Ketone body synthesis

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. 

These changes provide further biochemical support for the mechanisms proposed for regulation of ketone body synthesis that are discnssed above. 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

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). 

Gortisol promotes net protein breakdown in skeletal muscle to provide amino acids as precursors for gluconeogenesis and ketone body synthesis (keto-genesis). 

In the absence of insulin and in response to glucagon stimulation, triacylglycerol degradation in adipose tissue runs unabated and the flood of fatty acids reaching the liver leads to ketone body synthesis and packaging of some triacylglycerols into VLDLs. 

The symptoms of type 2 diabetes include hyperglycemia without the ketosis associated with type 1 disease due to residual effects of insulin on ketone body synthesis. 

A. 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. 

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

This shunts acetyl CoA toward ketone body synthesis, which becomes excessive. 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

Ketone body synthesis in the liver and use in peripheral tissues. 

The first two reactions in the cholesterol synthetic pathway are siri lar to those in the pathway that produces ketone bodies (see Figure 16.22, p. 194). They result in the production of 3-hydroxy-3-methyl-glutaryl CoA (HMG CoA, Figure 18.3). First, two acetyl CtA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound. [Note Liver parenchymal cells contain two isoenzymes of HMG CoA synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme Urc tions in the pathway for ketone body synthesis.]... 

Which one of the following is characteristic of low insulin levels A. Increased glycogen synthesis B. Decreased gluconeogenesis from lactate C. Decreased glycogenolysis D. Increased formation of 3-hydroxybutyrate E. Decreased action of hormone-sensitive lipase Correct answer = D. 3-hydroxybutyrate—a ketone body—synthesis is enhanced in the liver by taw insulin levels, which favor activation of hormone-sensitive lipase and release of fatty acids from adipose tissue. Glycogen synthesis is decreased, whereas gluconeogenesis is increased. 

In this section we have seen that fatty acids are oxidized in units of two carbon atoms. The immediate end products of this oxidation are FADH2 and NADH, which supply energy through the respiratory chain, and acetyl-CoA, which has multiple possible uses in addition to the generation of energy via the tricarboxylic acid cycle and respiratory chain. Unsaturated fatty acids can also be oxidized in the mitochondria with the help of auxiliary enzymes. Ketone body synthesis from acetyl-CoA is an important liver function for transfer of energy to other tissues, especially brain, when glucose levels are decreased as in diabetes or starvation. 

Fig. 13-6 Pathway of ketone body synthesis ketogenesis. Table 13.2 shows the reactions and enzymes involved in the production of acetoacetate and 3-hydroxybutyrate shown here.

The regulation of fatty acid oxidation, fatty acid synthesis and ketone body synthesis in the liver is summarized in fig. 10.10 ... 

The starting material for kotonc body synthesis and catabolism, shown in Figure 4.65, is acctyl-CoA. Ketogenesis occurs in the mitochondria of the liver. Hence, ketone body synthesis is, for acetyl-CoA, an alternate fate to immediate oxidation in the Krebs cycle, Tiais pathway results in the formation of acetoacetate and p-hydroxybutyrate. Both appear in the bloodstream (the latter at higher concentrations) and are taken up by various organs, such as the brain and muscle. Here, they are converted back to acetyKloAand then oxidized in the Krebs cycle. 

An additional factor may result in the use of acetyl-CoA for ketone body synthesis rather than for oxidation by the Krebs cycle. Fasting may result in a decrease in the concentration of OAA in liver mitochondria. Such a drop in OAA, a cosubstrate of citrate sjTithase, would impair the use of aoetyl-CoA by this enzyme. Thus, a drop in OAA may provoke the synthesis of the ketone bodies. 

Figure 6-13. Ketone body synthesis and utilization. FA = fatty acid AcCoA = acetyl CoA AcAcCoA = ace-toacetyl CoA aKG = a-ketoglutarate OAA = oxaloacetate HMG CoA = hydroxymethylglutaryl CoA. The thio-transferase is succinyl CoA-acetoacetate-CoA transferase.

Acetyl CoA undergoes similar reactions in the mitochondrion, where HMG CoA is used for ketone body synthesis. 

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