Acetoacetate, acetoacetyl

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. 

Acetoacetic ester synthesis, 839—841, 850. See also Ethyl acetoacetate Acetoacetyl acyl carrier protein, 1021 Acetoacetyl coenzyme A, 1021, 1032 Acetone... 

In the presence of strong acid, such as boron trifluoride [7637-07-2] appropriately substituted acyl chlorides (7, R = CCl ) add to ketene to form the corresponding acetoacetyl chlorides, which can further react with alcohols to form the corresponding acetoacetates. 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

As the most reactive and economical source of the acetoacetyl moiety, diketene is used as a valuable synthetic intermediate in the manufacture of acetoacetic acid derivatives and heterocycHc compounds which are used as intermediates in the manufacture of dyestuffs, agrochemicals, pharmaceuticals, and polymers. 

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. 

In peripheral tissues acetoacetate exported by the liver reacts with succinyl-CoA formed in the citrate cycle to give acetoacetyl-CoA and succinate catalyzed by a specific CoA transferase. 

QHiqO 141-97-9) see Aminophenazone Baclofen Cefotaxime Ceftazidime Chloroquine Cloricromen Cloxacillin Dipyridamole Felodipine Flutoprazepam Hymecromone Kawain Lacidipine Leflunomide Methylthiouracil Nevirapine Nitrendipine Oxacillin Pentoxifylline Propyphenazone Sulfamerazine acetoacetic acid 4-(trifluoromethyl)anilide (C H (,F3N02 351-87-1) see Leflunomide acetoacetyl chloride... 

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). 

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed cannot be reactivated directly except in the cytosol, where it is used in a much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver. 

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 Deacylase Pathway for Ketogenesis is feasible after the formation of acetoace-tyl-CoA which is subject to hydrolysis to acetoacetate in the liver with the involvement of acetoacetyl-CoA hydrolase, or deacylase. 

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

Ketone bodies are utilized in other tissues (but not the liver) by converting the acetoacetate to acetoacetyl-CoA and then converting the acetoacetyl-CoA to 2 acetyl-CoA, which are burned in the muscle mitochondria. 

The enzymes responsible for their metabolism, d-P-hydroxybutyrate dehydrogenase, acetoacetate-succinyl-CoA transferase and acetoacetyl-CoA-thiolase, are present in... 

Acetic anhydride trifluoroborane, 4 144t Acetoacetic acid arylides, 9 408 Acetoacetoxyethyl methacrylate, 16 242 Acetoacetyl, role in cholesterol synthesis, 5 142... 

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.

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.

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

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. 

At high concentrations of acetyl-CoA in the liver mitochondria, two molecules condense to form acetoacetyl CoA [1]. The transfer of another acetyl group [2] gives rise to 3-hydroxy-3-methylglutaryl-CoA (HMC CoA), which after release of acetyl CoA [3] yields free acetoacetate (Lynen cycle). Acetoacetate can be converted to 3-hydroxybutyrate by reduction [4], or can pass into acetone by nonenzymatic decarboxylation [5]. These three compounds are together referred to as "ketone bodies," although in fact 3-hydroxy-butyrate is not actually a ketone. As reaction [3] releases an ion, metabolic acidosis can occur as a result of increased ketone body synthesis (see p. 288). 

To channel ketone bodies into the energy metabolism, acetoacetate is converted with the help of succinyl CoA into succinic acid and acetoacetyl CoA, which is broken down by p-oxidation into acetyl CoA (not shown see p. 180). 

Thiophorase then catalyzes transfer of CoA to acetoacetate to produce acetoacetyl CoA. 

CoA, the coenzyme A derivative of acetoacetate, reduces its reactivity as a substrate for /3-ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of /3-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding handle that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. 

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. 

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