Acetoacetate metabolism

Walton, J. (1972). The effect of exercise upon acetoacetate metabolism in athletes and non-athletes. Quart. J. Exp. Physiol. 57, 73-79. 

Ketone body production and utilization. Ketone bodies are produced in the liver from fatty acids derived from adipocyte lipolysis. They are released and used as fuel in peripheral tissues. The initial step in acetoacetate metabolism is activation to acetoacetyl-CoA by succinyl-CoA. HMG-CoA, /S-hydroxy-y3-methylglutaryl-CoA HB, /i-hydroxybutyrate. 

The GST Zeta class was initially identified by a BLAST homology search (Tong et al., 1998). It appears to play a role in acetoacetate metabolic pathways. Its role in the metabolism of drugs is not known (Board and Anders 2005). 

Following this sequence, the acetyl CoA produced may enter any of the systems that use acetyl CoA. If the spiral oxidizes the 4-carbon butyric acid CoA thioester, or if reaction (5) is reversed with acetyl CoA as sole substrate, the product is acetoacetyl CoA. Two additional enzymes have been found to influence acetoacetate metabolism. One is a hydrolytic enzyme, the deacylase, that converts acetoacetyl CoA to acetoacetate and CoA. The other is the specific CoA-transferring enzyme that forms acetoacetyl CoA from succinyl CoA and acetoacetate, aceto-acetyl-succinic thiophorase. 

Acetoacetate Metabolism. An active deacylase in liver is responsible for the formation of free acetoacetate from its CoA derivative. The j8-hydroxybutyric dehydrogenase mentioned above and a decarboxylase are capable of converting acetoacetate into the other ketone bodies, /3-hydroxybutyrate, and acetone. liver does not contain a mechanism for activating acetoacetate. Heart muscle has been found to contain a specific thiophorase that forms acetoacetyl CoA at the expense of suc-cinyl CoA. Acetoacetate is thus used by peripheral tissues by activation through transfer, then reaction with either the enzymes of fatty acid synthesis or jS-ketothiolase and the enzymes that use acetyl CoA. 

Figure 15-3. Overview of fatty acid metabolism showing the major pathways and end products. Ketone bodies comprise the substances acetoacetate, 3-hy-droxybutyrate, and acetone.

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). 

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d(—)-3-liydroxyl)utyrate (P-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies (also called acetone bodies or [incorrectly ] ketones ) (Figure 22-5). Acetoacetate and 3-hydroxybu-... 

C[bicarbonate] and NMR were used to demonstrate that the first product in the metabolism of propene epoxide is acetoacetate, which is then reduced to (3-hydroxybutyrate (Allen and Ensign 1996). 

Administer one ampule (44 mEq) if arterial pH is <7.0 0 Monitor arterial or venous pH hourly ° Do not overcorrect pH as acetoacetate and P-hydroxy butyrate are metabolized to bicarbonate... 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

Nothing seems to be known as yet of the metabolic regulation of enzymes of poly(3HB) producing bacteria that catalyze the last step of the poly(3HB) cycle, i. e., the activation of acetoacetate (Fig. 1, steps 9,10). Since both enzymes are involved in a catabolic sequence, it may be speculated that they are inhibited, for... 

The reaction of D-glucose with ethyl acetoacetate was originally studied with a view to obtaining experimental information which would be useful in the interpretation of the biological phenomena of antiketogenesis. It is accepted that some kind of correlation exists between the metabolism of carbohydrates and that of /3-ketonie compounds, but views as to its nature differ. The supporters of the ketolysis theory1 contend that the oxi-... 

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

Most patients with pyruvate-carboxylase deficiency present with failure to thrive, developmental delay, recurrent seizures and metabolic acidosis. Lactate, pyruvate, alanine, [3-hydroxybutyrate and acetoacetate concentrations are elevated in blood and urine. Hypoglycemia is not a consistent finding despite the fact that pyruvate carboxylase is the first rate-limiting step in gluconeogenesis. 

During periods of fasting, muscles may also derive energy from the metabolism of ketone bodies (3-hydroxybutyrate and acetoacetate). These intermediates are... 

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. 

Acetoacetate picked up from the blood is activated in the mitochondria by succinyl CoA ace-toacetyl CoA transferase (common name thiophorase), an enzyme present only in extrahepatic tissues 3-hydroxybutyrate is first oxidized to acetoacetate. Because the liver lacks this enzyme, it carmot metabolize the ketone bodies. 

Formed from excess hepatic acetyl CoA during fasting acetoacetate, 3-hydroxybutyrate, and acetone (not metabolized further)... 

An underweight 4-year-old boy presents semi-comatose in the emergency room at 10 a.m. Plasma glucose, urea, and glutamine are abnormally low acetoacetate is elevated and lactate is normal. He Is admitted to the ICU, where an increase in blood glucose was achieved by controlled infusion of glucagon or alanine. Which metabolic pathway is most likely deficient in this child ... 

The increased degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipidemia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and p-hydroxy-butyrate see p. 312). As H"" ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria). 

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. 

During anaerobic glycolysis in the muscles and erythrocytes, glucose is converted into lactate, releasing protons in the process (see p. 338). The synthesis of the ketone bodies acetoacetic acid and 3-hydroxybutyric acid in the liver (see p. 312) also releases protons. Normally, the amounts formed are small and of little influence on the proton balance. If acids are formed in large amounts, however (e. g., during starvation or in diabetes mellitus see p. 160), they strain the buffer systems and can lead to a reduction in pH (metabolic acidoses lactacidosis or ketoacidosis). 

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). 

The ketone bodies are released by the liver into the blood, in which they are easily soluble. Blood levels of ketone bodies therefore rise during periods of hunger. Together with free fatty acids, 3-hydroxybutyrate and acetoacetate are then the most important energy suppliers in many tissues (including heart muscle). Acetone cannot be metabolized and is exhaled via the lungs or excreted with urine. 

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). 

Conversion of 3-hydroxybutyrate to acetoacetate is necessary as a first step in its metabolism. 

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

Nitisinone is a reversibile inhibitor of 4-hydroxy-phenylpyruvate oxidase, an enzyme that plays a crucial role in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic metabolites fumaryl acetoacetate, succinyl acetoacetate and succinyl acetone. Nitisinone is used for the treatment of hereditary tyrosinemia type 1. After oral administration bioavailability is 90% and peak levels are reached at 2.5 hours after dosing. The drug is eliminated mainly in the urine but some CYP3A4-mediated metabolism seems to occur. The elimination half-life is 45 hours. Blood dyscrasias are frequently occurring side effects as are eye problems like conjunctivitis, corneal opacity and keratitis. Exfoliative dermatitis, erythematous rash and pruritus... 

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