HMG-CoA lyase

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. 

Inherited defects in the enzymes of (3-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty hver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fetty liver of pr nancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30). 

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. 

Ketogenesis occurs in mitochondria of hepatocytes when excess acetyl CoA accumulates in the fasting state. HMG CoA synthase forms HMG-CoA, and HMG-CoA lyase breaks HMG-CoA into acetoacetate, which can subsequently be reduced to 3-hydroxybutyrate. Acetone is a minor side product formed nonenzymatically but is not used as a fuel in tissues. It does, however, impart a strong odor (sweet or fruity) to the breath, which is almost diagnostic for ketoacidosis. 

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. 

A very similar reaction is catalyzed by 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase), which functions in the formation of acetoacetate in the human body (Eq. 17-5, step c) and also in the catabolism of leucine (Fig. 24-18)182183 and in the synthesis of 3-hydroxy-3-methyIgIutaryI-CoA, the presursor of cholesterol (Eq. 17-5, step fr)183a... 

Other Claisen condensations are involved in synthesis of fatty acids and polyketides217 (Chapter 21) and in formation of 3-hydroxy-3-methylglutaryl-CoA, the precursor to the polyprenyl family of compounds (Chapter 22). In these cases the acetyl group of acetyl-CoA is transferred by a simple displacement mechanism onto an -SH group at the active site of the synthase to form an acetyl-enzyme.218 219 The acetyl-enzyme is the actual reactant in step b of Eq. 17-5 where this reaction, as well as that of HMG-CoA lyase, is illustrated. 

HMG-CoA lyase is normally present in the mitochondrial matrix.To understand the complexity of the metabolic problems of a patient with HMG-CoA lyase deficiency, it is necessary to consider the role of this enzyme in two very distinct metabolic pathways catabolism of leucine and ketogenesis. 

Individuals who are deficient in HMG-CoA lyase are unable to complete the metabolism of leucine. The increased urinary excretion of 3-hydroxy-3-methylglutaric acids is the primary biochemical criterion that distinguishes this particular enzymatic defect from other defects in enzymes of leucine catabolism that also result in metabolic acidosis and abnormal organic aciduria. There is also substantial urinary excretion of intermediates of leucine catabolism, such as 3-methylglutaconic acid, and their metabolites, including 3-hydroxy-isovaleric acid produced from isovaleric acid. 

For most patients with HMG-CoA lyase deficiency, strict dietary control can maintain... 

Figure 20-5. Biochemical pathway for ketogene-sis. Condensation of three molecules of acetyl-CoA results in synthesis of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA and release of free CoA-SH, which is then available for continued P-oxidation. Deficiency of HMG-CoA lyase results in the inability to cleave the HMG-CoA to form acetoacetate (the initial ketone body ) and its reduction product P-hydroxybutyrate.

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

Individuals with HMG-CoA lyase deficiency are particularly susceptible to carnitine deficiency. With restriction of red meats and dairy products, dietary carnitine intake is quite low. Carnitine is also synthesized endogenously from the modified, methylated lysine resides of various proteins free trimethyllysine is released when the protein is degraded. Since the therapy for patients with HMG-CoA lyase deficiency must minimize their endogenous protein catabolism, they also have limited availability of trimethyllysine for carnitine synthesis. 

Nutritional therapy for HMG-CoA lyase deficiency has two major goals. First, the prescribed diet aims to provide enough total protein and calories to achieve normal growth and maintain metabolic balance in the context of a leucine-restricted diet. Equally important, the nutritional therapy focuses on preventing excess catabolism, acidosis, and hypoglycemia, especially during times of acute illness. For these patients, it is particularly important to avoid fasting at any time. 

In summary, HMG-CoA lyase deficiency is a unique inborn error of metabolism with profound effects on both amino acid catabolism and metabolic homeostasis in the fasted state. Management of these patients is difficult and requires constant attention to daily nutrition and timely intervention during acute illness. Fortunately, nutritional therapy treatment that provides a diet adequate for growth but with limited intake of leucine and prevents fasting and hypoglycemia enables individuals with HMG-CoA lyase deficiency to live normal active lives. 

Why does deficiency of HMG-CoA lyase result in the excretion of a large number of organic acids in the urine ... 

Why do individuals with HMG-CoA lyase deficiency have difficulty fasting ... 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

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