Citric acid cycle ketone bodies

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 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. 

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies. 

Heart Pumping of blood Aerobic pathways, eg, P-oxidation and citric acid cycle Free fatty acids, lactate, ketone bodies, VLDL and chylomicron triacylglycerol, some glucose Lipoprotein lipase. Respiratory chain well developed. 

O Ketoacidosis is a dangerous condition that is characterized by the acidification of the blood and an acetone odour on the breath. The condition occurs when levels of oxaloacetic acid for the citric acid cycle are low. This leads to a buildup of acetyl CoA molecules, which the liver metabolizes to produce acidic ketone bodies. Since carbohydrates are the main source of oxaloacetic acid in the body, high-protein, low-carbohydrate diets have been linked to ketoacidosis. 

In a festing state, the liver produces more acetyl CoA from p oxidation than is used in the citric acid cycle. Much of the acetyl CoA is used to synthesize ketone bodies (essentially two acetyl CoA groups linked tc ether) that are released into the blood for other tissues. 

In extraliepatic tissues, d-/3-hydroxybutyrate is oxidized to acetoacetate by o-/3-hydroxybutyrate dehydrogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc-cinyl-CoA, an intermediate of the citric acid cycle (see Fig. 16-7), in a reaction catalyzed by P-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. 

The production and export of ketone bodies by the liver allow continued oxidation of fatty acids with only minimal oxidation of acetyl-CoA When intermediates of the citric acid cycle are being siphoned off for glucose... 

The ketone bodies—acetone, acetoacetate, and D-/3-hydroxybutyrate—are formed in the liver. The latter two compounds serve as fuel molecules in extrahepatic tissues, through oxidation to acetyl-CoA and entry into the citric acid cycle. 

T12. Fatty Acid Oxidation in Uncontrolled Diabetes When the acetyl-CoA produced during /3 oxidation in the liver exceeds the capacity of the citric acid cycle, the excess acetyl-CoA forms ketone bodies—acetone, acetoacetate, and D-/3-hydroxybutyrate. This occurs in severe, uncontrolled diabetes because the tissues cannot use glucose, they oxidize large amounts of fatty acids instead. Although acetyl-CoA is not toxic, the mitochondrion must divert the acetyl-CoA to ketone bodies. What problem would arise if acetyl-CoA were not converted to ketone bodies How does the diversion to ketone bodies solve the problem ... 

Oxidation of ketone bodies /3-hydroxybutyrate-----> acetyl-CoA----> C02 citric acid cycle... 

Individuals with either type of diabetes are unable to take up glucose efficiently from the blood recall that insulin triggers the movement of GLUT4 glucose transporters to the plasma membrane of muscle and adipose tissue (see Fig. 12-8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by JS oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by JS oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and /3-hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to /3-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate ... 

Conversion to fatty acid or ketone bodies. When the cellular energy level is high (ATP in excess), the rate of the citric acid cycle (Topic LI) decreases and acetyl CoA begins to accumulate. Under these conditions, acetyl CoA can be used for fatty acid synthesis or the synthesis of ketone bodies (Topic K3). 

Ketone bodies When the level of acetyl CoA from (3-oxidation increases in excess of that required for entry into the citric acid cycle, the acetyl CoA is converted into acetoacetate and D-3-hydroxybutyrate by a process known as ketogenesis. D-3-hydroxybutyrate, acetoacetate and its nonenzymic breakdown product acetone are referred to collectively as ketone bodies (Fig. 5). 

Answer Individuals with uncontrolled diabetes oxidize large quantities of fat because they cannot use glucose efficiently. This leads to a decrease in activity of the citric acid cycle (see Problem 17) and an increase in the pool of acetyl-CoA. If acetyl-CoA were not converted to ketone bodies, the CoA pool would become depleted. Because the mitochondrial CoA pool is small, liver mitochondria recycle CoA by condensing two acetyl-CoA molecules to form acetoacetyl-CoA + CoA (see Fig. 17-18). The acetoacetyl-CoA is converted to other ketones, and the CoA is recycled for use in the /8-oxidation pathway and energy production. 

To minimize ketosis, a slow but steady degradation of nonessential proteins would provide three-, four-, and five-carbon products essential to the formation of glucose by gluconeogene-sis. This would avoid the inhibition of the citric acid cycle that occurs when oxaloacetate is withdrawn from the cycle to be used for gluconeogenesis. The citric acid cycle could continue to degrade acetyl-CoA, rather than shunting it into ketone body formation. 

Acetyl-CoA is oxidized to C02 by the Krebs cycle, also called the tricarboxylic acid cycle or citric acid cycle. The origin of the acetyl-CoA may be pyruvate, fatty acids, amino acids, or the ketone bodies. The Krebs cycle may be considered the terminal oxidative pathway for all foodstuffs. It operates in the mitochondria, its enzymes being located in their matrices. Succinate dehydrogenase is located on the inner mitochondrial membrane and is part of the oxidative phosphorylation enzyme system as well (Chapter 17). The chemical reactions involved are summarized in Figure 18.7. The overall reaction from pyruvate can be represented by Equation (18.5) ... 

Acetyl-CoA is oxidized to carbon dioxide via the citric acid cycle (Chap. 12), thus transforming additional energy to that which has been transformed via /3-oxidation. In liver mitochondria only, acetyl-CoA may also be converted to ketone bodies ... 

A different pathway in a different compartment degrades fatty acids. Carnitine transports fatty acids into mitochondria, where they are degraded to acetyl CoA in the mitochondrial matrix by P-oxidation. The acetyl CoA then enters the citric acid cycle if the supply of oxaloacetate is sufficient. Alternatively, acetyl CoA can give rise to ketone bodies. The FADH2 and NADH formed in the P-oxidation pathway transfer their electrons to O2 through the electron-transport... 

Acetyl CoA. The major sources of this activated two-carbon unit are the oxidative decarboxylation of pyruvate and the P-oxidation of fatty acids (see Figure 30.11). Acetyl CoA is also derived from ketogenic amino acids. The fate of acetyl CoA, in contrast with that of many molecules in metabolism, is quite restricted. The acetyl unit can be completely oxidized to CO2 by the citric acid cycle. Alternatively, 3-hydroxy-3-methylglutaryl CoA can be formed from three molecules of acetyl CoA. This six-carbon unit is a precursor of cholesterol and of ketone bodies, which are transport forms of acetyl units released from the liver for use by some peripheral tissues. A third major fate of acetyl CoA is its export to the cytosol in the form of citrate for the synthesis of fatty acids. 

Because carbohydrate utilization is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins. Large amounts of acetyl CoA are then produced by P-oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. Recall that mammals can synthesize oxaloacetate from pyruvate, a product of glycolysis, but not from acetyl CoA instead, they generate ketone bodies. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney s capacity to maintain acid-base balance. The untreated diabetic can go into a coma because of a lowered blood pH level and dehydration. 

Figure 30.18. Entry of Ketone Bodies Into the Citric Acid Cycle.

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