Acetoacetic acid isoleucine

Leucine is exclusively ketogenic in its catabolism, forming acetyl CoA and acetoacetate (see Figure 20.10). The initial steps in the catabolism of leucine are similar to those of the other branched-chain amino acids, isoleucine and valine (see below). 

Tenuazonic Acid.— Tenuazonic acid (208) is generated in the fungus Alternaria tenuis from L-isoleucine and acetate. Recent experiments show that butyric acid is a specific precursor it is presumably implicated via acetoacetic acid. The likely mode of linking of acetoacetate and L-isoleucine was indicated by the isolation of (211) from the cultures. 

By contrast, those amino acids that yield intermediates that can be used for gluconeogenesis are termed glucogenic. As shown in Table 9.10, only two amino acids are purely ketogenic leucine and lysine. Three others yield both glucogenic fragments and either acetyl CoA or acetoacetate tryptophan, isoleucine and phenylalanine. 

Investigations of the biosynthesis of three tetramic acids, namely, tenua-zonic acid (1), erythroskyrin (3), and aCA (4), indicated that the primary step of tetramic acid biosynthesis involves the condensation of an amino acid (L-isoleucine, valine, and L-tryptophan, respectively) with an acetate-derived polyketide [(acetoacetic acid in the case of (1) and (4), a C20 poly-ketide in the case of (3)]. The details of the polyketide assembly and the... 

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. 

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.

Leucine, isoleucine, lysine, and tryptophan form acetyl CoA or ace toacetyl CoA directly, without pyruvate serving as an intermediate (through the pyruvate dehydrogenase reaction, see p. 107). As men tioned previously, phenylalanine and tyrosine also give rise to acetoacetate during their catabolism (see Figure 20.7). Therefore, there are a total of six ketogenic amino acids. 

Amino acids whose catabolism yields either acetoacetate or one of its precursors, acetyl CoA or acetoacetyl CoA, are termed ketogenic. Tyrosine, phenylalanine, tryptophan, and isoleucine are both ketogenic and glucogenic. Leucine and lysine are solely ketogenic. 

Figure 7-11. Degradation of the branched-chain amino acids. Valine forms propionyl CoA. Isoleucine forms pro-pionyl CoA and acetyl CoA. Leucine forms acetoacetate and acetyl CoA.

Four amino acids (lysine, threonine, isoleucine, and tryptophan) can form acetyl CoA, and phenylalanine and tyrosine form acetoacetate. Leucine is degraded to form both acetyl CoA and acetoacetate. 

D. Valine, isoleucine, and leucine (the branched-chain amino acids) are transaminated and then oxidized by an a-keto acid dehydrogenase that requires lipoic acid as well as thiamine pyrophosphate, coenzyme A, FAD, and NAD+. Four of the carbons of valine and isoleucine are converted to succinyl CoA. Isoleucine also produces acetyl CoA Leucine is converted to HMG CoA, which is cleaved to acetoacetate and acetyl CoA... 

Succinyl-CoA can also be synthesized from propionyl-CoA by way of methylmalonyl-CoA, which is formed in the oxidation of branched-chain amino acids (e.g., valine, isoleucine) and in the terminal stage of oxidation of odd-chain-length fatty acids (Chapter 18). Succinyl-CoA is utilized in the activation of acetoacetate (Chapter 18) and the formation of (5-aminolevulinate, a precursor of pro-phyrin (Chapter 29). 

C. Leucine but none of the other amino acids listed is a branched-chain amino acid. The muscle has a very active branched-chain amino acid metabolic pathway and uses that pathway to provide energy for its own use. The products of leucine metabolism are acetyl-CoA and acetoacetate, which are used in the tricarboxylic acid cycle. Acetoacetate is activated by succinyl-CoA and cleaved to two molecules of acetyl-CoA in the P-ketothiolase reaction. The other branched-chain amino acids, valine, and isoleucine, yield succinyl-CoA and acetyl-CoA as products of their catabolism. 

Acetyl CoA serves as a common point of convergence for the major pathways of fuel oxidation. It is generated directly from the (3-oxidation of fatty acids and degradation of the ketone bodies (3-hydroxybutyrate and acetoacetate (Fig. 20.14). It is also formed from acetate, which can arise from the diet or from ethanol oxidation. Glucose and other carbohydrates enter glycolysis, a pathway common to all cells, and are oxidized to pyruvate. The amino acids alanine and serine are also converted to pyruvate. Pyruvate is oxidized to acetyl CoA by the pyruvate dehydrogenase complex. A number of amino acids, such as leucine and isoleucine are also oxidized to acetyl CoA. Thus, the final oxidation of acetyl CoA to CO2 in the TCA cycle is the last step in all the major pathways of fuel oxidation. 

Some amino acids with carbons that produce glucose also contain other carbons that produce ketone bodies. Tryptophan, isoleucine, and threonine produce acetyl CoA, and phenylalanine and tyrosine produce acetoacetate These amino acids are both glucogenic and ketogenic. 

Seven amino acids produce acetyl CoA or acetoacetate and therefore are categorized as ketogenic. Of these, isoleucine, threonine, and the aromatic amino acids (phenylalanine, tyrosine, and tryptophan) are converted to compounds that produce both glucose and acetyl CoA or acetoacetate (Fig. 39.16). Leucine and lysine do not produce glucose they produce acetyl CoA and acetoacetate. 

P-Hydroxybutyrate dehydrogenase (located in mitochondria) catalyses the conversion of acetoacetate to P-hydroxybutyrate. Acetone is formed by the spontaneous decarboxylation of acetoacetate (Fig. 1). Acetoacetate is also produced by degradation of the keto-plastic amino acids, leucine, isoleucine, phenylalanine and tyrosine. 

The carbon skeletons of isoleucine, leucine, phenylalanine, and alanine can yield acetoacetate, and these amino acids may therefore be ketogenic. 

The disorders of isoleucine and valine metabolism are detected in a sequential process that begins with the evaluation of the symptoms and signs displayed by the patient. Clinical chemistry is helpful in the assessment of ketogenesis by urinary tests for ketones or quantification of 3-hydroxybuty-rate and acetoacetate in the blood. The electrolytes and pH may provide evidence of acidosis and it is important to assess the presence or absence of hyperammonemia. Amino acid analysis of the plasma and urine may be helpful. In virtually all instances the definitive diagnosis will come from organic acid analysis of the urine. 

DL-Isoleucine is synthesized in about 56% over-all yield by the method of Hamlin and Hartung (366). o-Oximino- -methyl-w-valeric acid (A) is prepared in 70% yield from ethyl sec.-bulyl acetoacetate, butyl nitrite and sulfuric acid. DL-Isoleucine is prepared in 80% yield by the reduction of (A) with hydrogen, palladium chloride and ethanol. This method is essentially the same as that originated by Bouveault and Locquin (117, 118, 525). By the comparable procedure of Feofilaktov (264, 265) the phenylhydrazone of methyl ethyl pyruvic acid, prepared from sec.-butyl acetoacetate and phenyldiazonium chloride (aniline and NaN02) in 68% yield, is reduced by means of rinc and alcoholic HCl to nearly the theoretical yield of a mixture of DL-isoleucine and DL-allo-isoleucine. Ehrlich (235) synthesized a mixture of isoleucine and allo-isoleucine from 2-methyl-n-butyraldehyde by the Strecker reaction. 

The amino acids leucine, isoleucine, phenylalanine, tryptophan, and tyrosine are capable of undergoing a metabolic conversion to acetoacetate, a ketone body. Thus, they are said to be ketogenic. 

Valine, isoleucine, and leucine are degraded in a quite analogous manner. Acti-yated fatty acids shortened by one C atom are treated in metabolism in essentially the same way as ordinary fatty acids. The only problem is raised by amino acids with a methyl group as a side chain of the carbon skeleton. We will discuss their degradation in connection with j3-oxidation of fatty acids (Chapt. XII-5). As mentioned already, leucine is converted to acetoacetate, isoleucine partially so. Valine, however, becomes methylmalonate, and is changed further by a rearrangement of the carboxyl group to succinate the way to the carbohydrates is thereby opened. 

In the metabolism of L-leucine, the isovaleryl-CoA produced by the oxidative decarboxylation step is further metabolized by a series of enzyme-catalysed steps to acetoacetate and acetyl-CoA and thence into the tricarboxylic acid cycle. Specific enzyme deficiencies at every stage of this metabolic pathway are known and are described in Section 10.3. In contrast, only one disorder of L-isoleucine metabolism subsequent to the oxidative decarboxylation step has been recognized (Section 10.4), and no disorders of the L-valine pathway from isobutyryl-CoA have been described. This may be due to their relative rarity but possibly also to greater difficulty in their detection. The metabolism of valine and leucine is, however, of particular interest in the organic acidurias, since both are major precursors of propionyl-CoA and methylmalonyl-CoA, defects in the metabolism of which lead to propionic acidaemia and methylmalonic aciduria (Chapter 11). 

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