3-hydroxybutyrate oxidation

After 60 hours of starvation in lean subjects, fat utilisation (i.e. ketone bodies plus fatty acids) accounts for three-quarters of the energy expenditure (Table 16.1) a value which will rise even higher as starvation continues. Much of this increase is accounted for by hydroxybutyrate oxidation (the major ketone body) since, by 60 hours of starvation, the plasma concentration of hydroxybutyrate has increased 26-fold compared with a threefold increase in the concentration of fatty acid (the glucose concentration falls by less than 30%). By eight days of starvation there has been a sixfold increase in fatty acid concentration, whereas the concentration of hydroxybutyrate has increased about 50-fold (Table 16.2). The changes in these three major fuels in obese subjects during starvation for 38 days are shown in Figure 16.10. 

Polymer Blends. The miscibility of poly(ethylene oxide) with a number of other polymers has been studied, eg, with poly (methyl methacrylate) (18—23), poly(vinyl acetate) (24—27), polyvinylpyrroHdinone (28), nylon (29), poly(vinyl alcohol) (30), phenoxy resins (31), cellulose (32), cellulose ethers (33), poly(vinyl chloride) (34), poly(lactic acid) (35), poly(hydroxybutyrate) (36), poly(acryhc acid) (37), polypropylene (38), and polyethylene (39). 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, Uver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide energy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxylases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabohsm of L-tyrosine, cholesterol, and histamine (128). 

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. 

Most of the acetyl-CoA formed by 3-oxidation in liver is converted to acetoacetate by the 3-hydroxy-3-methylglutaryl-CoA pathway (Guzman and Gelen, 1993). Acetoacetate is reversibly converted to D-3-hydroxybutyrate by D-3-hy-droxybutyrate dehydrogenase in the mitochondrial matrix in all tissues. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Senior, A.E. Shenatt, H.S.A. (1968). Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycemic fatty acids. Oxidative phosphorylation and mitochondrial oxidation of pyruvate, 3-hydroxybutyrate and tricarboxylic acid-cycle intermediates. Biochem. J. 110,499-509. 

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-... 

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. 

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. 

Incorporation of C02 into poly-p-hydroxybutyrate by a strain of Xanthomonas sp. that metabolizes propene or its oxide (Small and Ensign 1995 Allen and Ensign 1996)... 

Allen and DuBois136 have calculated that the R. Q. of 0.707, obtainable when fat is completely oxidized, would be lowered to 0.669 if the /3-hydroxybutyric acid were not metabolized. If more than one molecule of the ketone bodies is produced from one molecule of the fatty acid, as has been suggested,83 the R. Q. would be further lowered. This may be further complicated by a resulting upset in acid-base balance. 

With these improved techniques P-hydroxybutyrate, which penetrates mitochondria easily and is oxidized to acetoacetate using NAD+ as H acceptor, gave a P/O ratio of 3, the value equivalent to that from the reoxidation of NADH found by Lehninger. Succinate, which bypassed the NAD+/NADH step, gave a ratio of 2. When cytochrome c-Fe2+ was... 

Carboxvalkvlation of Propylene Oxide. These reagents were also used in a similar carboxyalkylation scheme to prepare methyl 3-hydroxybutyrate by reaction with propylene oxide (Equation 3). This might represent a way to prepare substitute 1,3 diols(48) following reduction of the ester or reactive monomers by pyrolys is/dehydration. 

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. 

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. 

In some poorly controlled diabetic patients the high rate of fatty acid oxidation decreases the mitochondrial NADVNADH concentration ratio so that the 3-hydroxybutyrate/acetoacetate concentration ratio can rise to as high as 15 in the blood. Since a test for ketone bodies in the urine (using Clinistix or similar material) detects only acetoacetate this can result in a serious underestimate of the concentration of ketone bodies in the urine. 

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.

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