Glutaryl dehydrogenase

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. 

Hartel U, E Eckel, J Koch, G Fuchs, D, Linder, W Buckel (1993) Purification of glutaryl-CoA dehydrogenase from Pseudomonas sp., an enzyme involved in the anaerobic degradation of benzoate. Arch Microbiol 159 174-181. 

Elaborate cascades initiate the clotting of blood (Chapter 12) and the action of the protective complement system (Chapter 31). Cascades considered later in the book are involved in controlling transcription (Fig. 11-13) and in the regulation of mammalian pyruvate dehydrogenase (Eq. 17-9), 3-hydroxy-3-methyl-glutaryl-CoA reductase and eicosanoids (Chapter 21), and glutamine synthetase (Chapter 24). 

Fig. 3. Steroidogenic pathway in granulosa cells. A. Lipoprotein in receptors. B. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). C. Acyl-coenzyme A (cholesterol acyl transferase). D. Cholesterol esterase. E. Cholesterol transport to the mitochondria. F. Cholesterol side-chain cleavage enzymes (phospholipid membrane environment and enzyme levels). G. 3/3-Hydroxysteroid dehydrogenase (3/3-HSD). H. 20a-Hydroxysteroid dehydrogenase (20a-HSD). I. Aromatases.

A distinct electron transfer flavoprotein (ETF) is the single-electron acceptor for a variety of flavoprotein dehydrogenases, including acyl CoA, glutaryl CoA, sarcosine, and dimethylglycine dehydrogenases. It then transfers the electrons to ETF-ubiquinone reductase, the iron-sulfur flavoprotein that reduces ubiquinone in the mitochondrial electron transport chain. 

Much of the endogenous lipid that is eventually used by peripheral tissues is transported in the form of water-soluble ketone bodies, the two most important being jS-hydroxybutyrate and acetoacetate. The metabolic pathway of ketone body formation and its relationship to cholesterol biosynthesis is shown in Fig. 4.10. Four enzymes are Involved in the formation of ketone bodies, namely acetyl-CoA transferase (also known as thiolase), hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), hydroxymethyl-glutaryl-CoA lyase (HMG-CoA lyase) and jS-hy-droxybutyrate dehydrogenase. Tbe last of these catalyses the interconversion of the two principal ketone bodies. All four enzymes are present in liver, the principal site of ketone body formation. Acyl-CoAs are unable to pass through the plasmalemma, and HMG-CoA lyase thus controls the release of ketone... 

Kolker S, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res. 2006 59(6) 840-7. 

Strauss KA, et al. Safety, efficacy and physiological actions of a lysine-free, aiginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency focus on cerebral amino acid influx. Mol Genet Metab. 2011 104(l-2) 93-106. 

Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism caused by a deficiency of glutaryl-CoA dehydrogenase. It results in the accumulation of 3-hydroxyglutaric and glutaric acid [1],... 

GA-1 is an autosomal recessive disorder which results from mutations in the glutaryl-CoA dehydrogenase (GCD) gene [15]. Although a few... 

Goodman SI, et al. Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coh. Hum Mol Genet. 1995 4(9) 1493-8. 

Lindner M, et al. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004 27(6) 851-9. 

Gallagher RC, et al. Glutaryl-CoA dehydrogenase deficiency and newborn screening retrospective analysis of a low excretor provides further evidence that some cases may be missed. Mol Genet Metab. 2005 86(3) 417-20. 

Busquets C, et al. Glutaryl-CoA dehydrogenase deficiency in Spain evidence of two groups of patients, genetically, and biochemically distinct. Pediatr Res. 2000 48(3) 315-22. 

Miihlhausen C, et al. Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity a novel mutation in a Turkish patient with glutaric aciduria type I. J Inherit Metab Dis. 2003 26(7) 713. ... 

Hoffmann GF, et al. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics. 1996 27(3) 115-23. 

A defect of glutaryl-CoA dehydrogenase results in the accumulation of 3-hydroxyglutaric add and glutaric acid. 

Glutaric acid 3-hydroxy-glutaric acid Glutaryl-CoA glutarylcamitine Dehydrogenase... 

Brandt NJ, et al. Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue. J Pediatr. 1979 94(4) 669-73. 

Chalmers RA, Bain MD, Zschocke J. Riboflavin-responsive glutaryl CoA dehydrogenase deficiency. Mol Genet Metab. 2006 88(l) 29-37. 

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