Metabolism of ketones

Nehhg, A. Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot. Essent. Fatty Acids 70 265-275, 2004. 

Patel, M. S., Johnson, C. A., Rajan, R. etal. The metabolism of ketone bodies in developing human brain development of ketone-body-utilizing enzymes and ketone bodies as precursors for lipid synthesis. /. Neurochem. 25 905-908, 1975. 

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

Physiological and Pathological Aspects of Metabolism of Ketone Bodies... 

FIGURE 24.29 Reconversion of ketone bodies to acetyl-CoA in the mitochondria of many tissues (other than liver) provides significant metabolic energy. 

The primary fate of acetyl CoA under normal metabolic conditions is degradation in the citric acid cycle to yield C02. When the body is stressed by prolonged starvation, however, acetyl CoA is converted into compounds called ketone bodies, which can be used by the brain as a temporary fuel. Fill in the missing information indicated by the four question marks in the following biochemical pathway for the synthesis of ketone bodies from acetyl CoA ... 

The citrate cycle is the final common pathway for the oxidation of acetyl-CoA derived from the metabolism of pyruvate, fatty acids, ketone bodies, and amino acids (Krebs, 1943 Greville, 1968). This is sometimes known as the Krebs or tricarboxylic acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate which then undergoes a series of reactions involving the loss of two molecules of CO2 and four dehydrogenation steps. These reactions complete the cycle by regenerating oxaloacetate which can react with another molecule of acetyl-CoA (Figure 4). 

Ensign SA, FJ Smakk, JR Allen, MK Sluis (1998) New roles for COj in the microbial metabolism of aliphatic epoxides and ketones. Arch Microbiol 169 179-187. 

Ketosis An abnormal increase of ketone bodies present in conditions of reduced or disturbed carbohydrate metabolism. 

VHL Lee, DS Chien, H Sasaki. (1988). Ocular ketone reductase distribution and its role in the metabolism of ocularly applied levobunolol in the pigmented rabbit. J Pharmacol Exp Therap 246 871-878. 

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. 

Ketosis is a pathologic state produced by an excess of ketone bodies in the organism. However, ketosis may be regarded as a lipid metabolism pathology with a certain reserve, since excessive biosynthesis of ketone bodies in the liver is sequent upon an intensive hepatic oxidation not only of fatty acids, but also of keto-genic amino acids. The breakdown of the carbon frameworks of these amino acids leads to the formation of acetyl-CoA and acetoacetyl-CoA, which are used in... 

In addition to these interconversions, the metabolism of fat and the metabolism of carbohydrate are inseparably related. This fact is most clearly demonstrated by the appearance of such abnormal products of fat oxidation as the so-called ketone bodies in the blood and urine whenever the supply of carbohydrate is deficient or in cases where the organism is unable to metabolize this foodstuff. Whether ketonuria results because the metabolism of fat must occur concomitantly with that of D-glucose (ketolysis), or whether the presence of D-glucose prevents any fat breakdown because it is preferentially oxidized (antiketogenesis) is still a moot question. 

The formation of ketone bodies is a consequence of prolonged metabolism of fat (Fig. 17-12). Their formation in the liver actually enables liver to metabolize even more fat by freeing up CoA that would otherwise be tied up as acetyl-CoA waiting to get into the TCA cycle. The liver exports the ketone bodies and other tissues, particularly the brain, can adapt to use them. 

With increasing metabolism of fat through p oxidation, much of the mitochondrial CoA pool may become tied up as acyl- or acetyl-CoA. In such cases, the supply of free CoA can be diminished, and this may limit the rate of p oxidation. Upon prolonged fasting and heavy reliance on fat for energy, the liver induces the enzymes required for the formation of ketone bodies and brain induces enzymes required for their metabolism. 

Aldehyde reductases are a group of isoenzymes that catalyze the NADPH-specific reduction of aldehydes. Ketones do not serve as substrates for these enzymes. The best substrates for aldehyde reductase are aromatic aldehydes and those aldehydes obtained through metabolism of biogenic amines. The species distribution, specificity, and inhibition of aldehyde reductases have been reviewed (792). 

Exposure to other chemicals can influence the metabolism of -hexane. The effect of oral pretreatment with methyl ethyl ketone (MEK) on the metabolism of inhaled -hexane was investigated in male Fischer 344 rats (Robertson et al. 1989). Groups of 2-4 rats were given MEK (1.87 mL/kg, approximately 1,500 mg/kg) by gavage for 4 days prior to a single 6-hour inhalation exposure to w-hexane (1,000 ppm). Animals were sacrificed at 0, 1, 2, 4, 6, 8, and 18 hours after exposure ended, and samples of blood, liver, testis, and sciatic nerve were obtained and analyzed for -hexane, MEK, and their metabolites. Significant increases in the levels of the neurotoxic metabolite 2,5-hexanedione and 2,5-dimethylfuran (derived from 2,5-hexanedione) were found in blood and sciatic nerve of rats pretreated with MEK. Levels of 2,5-hexanedione in blood were approximately 10-fold higher than control immediately after -hexane exposure in rats and fell rapidly to approximately 2-fold after 6 hours. In sciatic nerve, increases in 2,5-hexanedione were approximately 6-fold at 2 hours and 3-fold at 4 hours. Similar patterns were found with 2,5-dimethylfuran. 2,5-Hexanedione was not detected in the testis of non-pretreated rats levels were measurable but very low in pretreated rats (0.3-0.6 g/g compared to... 

Robertson P, White EL, Bus JS. 1989. Effects of methyl ethyl ketone pretreatment on hepatic mixed-function oxidase activity and on in vivo metabolism of -hexane. Xenobiotica 19(7) 721-729. 

Aldehydes and ketones are readily reduced back to primary and secondary alcohols, respectively. In the case of ketones, although the reduction is reversible, ketoreductase utilizes NADPH, the concentration of which is higher than NADP+, and this drives the reaction toward the secondary alcohol. A good example is warfarin as shown in Figure 5.3 (19). However, aldehydes are further oxidized to carboxylic acids and carboxylic acids are not reduced back to aldehydes thus eliminating the aldehyde. Reductive metabolism of esters and amides also does not generally occur. 

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