Succinyl CoA: acetoacetate

When ketone bodies are being metabolized in extra-hepatic tissues there is an alternative reaction catalyzed by succinyl-CoA-acetoacetate-CoA transferase (thio-phorase)—involving transfer of CoA from succinyl-CoA to acetoacetate, forming acetoacetyl-CoA (Chapter 22). 

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies. 

The following experiments shed some light. Kinetic studies of succinyl-CoA-acetoacetate CoA transferase indicate a ping-pong mechanism. The enzyme alternates between two distinct forms, one of which has been shown to contain bormd CoA. The E-CoA intermediate formed from enzyme plus acetoacetyl-CoA was reduced with H-containing sodium borohydride and the protein was completely hydrolyzed with HCl. Trihum-containing a-amino-5-hydroxyvaleric acid was isolated. Since thioesters (as well as oxygen esters) are cleaved in a two-step process... 

Figure 6-13. Ketone body synthesis and utilization. FA = fatty acid AcCoA = acetyl CoA AcAcCoA = ace-toacetyl CoA aKG = a-ketoglutarate OAA = oxaloacetate HMG CoA = hydroxymethylglutaryl CoA. The thio-transferase is succinyl CoA-acetoacetate-CoA transferase.

The liver lacks succinyl CoA-acetoacetate-CoA transferase (a thiotrans-ferase) so it cannot use ketone bodies. Therefore, acetoacetate and 3-hydroxybutyrate are released into the blood by the liver. 

Acetoacetate is activated by reacting with succinyl CoA to form ace-toacetyl CoA and succinate. The enzyme is succinyl CoA-acetoacetate-CoA transferase (a thiotransferase). 

Succinyl-CoA - - acetoacetate acetoacetyl-CoA - -succinate. This reaction is important in the activation of acetoacetate (a ketone body) and hence for its utilization in extrahepatic tissues. 

Activation of acetoacetate requires transfer of coenzyme A from succinyl-CoA, derived from the TCA cycle, by succinyl-CoA-acetoacetate-CoA transferase (thiophorase) ... 

The major process for activating ketone bodies occurs in the mitochondrion, catalyzed by succinyl CoA-acetoacetate thiotransferase, which, starting with succinyl CoA + acetoacetate, forms succinate + acetoacetyl CoA the latter, via beta keto thiolase, can then react with CoA to produce two acetyl CoAs (Fig. 14.4). Although the GTP that would have been obtained from... 

This is illustrated in Fig. 6 for the reaction of succinyl CoA acetoacetate coenzyme A transferase with its specific substrate succinyl CoA, compared with the corresponding nonenzymic reaction through the transition state [34]. Both reactions involve thiol interchange to form a new thiol ester of coenzyme A. Catalysis by the enzyme increases the reaction rate by a factor of 5 x 10, which corresponds to a stabilization of the transition state by 18.7 kcal moP Most of this stabilization arises from the utilization of noncovalent binding interactions between the coenzyme A moiety of the substrate and the enzyme. A short chain thiol ester of succinate with methyl mercaptopropionate has the same chemical properties as succinyl CoA but lacks the specific binding groups of the normal substrate this compound reacts with the enzyme some 10 more slowly than succinyl CoA, only an order of... 

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