0-hydroxybutyrate 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. 

Figure 22-5. Interrelationships of the ketone bodies. D(-)-3-hydroxybutyrate dehydrogenase is a mitochondrial enzyme.

Fig. 1. The metabolic cycle for the synthesis and degradation of poly(3HB). (1) 3-ketothiolase (2) NADPH-dependent acetoacetyl-CoA reductase (3) poly(3HB) synthase (4) NADH-dependent acetoacetyl-CoA reductase (5), (6) enolases (7) depolymerase (8) d-(-)-3-hydroxybutyrate dehydrogenase (9) acetoacetyl-CoA synthetase (10) succinyl-CoA transferase (11) citrate synthase (12) see Sect. 3...

Once equilibrium is established for the 3-hydroxybutyrate dehydrogenase reaction, the following equation applies ... 

Hydroxymethylglutaryl-CoA lyase 4.1.3.4 3-Hydroxybutyrate dehydrogenase 1.1.1.30 Nonenzymatic reaction... 

Fig. 10. A plot of the maximal relative activity (uRmax) of /3 hydroxybutyrate dehydrogenase-lecithin mixtures versus the number of carbon atoms in the saturated fatty acid side chains of the lecithins.

Phospholipid vesicles (and bilayers) composed of phospholipids with well-defined fatty acid side chains undergo a sharp transition from a crystallinelike state to an amorphous state as the temperature is raised.107 The transition temperature depends on the nature of the fatty acid side chains. For example, for C12 saturated fatty acid chains on lecithin the transition temperature is 0° and for C18 saturated fatty acid chains it is 58°C for unsaturated lecithins the transition temperature is below zero.107 For real membranes sharp phase transitions are not observed, because of the heterogeneous composition of the membrane. In the case of /3 hydroxybutyrate dehydrogenase, the enzymic activity apparently is not influenced by this phase transition as judged by the temperature dependence of the reaction rate. However, for some membrane-bound proteins, a plot of the reaction rate versus the reciprocal temperature... 

In extraliepatic tissues, d-/3-hydroxybutyrate is oxidized to acetoacetate by o-/3-hydroxybutyrate dehydrogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc-cinyl-CoA, an intermediate of the citric acid cycle (see Fig. 16-7), in a reaction catalyzed by P-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. 

Beis A., Zammit V. A. and Newsholme V. A. (1980) Activities of 3-hydroxybutyrate dehydrogenase, 3-oxoacid CoA-transferase and acetoacetyl-CoA thiolase in relation to ketone body utilisation in muscles from vertebrates and invertebrates. Eur. J. Biochem. 104, 209-215. 

NADH UQ UQH2d Acetoacetate — /3-hydroxybutyrate Complex I system /3-Hydroxybutyrate dehydrogenase... 

Figure 10-5. Intrahepatic metabolism of free fatty acids (FFA). CPT I, CPT II, carnitine palmitoyltransferase I, II, respectively LCFA, long-chain fatty acid VLDL, very low-density lipoprotein. 1, Long-chain acyl-CoA synthase 2, acetoacetyl-CoA thiolase 3, hydrox-ymethylglutaryl-CoA synthase 4, hydroxymethylglutaryl-CoA lyase 5, 3-hydroxybutyrate dehydrogenase 6, acetyl-CoA carboxylase 7, fatty acid synthase 8, glycerolphosphate acyltransferase Reprinted with permission from Girard et al. (1992).

Figure 22.19. Formation of Ketone Bodies. The Ketone bodies-acetoacetate, d-3-hydroxybutyrate, and acetone from acetyl CoA are formed primarily in the liver. Enzymes catalyzing these reactions are (1) 3-ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) d-3-hydroxybutyrate dehydrogenase. Acetoacetate spontaneously decarboxylates to form acetone.

Acetoacetate may be reduced by an NAD-requiring dehydrogenase (3-hydroxybutyrate dehydrogenase) to 3-hydroxybutyrate. This is a reversible reaction. 

Acetoacetate may enter cells directly, or it may be produced from the oxidation of 3-hydroxybutyrate by 3-hydroxybutyrate dehydrogenase. NADH is produced by this reaction and can generate ATP. 

Glycerol 3 phosphate dehydrogenase 3-Hydroxybutyrate dehydrogenase Insulysin (insulin degrading enzyme) Isocitrate dehydrogenase Lactate dehydrogenase Leucine aminopeptidase Lipase... 

D-3-Hydroxybutyrate is formed by the reduction of acetoacetate in the mitochondrial matrix by D-3-hydroxybutyrate dehydrogenase. The ratio of hydroxybutyrate to acetoacetate depends on the NADH/NAD ratio inside mitochondria. 

Hydroxybutyrate Dehydrogenase Origin Rhodobacter sphaeroides (formerly Rhodopseudomonas sphaeroides) Roche Diagnostics 3-Hydroxybutyrate Dehydrogenase (3-HBDH), Grade II... 

Hydroxybutyrate Dehydrogenase Origin Rhodopseudomonas spheroides Fluka... 

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