diet is absorbed by cells other than those in the liver and enters a different pathway via 1,2-propanediol. Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can be turned into pyruvate.

The heart preferentially utilizes fatty acids for energy under normal physiologic conditions. However, under ketotic conditions, the heart can effectively utilize ketone bodies for energy.

The brain gets a portion of its energy from ketone bodies when glucose is less available (e.g., during fasting, strenuous exercise, low carbohydrate, ketogenic diet and inneonates). In the event of low blood glucose, most other tissues have additional energy sources besides ketone bodies (such as fatty acids), but the brain likely has an obligatory requirement for some glucose. After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies.After about 4 days, this goes up to 70% (during the initial stages the brain does not burn ketones, since they are an important substrate for lipid synthesis in the brain). Furthermore, ketones produced from omega-3 fatty acids may reduce cognitive deterioration in old age.

2.  propionyl-CoA (3 carbons) produced during the last cycle enter the TCA cycle. The citric acid cycle – also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle– is a series ofchemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of guanosine triphosphate(GTP). In addition, the cycle provides precursors of certain amino acids as well as the reducing agent NADH that is used in numerous other biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically.