3- Oxoacid transferase

Figure 7.17 The pathway of ketone body oxidation hydroxybutyrate to acetyl-CoA. Hydroxybutyrate is converted to acetoacetate catalysed by hydroxybutyrate dehydrogenase acetoacetate is converted to acetoacetyl-CoA catalysed by 3-oxoacid transferase and finally acetoacetyl-CoA is converted to acetyl-CoA catalysed by acetyl-CoA acetyltransferase, which is the same enzyme involved in synthesis of acetoacetyl-CoA.

The enzyme 3-oxoacid transferase is in mitochondria of muscle and converts acetoacetate to acetoacetyl-CoA however, it is absent from liver mitochondria. The acetoacetyl-CoA is cleaved to acetyl-CoA by thiolase, which is in the mitochondria of all tissues (see Fig. 13-7). 

After the activation to its coenzyme A ester of acetoacetate by succinyl-CoA 3-oxoacid transferase, the acetoacetyl-coenzyme A must be cleaved into acetyl-CoA by thiolase. There are three thiolase enzymes one cytosolic enzyme and two mitochondrial enzymes (distinguished by the laboratory property of one being activated by potassium and the other is not). The main enzyme only cleaves acetoacetyl-CoA and provides a baseline thiolase activity. The other enzyme cleaves both acetoacetyl-CoA and... 

Figure 7.18 Oxoacid transferase is the key reaction in acetoacetate oxidation. The reaction produces acetoacetyl-CoA and succinate the former produces the substrate acetyl-CoA, and the latter produces the co-substrate, oxaloacetate, for the first reaction in the Krebs cycle.

Degradation of acetoacetate to acetyl CoA takes place in two steps (not shown). First, acetoacetate and succinyl CoA are converted into acetoacetyl CoA and succinate (enzyme 3-oxoacid-CoA transferase 2.8.3.5). Acetoacetyl CoA is then broken down by p-oxidation into two molecules of acetyl CoA (see p. 164), while succinate can be further metabolized via the tricarboxylic acid cycle. 

This enzyme [EC 2.S.3.5], also known as succinyl-CoA 3-ketoacid CoA-transferase and 3-oxoacid CoA-transferase, catalyzes the reversible reaction of succinyl-CoA with a 3-oxo acid to produce succinate and a 3-oxo-acyl-CoA derivative. 

The 2-oxoacid p-hydroxyphenylpyruvate is decar-boxylated by the action of a dioxygenase (Eq. 18-49). The product homogentisate is acted on by a second dioxygenase, as indicated in Fig. 25-5, with eventual conversion to fumarate and acetoacetate. A rare metabolic defect in formation of homogentisate leads to tyrosinemia and excretion of hawkinsin97 a compound postulated to arise from an epoxide (arene oxide) intermediate (see Eq. 18-47) which is detoxified by a glutathione transferase (Box 11-B). 

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. 

Most tissues oxidize the acetyl-CoA produced during P-oxidation to C02 and water via the TCA cycle. During fasting, however, the liver utilizes the intermediates of the TCA cycle as gluconeogenic substrates. Under these conditions, the Ever converts acetyl-CoA to ketone bodies (acetoacetate and P-hydroxybutyrate) (Figure 32-5). Most other peripheral tissues can oxidize ketone bodies by the pathway shown in the figure. After entering the mitochondria, acetoacetate reacts with succinyl-CoA to form acetoacetyl-CoA, a reaction that is catalyzed by 3-oxoacid-CoA transferase. Alternatively, acetoacetyl-CoA is formed by direct activation of acetoacetate by the enzyme acetoacetyl-CoA synthetase. Acetoacetyl-CoA is then cleaved to form two molecules of acetyl-CoA by acetoacetyl-CoA thiolase.As noted earlier in... 

Some organs (e.g., heart and skeletal muscle) can use ketone bodies (/J-hydroxybutyrate and acetoacetate) as an energy source under normal conditions. During starvation the brain uses them as an important fuel source. Because liver does not have /J-oxoacid-CoA transferase, it cannot use ketone bodies as an energy source. These reactions are reversible. 

The liver is clearly well equipped to utilize free fatty acids and to interconvert acetoacetate and hydroxybutyrate, but the virtual absence of 3-Oxoacid-CoA transferase and lipoprotein lipase means that any significant uptake of ketone bodies and triglycerides is restricted to extra-hepatic tissues. Heart and kidney contain the necessary enzymes to deal with all four fuels and this may reflect their high metabolic activity. Page and Williamson (1971) have shown that normal human brain has the capacity to utilize ketone bodies. 

Succinyl-CoA 3-oxoacid-CoA transferase deT Urea cycle defects Lipoid adrenal hyperplasia Biotinidase def. 

The acetyl-CoA molecules are the immediate sources of the ketone bodies. The actual formation of acetoacetate proceeds via the 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA) cycle with HMG-CoA synthetase (HMGS) and HMG-CoA lyase (HMGL, see Sect. 6.8) as the key enzymes. Extrahepatic tissues are able to utilize the ketone bodies and require for this the action of succinyl-CoA 3-oxoacid CoA transferase (SCOT) and 3-oxothiolase (see Sect. 7.4). 

Succinyl-CoA 3-oxoacid-CoA-transferase deficiency (SCOT, 14.13) was already described in the early seventies. More than 10 patients are known now they all had multiple episodes of severe ketoacidosis, similar to the patients with jff-ketothiolase deficiency (see Sect. 7.4). Whenever there is hypoglycemia, this is denoted hyperketotic. Urine organic acids and plasma acylcarnitines are non-informative. Various mutations have been reported [17]. Growth and development of the patients was reported to be normal. 

Each cycle of )9-oxidation produces one molecule of acetyl-CoA. This cannot leave the cell, but has to be transformed to acetoacetate (and D-3-hydroxybutyrate) by a series of reactions in the so-called hydroxymethyl-glutaryl cycle. This includes HMG-CoA synthase and HMG-CoA lyase (see Sect. 6.8). Ketone bodies need several enzymes for their utilization in peripheral tissues, i.e. 3-oxothiolase (Sect. 7.4) and succinyl-CoA 3-oxoacid CoA transferase (SCOT). 

---