Hydroxymethylglutaryl CoA synthase

Further, acetoacetyI CoA becomes coupled once more to an acetyl-CoA molecule through the assistance of hydroxymethylglutaryl-CoA synthase ... 

Fructose bisphosphate aldolase— aldolase Hydroxymethylglutaryl-CoA lyase Hydroxymethylglutaryl-CoA synthase Citrate synthase ATP-citrate lyase... 

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.

In the liver, there is an alternative mechanism for regenerating CoA from acetyl-CoA two acetyl-CoA molecules react to form a 4-carbon compound called a ketone body. (Naming a class of molecules bodies is a quaint hangover from the past, but in reality these compounds embody the molecule of acetyl-CoA.) The enzyme in the hepatocyte that catalyzes the relevant reaction is hydroxymethylglutaryl CoA synthase. The consequent release of CoA from acetyl-CoA enables P-oxidation to continue rapidly. The ketone body that is formed first is acetoacetate, it is reduced to -hydroxybutyrate by NADH and the oxidation of NADH further stimulates flux via the fatty acid P-oxidation pathway. Recall that P-oxidation requires regeneration of NAD+ (Sec. 10.5). 

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... 

The hydroxymethylglutaryl-CoA pathway, the major route involved in acetoacetate production, requires the participation of acetyl-CoA ace-tyltransferase (EC 2.3.1.9) for the conversion of acetyl-CoA to acetoacetyl-CoA, and of the hydroxymethylglutaryl-CoA synthase (EC 4.1.3.5) which catalyzes the reaction acetoacetyl-CoA + acetyl-CoA = 3-hydroxy-3-methylglutaryl-CoA + CoA. The activity of acetyl-CoA acetyltransferase is strongly inhibited by acetoacetyl-CoA and CoA, both of which decrease its affinity for acetyl-CoA (Huth et al., 1978). Acetoacetyl-CoA inhibits the activity of 3-hydroxy-3-methylglutaryl-CoA synthase (Reed et a/., 1975) also. For both the above steps, acetyl-CoA is a substrate and CoA is a product. One would expect, therefore, an elevation in acetyl-CoA/CoA ratio to favor acetoacetate production and many data support it (Sauer and Erfle, 1966 Lopes-Cardozo et a/., 1975 Siess et a/., 1976). 

Acetyl CoA acetyltransferase 2 hydroxymethylglutaryl CoA synthase 3 hydroxymethyl-glutaryl CoA reductase 4 mevalonate kinase 5 phosphomevalonate kinase 6 pyrophospho-mevalonate decarboxylase... 

As shown in Scheme 11.39, acetyl-CoA is transferred to the enzyme acetyl-CoA C-acetyltransferase (EC 2.3.1.9) where it is attacked (Claisen condensation) by the anion of acetyl-CoA to produce acetoacetyl-CoA. Then, the aldol-like condensation between acetoacetyl-CoA and acetyl-CoA is catalyzed by hydroxymethylglutaryl-CoA synthase (EC 2.3.3.10). It is held that the acetoacetyl-CoA binds to the enzyme (with the CoAS being replaced by a sulfhydryl bond from the enzyme) and that the addition to the carbonyl occurs on the re-face to yield (35) -3-hydroxy-3 -methylglutaryl CoA. 

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