Ketone bodies biosynthesis

Know pathways and attendant cofactors and key enzymes for fatty acid biosynthesis ketone body biosynthesis, utilization, and clinical implications and fatty acid elongation and unsaturation mechanisms. 

Figure 19.10 Ketone body biosynthesis in the mitochondria. HBDH is /3-hydroxybu-tyrate dehydrogenase. (Reproduced by permission from Li PK. /3-Hydroxybutyrate. Clin Chem News February 13, 1985.)...

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. 

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

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

Ketosis is a pathologic state produced by an excess of ketone bodies in the organism. However, ketosis may be regarded as a lipid metabolism pathology with a certain reserve, since excessive biosynthesis of ketone bodies in the liver is sequent upon an intensive hepatic oxidation not only of fatty acids, but also of keto-genic amino acids. The breakdown of the carbon frameworks of these amino acids leads to the formation of acetyl-CoA and acetoacetyl-CoA, which are used in... 

Several cycles are required for complete degradation of long-chain fatty acids—eight cycles in the case of stearyl-CoA (C18 0), for example. The acetyl CoA formed can then undergo further metabolism in the tricarboxylic acid cycle (see p. 136), or can be used for biosynthesis. When there is an excess of acetyl CoA, the liver can also form ketone bodies (see p. 312). 

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... 

Healthy, well-nourished individuals produce ketone bodies at a relatively low rate. When acetyl-CoA accumulates (as in starvation or untreated diabetes, for example), thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA, the parent compound of the three ketone bodies The reactions of ketone body formation occur in the matrix of liver mitochondria. The six-carbon compound /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) is also an intermediate of sterol biosynthesis, but the enzyme that forms HMG-CoA in that pathway is cytosolic. HMG-CoA lyase is present only in the mitochondrial matrix. 

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

The terpenes, carotenoids, steroids, and many other compounds arise in a direct way from the prenyl group of isopentenyl diphosphate (Fig. 22-1).16a Biosynthesis of this five-carbon branched unit from mevalonate has been discussed previously (Chapter 17, Fig. 17-19) and is briefly recapitulated in Fig. 22-1. Distinct isoenzymes of 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) in the liver produce HMG-CoA destined for formation of ketone bodies (Eq. 17-5) or mevalonate.7 8 A similar cytosolic enzyme is active in plants which, collectively, make more than 30,000 different isoprenoid compounds.910 However, many of these are formed by an alternative pathway that does not utilize mevalonate but starts with a thiamin diphosphate-dependent condensation of glyceraldehyde 3-phosphate with pyruvate (Figs. 22-1,22-2). 

Fatty Acid Oxidation Yields Large Amounts of ATP Additional Enzymes Are Required for Oxidation of Unsaturated Fatty Acids in Mitochondria Ketone Bodies Formed in the Liver Are Used for Energy in Other Tissues Summary of Fatty Acid Degradation Biosynthesis of Saturated Fatty Acids... 

The biosynthesis of ketone bodies (acetoacetate, hydroxybutyrate, and acetone) occurs in the mitochondria of the liver. 

HMG-CoA is an important intermediate for the biosynthesis of both cholesterol and ketone bodies (discussed... 

Two molecules of acetyl CoA initially condense to form acetoacetyl CoA in a reaction which is essentially the reverse of the thiolysis step in (3-oxidation. The acetoacetyl CoA reacts with another molecule of acetyl CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA) (Fig. 5). This molecule is then cleaved to form acetoacetate and acetyl CoA. (HMG CoA is also the starting point for cholesterol biosynthesis see Topic K5.) The acetoacetate is then either reduced to D-3-hydroxybutyrate in the mitochondrial matrix or undergoes a slow, spontaneous decarboxylation to acetone (Fig. 5). In diabetes, acetoacetate is produced faster than it can be metabolized. Hence untreated diabetics have high levels of ketone bodies in their blood, and the smell of acetone can often be detected on their breath. 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Understand the biosynthesis of cholesterol compare this process with that of ketone body production know what controls cholesterol biosynthetic reactions. 

The first two steps in cholesterol biosynthesis from acetyl-CoA are identical to those of ketone body formation (Figure 19.10). The difference is that ketone bodies are formed in the mitochondria, whereas cholesterol synthesis initially takes place in the ER. A thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA, and the combination of a third acetyl-CoA with acetoacetyl-CoA to form /8-hydroxymethylglutaryl-CoA (HMG-CoA) is catalyzed by HMG-CoA synthase. Although HMG-CoA is split into acetoacetate and acetyl-CoA in the mitochondria, in cholesterol biosynthesis, HMG-CoA is reduced by a microsomal enzyme, HMG-CoA reductase, to mevalonate (see Figure 19.17). The reducing agent is NADPH. 

NAD tends to be an electron acceptor in catabolic reactions involving the degradation of carbohydrates, fatty acids, ketone bodies, amino acids, and alcohol. NAD is used in energy-producing reactions. NADP, which is cytosolic, tends to be involved in biosynthetic reactions. Reduced NADP is generated by the pentose phosphate pathway (cytosolic) and used by cytosolic pathways, such as fatty acid biosynthesis and cholesterol synthesis, and by ribonucleotide reductase. The niacin coenzymes are used for two-electron transfer reactions. The oxidized form of NAD is NAD". There is a positive charge on the cofactor because the aromatic amino group is a quaternary amine. A quaternary amine participates in four... 

C. HMG CoA is not formed from glutamic acid, but from acetyl CoA and acetoacetyl CoA. It is also formed by degradation of leucine in muscle. It is cleaved to form acetyl CoA and the ketone body acetoacetate. It is reduced to mevalonic acid in cholesterol biosynthesis. 

Various inborn errors of metabolism (Table 25-1) result from deficiencies or absence of some of the enzymes listed in Figure 25-9. Some of these are discussed later in the chapter. The relationship of carbohydrate metabolism to the production of lactate, ketone bodies, and triglycerides is also depicted in Figure 25-9. The pentose phosphate pathway, also known as the hexose monophosphate shunt, is an alternative pathway for glucose metaboUsm that generates the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), which is used in maintaining the integrity of red blood cell membranes, in lipid and steroid biosynthesis, in hydroxylation reactions, and in other anabolic reactions. The complete picture of intermediary metabolism of carbohydrates is rather complex and interwoven with the metabolism of lipids and amino acids. For details, readers should consult a biochemistry textbook. 

Mitochondrial and cytosolic biosynthesis and utilization of HMG-CoA in the liver. The molecules indicated by an asterisk are the ketone bodies. Acetoacetate and /i-hydroxybutyrate (after conversion to acetoacetate) are metabolized in extrahepatic tissues. Acetone is excreted in the lungs. Note the cytosolic multifunctional isoprenoid pathway for cholesterol biosynthesis. The double arrow indicates a multistep pathway. 

The answer is e. (Murray, pp 190—198. Scriver, pp 1521—1552. Sack, pp 121-138. Wilson, pp 287-317.) The major fate of acetoacetyl CoA formed from condensation of acetyl CoA in the liver is the formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA). Under normal postabsorp-tive conditions, HMG CoA production occurs in the cytoplasm of hepatocytes as part of the overall process of cholesterol biosynthesis. However, in fasting or starving persons, as well as in patients with uncontrolled diabetes mellitus, HMG CoA production occurs in liver mitochondria as part of ketone body synthesis. In this process, HMG CoA is cleaved by HMG CoA lyase to yield acetoacetate and acetyl CoA. The NADH-dependent enzyme P-hydroxybutyrate dehydrogenase converts most of the acetoacetate to P-hydroxybutyrate, These two ketone bodies, acetoacetate and P-hydroxybutyrate, diffuse into the blood and are transported to peripheral tissues. 

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