Acetone, ketone body synthesis

At high concentrations of acetyl-CoA in the liver mitochondria, two molecules condense to form acetoacetyl CoA [1]. The transfer of another acetyl group [2] gives rise to 3-hydroxy-3-methylglutaryl-CoA (HMC CoA), which after release of acetyl CoA [3] yields free acetoacetate (Lynen cycle). Acetoacetate can be converted to 3-hydroxybutyrate by reduction [4], or can pass into acetone by nonenzymatic decarboxylation [5]. These three compounds are together referred to as "ketone bodies," although in fact 3-hydroxy-butyrate is not actually a ketone. As reaction [3] releases an ion, metabolic acidosis can occur as a result of increased ketone body synthesis (see p. 288). 

Fig. 13-14 Ketone body synthesis. Note that the conversion of acetoacetate to acetone is a siow spontaneous (not enzyme-cataiyzed) decarboxyiation reaction.

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

The increased degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipidemia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and p-hydroxy-butyrate see p. 312). As H"" ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria). 

FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 909). 

Synthesis of the ketone bodies HMG CoA is cleaved to produce acetoacetate and acetyl CoA, as shown in Figure 16.23, Acetoacetate can be reduced to form 3-hydroxybutyrate with NADH as the hydrogen donor. Acetoacetate can also spontaneously decarboxylate in the blood to form acetone—a volatile, biologically non-metabolized compound that can be released in the breath. [Note The equilibrium between acetoacetate and 3-hydroxybutyrate is determined by the NADVNADH ratio. Because this ratio is high during fatty acid oxidation, 3-hydroxy-butyrate synthesis is favored.]... 

D. Decreased insulin levels cause fatty acid synthesis to decrease and glucagon levels to increase. Adipose triacylglycerols are degraded. Fatty acids are converted to ketone bodies in liver a ketoacidosis can occur. There is increased decarboxylation of acetoacetate to form acetone, which causes the odor associated with diabetic ketoacidosis. 

As shown in Figure 26-9, the first product, acetoacetyl-CoA, condenses in the mitochondria with a third molecule of acetyl-CoA to yield HMG-CoA. This pool of HMG-CoA is distinct from that in the cytosol that is an intermediate in cholesterol synthesis. The HMG-CoA produced in the mitochondria is then cleaved enzymatically to yield acetoacetate and acetyl-CoA. Some of the acetoacetate formed in liver cells is usually reduced to p-hydroxybutyrate. Because acetoacetate is unstable, a further portion decomposes to form carbon dioxide and acetone, the third ketone body found in... 

HMG-CoA is also synthesized in mitochondria by the same sequence of reactions but yields the ketone bodies acetoacetate, D(—)- 8-hydroxybutyrate, and acetone (Figure 19-10). Mitochondrial HMG-CoA also arises from oxidation of leucine (Chapter 17), which is keto-genic. Although HMG-CoA derived from leucine is not utilized in mevalonate synthesis, the carbon of leucine can be incorporated into cholesterol by way of acetyl-CoA. Thus, two distinct pools of HMG-CoA exist one... 

THE KETONE BODIES Most of the acetyl-CoA produced during fatty acid oxidation is used by the citric acid cycle or in isoprenoid synthesis (Section 12.3). Under normal conditions, fatty acid metabolism is so carefully regulated that only small amounts of excess acetyl-CoA are produced. In a process called ketogenesis, acetyl-CoA molecules are converted to acetoacetate, /3-hydroxybutyrate, and acetone, a group of molecules called the ketone bodies (Figure 12.7). 

Ketone bodies are produced by the process of ketogenesis, which occurs when acetyl-CoA accumulates beyond its capacity to be oxidized or used for fatty acid synthesis. Under these conditions, the thiolase-catalyzed reaction favors production of acetoacetyl-CoA (Figure 18.21), which is ultimately converted to the ketone bodies - acetoacetate, acetone, and -hydroxybutyrate. 

Fig. 23.18. Synthesis of the ketone bodies acetoacetate, P-hydroxybulyrate, and acetone. The portion of HMG-Co A shown in blue is released as acetyl CoA, and the remainder of the molecule forms acetoacetate. Acetoacetate is reduced to P-hydroxybutyrate or decarboxy-lated to acetone. Note that the dehydrogenase that interconverts acetoacetate and P-hydroxybutyrate is specific for the D-isomer. Thus, it differs from the dehydrogenases of P-oxidation, which act on 3-hydroxy acyl CoA derivatives and is specific for the L-isomer.

Fatty acids undergo 3-oxidation, producing acetyl CoA, NADH and FADH2. The NADH and FADH2 are oxidised by the respiratory chain to form ATP which is used for gluconeogenesis (Chapter 34) and for urea synthesis (Chapter 44). The acetyl CoA forms the ketoacids acetoacetate and P-hydroxybutyrate, known as the ketone bodies . Acetone, formed in small amounts from acetoacetate, causes the fruity smell of the breath in ketotic patients or people on low carbohydrate diets (e.g. the Atkins diet ). NB When the ratio of NADH NAD is high, as in diabetic ketoacidosis (DKA), the equilibrium of the P-... 

Ketone bodies The substances acetoace-tate, p-hydroxybutyrate, and acetone, which are produced from excess acetyl-CoA in the fiver when the rate of fatty acid p-oxidation in fiver mitochondria exceeds the rate at which acetyl-CoA is used for energy generation or fatty acid synthesis. 

Acetoacetate Metabolism. An active deacylase in liver is responsible for the formation of free acetoacetate from its CoA derivative. The j8-hydroxybutyric dehydrogenase mentioned above and a decarboxylase are capable of converting acetoacetate into the other ketone bodies, /3-hydroxybutyrate, and acetone. liver does not contain a mechanism for activating acetoacetate. Heart muscle has been found to contain a specific thiophorase that forms acetoacetyl CoA at the expense of suc-cinyl CoA. Acetoacetate is thus used by peripheral tissues by activation through transfer, then reaction with either the enzymes of fatty acid synthesis or jS-ketothiolase and the enzymes that use acetyl CoA. 

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