Acetoacetate ketone bodies

Hepatic yd-oxidation, without oxidation of acetyl-CoA through the TCA cycle, produces a substantial amount of energy. At such a time, liver is actively engaged in gluconeogenesis so that mitochondrial oxaloacetate is depleted, TCA cycle activity is depressed, and acetyl-CoA levels rise. The last reaction in -oxidation is conversion of acetoacetyl-CoA to acetyl-CoA, with an equilibrium in favor of high levels of acetoacetyl-CoA. Thus, acetyl-CoA and acetoacetyl-CoA accumulate and form HMG-CoA cleavage of this last compound yields acetoacetate, which is reduced to jd-hydroxybutyrate. Acetone results from nonenzymatic decarboxylation of acetoacetate. Ketone body formation occurs exclusively in liver (see Chapter 18) and is prominent in starvation and diabetes owing to the... 

Ketone bodies Acetoacetate, P-hydroxybntyrate, and acetone. Acetoacetate and P-hydroxybntyrate are formed by liver enzymes that condense molecnles of acetyl-CoA, thns regenerating CoA for continual use in P-oxidation of fatty acids. Acetone is a spontaneous decomposition prodnct of acetoacetate. Ketone bodies are exported from the liver and can be nsed by some extrahepatic tissnes for energy generation. 

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. 

Acetoacetate and /3-hydroxybutyrate are transported through the blood from liver to target organs and tissues, where they are converted to acetyl-CoA (Figure 24.29). Ketone bodies are easily transportable forms of fatty acids that move through the circulatory system without the need for eomplexation with serum albumin and other fatty acid—binding proteins. 

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-... 

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. 

In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and d(—)-3-hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs. 

Higher than normal quantities of ketone bodies present in the blood or urine constitute ketonemia (hyperke-tonemia) or ketonuria, respectively. The overall condition is called ketosis. Acetoacetic and 3-hydroxybutyric acids are both moderately strong acids and are buffered when present in blood or other tissues. However, their continual excretion in quantity progressively depletes the alkah reserve, causing ketoacidosis. This may be fatal in uncontrolled diabetes mellitus. 

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

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. 

Acetyl-CoA is again used at the first step and closes thereby the whole process into a cycle. Acetoacetate, as a representative of the ketone body family, is the end product of the hydroxymethyl- glutarate cycle. 

The other ketone bodies are derived from acetoacetate P-hydroxybutyrate, by reduction with the involvement of NAD-dependent hydroxybutyrate dehydrogenase, and acetone, by decarboxylation of acetoacetate with the participation of aceto-acetate decarboxylase ... 

In the liver, the ketone bodies suffer no transformation, and are excreted into the blood. The normal contents of ketone bodies (as acetoacetate or P-hydroxy-butyrate) amount to mere 0.1-0.6 mmol/ litre). Other tissues and organs (heart, lung, kidney, muscle, and nervous tissue), as distinct from the liver, utilize the ketone bodies as energy substrates. In the cells of these tissues, acetoacetate and 1-hydroxybutyrate enter ultimately the Krebs cycle and burn down to C02 and H,0 to release energy. 

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. 

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

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. 

Alcoholics can also develop ketoaddosis. In alcoholic ketoacidosis, 3-hydroxybutyrate is the major ketone body produced because there is usually a high NADH/NAD ratio in the hver. The urinary nitroprusside test detects only acetoacetate and may dramatically underestimate the extent of ketosis in an alcoholic. 3-Hydroxybutyrate levels (P-hydroxybutyrate) should always be measured in these patients. 

Ketone bodies (acetoacetate, hydroxybutyrate) free liver cardiac muscle, brain, kidney, skeletal muscle, small intestine... 

Acetoacetate and 3-hydroxybutyrate are known as ketone bodies. They are classified as fat fuels since they arise from the partial oxidation of fatty acids in the liver, from where they are released into the circulation and can be used by most if not all aerobic tissues (e.g. muscle, brain, kidney, mammary gland, small intestine) (Figure 7.7, Table 7.1). There are two important points (i) ketone bodies are used as fuel by the brain and small intestine, neither of which can use fatty acids (ii) ketone bodies are soluble in plasma so that they do not require albumin for transport in the blood. 

Total ketone body concentration is acetoacetate plus hydroxybutyrate. Exercise was at high percentage V09.n for 90 min. 

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