Ketone-bodies

Ketone body synthesis (ketogenesis) occurs only in the mitochondria of liver cells when acetyl CoA levels exceed the needs of the organ for use in energy production. 

Acetyl CoA is the precursor for all three ketone bodies, acetoacetate, 3-hydroxybutyrate, and acetone. 

Only acetoacetate and 3-hydroxybutyrate can be used as fuel by peripheral tissues. 

Acetone is a byproduct of acetoacetate decarboxylation and cannot be used as a fuel but is instead expired via the lungs. 

Ketone body synthesis is active mainly during starvation, times of intensive 

The term ketone bodies refers primarily to two compounds acetoacetate and P-hydroxy-butyrate, which are formed from acetyl-CoA when the supply of TCA-cycle intermediates is low, such as in periods of prolonged fasting. They can substitute for glucose in skeletal muscle, and, to some extent, in the brain. The first step in ketone body formation is the condensation of two molecules of acetyl-CoA in a reverse of the thiolase reaction. 

The product, acetoacetyl-CoA, accepts another acetyl group from acetyl-CoA to form P-hydroxy-P-hydroxymethylglutaryl-CoA (HMG-CoA). HMG-CoA has several purposes It serves as the initial compound for cholesterol synthesis or it can be cleaved to ace-toacetate and acetyl-CoA. Acetoacetate can be reduced to P-hydroxybutyrate or can be exported directly to the bloodstream. Acetoacetate and p-hydroxybutyrate circulate in the blood to provide energy to the tissues. 

Acetoacetate can also spontaneously decarboxylate to form acetone  

Although acetone is a very minor product of normal metabolism, diabetics whose disease is not well-managed often have high levels of ketone bodies in their circulation. The acetone that is formed from decarboxylation of acetoacetate is excreted through the lungs, causing characteristic acetone breath.  

Substances related to acetone ( ketone bodies ) are produced when an excess of acetyl-GoA arises from P-oxidation. This condition occurs when not enough oxaloacetate is available to react with the large amounts of acetyl-CoA that could enter the citric acid cycle. Oxaloacetate in turn arises from glycolysis because it is formed from pyruvate in a reaction catalyzed by pyruvate carboxylase. 

A situation like this can come about when an organism has a high intake of lipids and a low intake of carbohydrates, but there are also other possible causes, such as starvation and diabetes. Starvation conditions cause an organism to break down fats for energy, leading to the production of large amounts of acetyl-GoA by P-oxidation. The amount of acetyl-CoA is excessive by comparison with the amount of oxaloacetate available to react with it. In the case of people with diabetes, the cause of the imbalance is not inadequate intake of carbohydrates but rather the inability to metabolize them. 

Do acetone and acetyl-CoA have a connection in lipid metabolism  

The principal site of synthesis of ketone bodies is liver mitochondria, but they are not used there because the liver lacks the enzymes necessary to recover acetyl-GoA from ketone bodies. It is easy to transport ketone bodies in the bloodstream because, unlike fatty acids, they are water-soluble and do not need to be bound to proteins, such as serum albumin. Organs other than the liver can use ketone bodies, particularly acetoacetate. Even though glucose is the usual fuel in most tissues and organs, acetoacetate can be used as a fuel. In heart muscle and the renal cortex, acetoacetate is the preferred source of energy. 

If an organism has an excess of acetyl-GoA, it produces substances related to acetone thus the name ketone bodies.  

The relative proportions in which the three ketone bodies are present in blood vary depending on the redox state of the cell. In healthy people, P-hydroxybutyrate and acetoacetate— which are present at approximately equimolar concentrations —constitute virtually all the serum 

None of the commonly used methods for the detection and determination of ketone bodies in serum or urine reacts with ah three ketone bodies. Gerhardt s ferric chloride test reacts with acetoacetate only. Tests using nitroprusside are at least 10 times more sensitive to acetoacetate than to acetone, and give no reaction at all with P hydroxybutyrate. 

The fact that most of the tests for ketosis essentially detect or measure acetoacetate only may produce a paradoxical situation. When a patient initially presents in ketoacidosis, the test results for ketones may be only weakly positive. With therapy, -hydroxybutyrate is converted to acetoacetate and the ketosis appears to worsen. 

Traditional tests for P-hydroxybutyrate are indirect they require brief boiling of the urine to remove acetone and acetoacetate by evaporation (acetoacetate first breaks down spontaneously to acetone), followed by gentle oxidation of p-hydroxybutyrate to acetoacetate and acetone with peroxide, ferric ions, or dichromate. The acetoacetate thus formed may be detected with Gerhardt s test or one of the procedures using nitroprusside. 

Metabolized in other tissues, including brain, as an energy source 

The formation of ketone bodies is a consequence of prolonged metabolism of fat (Fig. 17-12). Their formation in the liver actually enables liver to metabolize even more fat by freeing up CoA that would otherwise be tied up as acetyl-CoA waiting to get into the TCA cycle. The liver exports the ketone bodies and other tissues, particularly the brain, can adapt to use them. 

With increasing metabolism of fat through p oxidation, much of the mitochondrial CoA pool may become tied up as acyl- or acetyl-CoA. In such cases, the supply of free CoA can be diminished, and this may limit the rate of p oxidation. Upon prolonged fasting and heavy reliance on fat for energy, the liver induces the enzymes required for the formation of ketone bodies and brain induces enzymes required for their metabohsm. 

KETONE BODIES are generated by the liver and used by muscle and brain (after adaptation during starvation). 

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

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Possibly the most serious nutrition problem in the United States is excessive food consumption, and many people have experimented with fad diets in the hope of losing excess weight. One of the most popular of the fad diets has been the high-protein, high-fat (low-carbohydrate) diet. The premise for such diets is tantalizing because the tricarboxylic acid (TCA) cycle (see Chapter 20) is the primary site of fat metabolism, and because glucose is usually needed to replenish intermediates in the TCA cycle, if carbohydrates are restricted in the diet, dietary fat should merely be converted to ketone bodies and excreted. This so-called diet appears to work at first because a low-carbohydrate diet results in an initial water (and weight) loss. This occurs because... 

Ketone Bodies Are a Significant Source of Fuel and Energy for Certain Tissues... 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

Acetoacetate and /3-hydroxybutyrate are transported through the blood from liver to target organs and tissues, where they are converted to acetyl-CoA (Figure 24.29). Ketone bodies are easily transportable forms of fatty acids that move through the circulatory system without the need for eomplexation with serum albumin and other fatty acid—binding proteins. 

FIGURE 24.28 The formation of ketone bodies, synthesized primarily in liver mitochondria. 

FIGURE 24.29 Reconversion of ketone bodies to acetyl-CoA in the mitochondria of many tissues (other than liver) provides significant metabolic energy. 

McGarry, J. D., and Foster, D. W., 1980. Regulation of hepatic fatty acid oxidation and ketone body production. Annual Review of Biochemistry 49 395-420. 

The primary fate of acetyl CoA under normal metabolic conditions is degradation in the citric acid cycle to yield C02. When the body is stressed by prolonged starvation, however, acetyl CoA is converted into compounds called ketone bodies, which can be used by the brain as a temporary fuel. Fill in the missing information indicated by the four question marks in the following biochemical pathway for the synthesis of ketone bodies from acetyl CoA ... 

The citrate cycle is the final common pathway for the oxidation of acetyl-CoA derived from the metabolism of pyruvate, fatty acids, ketone bodies, and amino acids (Krebs, 1943 Greville, 1968). This is sometimes known as the Krebs or tricarboxylic acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate which then undergoes a series of reactions involving the loss of two molecules of CO2 and four dehydrogenation steps. These reactions complete the cycle by regenerating oxaloacetate which can react with another molecule of acetyl-CoA (Figure 4). 

Precursor and derived lipids These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, and ketone bodies (Chapter 22), hydrocarbons, hpid-soluble vitamins, and hormones. 

Figure 15-3. Overview of fatty acid metabolism showing the major pathways and end products. Ketone bodies comprise the substances acetoacetate, 3-hy-droxybutyrate, and acetone.

In the liver, it forms ketone bodies (acetone, ace-toacetate, and 3-hydroxybutyrate) that are important fuels in prolonged starvation. 

The amino acids are required for protein synthesis. Some must be supplied in the diet (the essential amino acids) since they cannot be synthesized in the body. The remainder are nonessential amino acids that are supplied in the diet but can be formed from metabolic intermediates by transamination, using the amino nitrogen from other amino acids. After deamination, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination (1) are oxidized to CO2 via the citric acid cycle, (2) form glucose (gluconeogenesis), or (3) form ketone bodies. 

Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids steroids, including cholesterol and ketone bodies. 

When ketone bodies are being metabolized in extra-hepatic tissues there is an alternative reaction catalyzed by succinyl-CoA-acetoacetate-CoA transferase (thio-phorase)—involving transfer of CoA from succinyl-CoA to acetoacetate, forming acetoacetyl-CoA (Chapter 22). 

Inherited aldolase A deficiency and pyruvate kinase deficiency in erythrocytes cause hemolytic anemia. The exercise capacity of patients with muscle phos-phofiaictokinase deficiency is low, particularly on high-carbohydrate diets. By providing an alternative lipid fuel, eg, during starvation, when blood free fatty acids and ketone bodies are increased, work capacity is improved. 

Phosphofructokinase-1 T T Insulin Glucagon (cAMP) AMP, fructose 6-phosphate, P, fructose 2,6-bisphos-phate Citrate (fatty acids, ketone bodies), ATP, glucagon (cAMP)... 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d(—)-3-liydroxyl)utyrate (P-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies (also called acetone bodies or [incorrectly ] ketones ) (Figure 22-5). Acetoacetate and 3-hydroxybu-... 

The term ketones should not be used because 3-hydroxybu-tyrate is not a ketone and there are ketones in blood that are not ketone bodies, eg, pyruvate, fructose. 

Figure 22-5. Interrelationships of the ketone bodies. D(-)-3-hydroxybutyrate dehydrogenase is a mitochondrial enzyme.

Enzymes responsible for ketone body formation are associated mainly with the mitochondria. Two acetyl-CoA molecules formed in P-oxidation condense with one another to form acetoacetyl-CoA by a reversal of the thiolase reaction. Acetoacetyl-CoA, which is the... 

Figure 22-6. Formation, utilization, and excretion of ketone bodies. (The main pathway is indicated by the solid arrows.)...

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