Isoleucine catabolism

Pyruvate carboxylase, which participates in gluconeogenesis and lipogenesis Acetyl-CoA carboxylase, which participates in fatty acid biosynthesis Propionyl-CoA carboxylase, which participates in isoleucine catabolism 3-Methylcrotonyl-CoA carboxylase, which participates in leucine catabolism... 

Figure 5 Pathways of valine and isoleucine catabolism and their postulated relationship to avermectin biosynthesis.

Chemical Strategy of Isoleucine Catabolism Isoleucine is degraded in six steps to propionyl-CoA and acetyl-CoA. 

The fatty acid oxidation pathway comprises a sequence of steps frequently encountered in biology (1) oxidation of an alkane to produce an alkene (2) hydration of the alkene to form a hydroxyl group and (3) oxidation of the hydroxyl group to form a keto group. This three-step sequence is also foimd in the Krebs cycle and the isoleucine catabolic pathway. 

The products of the isoleucine catabolic pathway are propionyl-CoA and ace-tyl-CoA valine catabolism produces one molecule of propionyl-CoA and two molecules of carbon dioxide. Propionyl-CoA is further cataboli25ed to succinyl-CoA, an intermediate of the Krebs cycle (Figure 8.7). This pathway is also used for catabolism of the short-chain fatty acid propionic acid, after its conversion to the thiol ester form by thiokinase. The first step in propionyl-CoA breakdown is catalyzed by propionyl-CoA carboxylase, a biotin-requiring enzyme. The second step is catalyzed by methylmalonyl-CoA mutase, a vitamin Bi2-requiring enzyme. 

O.A. Mamer, S.S. Tjoa, Ch. R. Stiver and G.A. Klassen. Demonstration of a new mammalian isoleucine catabolic pathway yielding an (R)-Series of metabolites. Biochem. J., 160. 417-426 (1976) and literature cited therein. 

The major route of valine and isoleucine catabolism in skeletal muscle is to enter the TCA cycle as succinyl CoA and exit as a-ketoglutarate to provide the carbon skeleton for glutamine formation (see Fig. 42.9). Some of the glutamine and CO2 that is formed from net protein degradation in skeletal muscle may also arise from... 

Daum, R.S., Scriver, C.R., Mamer, O.A., Delvin, E., Lamm, P. and Goldman, H. (1973), An inherited disorder of isoleucine catabolism causing accumulation of a-methylacetoacetate and a-methyl-j8-hydroxybutyrate, and intermittent metabolic acidosis. Pediatr. Res., 7,149. 

Przyrembel, H., Bremer, H.J., Duran, M., Bruinvis, L., Ketting, D., Wadman, S.K., Baumgartner, R., Irle, U. and Bachmann, C. (1979), Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels. Eur. J. Pediatr., 130,1. 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

Figure 30-19. The analogous first three reactions in the catabolism of leucine, valine, and isoleucine. Note also the analogy of reactions and to reactions of the catabolism of fatty acids (see Figure 22-3). The analogy to fatty acid catabolism continues, as shown in subsequent figures.

Figure 30-21. Subsequent catabolism of the tiglyl-CoA formed from L-isoleucine.

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

Methylmalonyl CoA mutase, leucine aminomutase, and methionine synthase (Figure 45-14) are vitamin Bj2-dependent enzymes. Methylmalonyl CoA is formed as an intermediate in the catabolism of valine and by the carboxylation of propionyl CoA arising in the catabolism of isoleucine, cholesterol, and, rarely, fatty acids with an odd number of carbon atoms—or directly from propionate, a major product of microbial fer-... 

Guillouet S, Rodal AA, An G-H, Lessard PA, Sinskey AJ. (1999) Expression of the Escherichia coli catabolic threonine dehydratase in Corynebacterium glutamicum and its effect on isoleucine production. Appl Environ Microbiol 65 3100-3107. 

The intermediary metabolism has multienzyme complexes which, in a complex reaction, catalyze the oxidative decarboxylation of 2-oxoacids and the transfer to coenzyme A of the acyl residue produced. NAD" acts as the electron acceptor. In addition, thiamine diphosphate, lipoamide, and FAD are also involved in the reaction. The oxoacid dehydrogenases include a) the pyruvate dehydrogenase complex (PDH, pyruvate acetyl CoA), b) the 2-oxoglutarate dehydrogenase complex of the tricarboxylic acid cycle (ODH, 2-oxoglutarate succinyl CoA), and c) the branched chain dehydrogenase complex, which is involved in the catabolism of valine, leucine, and isoleucine (see p. 414). 

FIGURE 18-21 Catabolic pathways for tryptophan, lysine, phenylalanine, tyrosine, leucine, and isoleucine. These amino acids donate some of their carbons (red) to acetyl-CoA. Tryptophan, phenylalanine, tyrosine, and isoleucine also contribute carbons (blue) to pyruvate or... 

FIGURE 18-27 Catabolic pathways for methionine, isoleucine, threonine, and valine. 

FIGURE 18-28 Catabolic pathways for the three branched-chain amino acids valine, isoleucine, and leucine. The three pathways, which occur in extrahepatic tissues, share the first two enzymes, as shown here. The branched-chain -keto acid dehydrogenase complex... 

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. 

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). 

The branched-chain amino acids, isoleucine, leucine, and valine, are essential amino acids. In contrast to other amino acids, they are metabolized primarily by the peripheral tissues (particularly muscle), rather than by the liver. Because these three amino acids have a similar route of catabolism, it is convenient to describe them as a group (see Figure 20.10). 

End products The catabolism of isoleucine ultimately yields acetyl CoA and succinyl CoA, rendering it both ketogenic and glucogenic. Valine yields succinyl CoA and is glucogenic. Leucine is ketogenic, being metabolized to acetoacetate and acetyl CoA. 

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. 

In the degradation of isoleucine, (3 oxidation proceeds to completion in the normal way with generation of acetyl-CoA and propionyl-CoA. However, in the catabolism of leucine after the initial dehydrogenation in the (3-oxidation sequence, carbon dioxide is added using a biotin enzyme (Chapter 14). The double bond conjugated with the carbonyl of the thioester makes this carboxylation analogous to a standard (3-carboxylation reaction. Why add the extra C02 ... 

Free amino acids are further catabolized into several volatile flavor compounds. However, the pathways involved are not fully known. A detailed summary of the various studies on the role of the catabolism of amino acids in cheese flavor development was published by Curtin and McSweeney (2004). Two major pathways have been suggested (1) aminotransferase or lyase activity and (2) deamination or decarboxylation. Aminotransferase activity results in the formation of a-ketoacids and glutamic acid. The a-ketoacids are further degraded to flavor compounds such as hydroxy acids, aldehydes, and carboxylic acids. a-Ketoacids from methionine, branched-chain amino acids (leucine, isoleucine, and valine), or aromatic amino acids (phenylalanine, tyrosine, and tryptophan) serve as the precursors to volatile flavor compounds (Yvon and Rijnen, 2001). Volatile sulfur compounds are primarily formed from methionine. Methanethiol, which at low concentrations, contributes to the characteristic flavor of Cheddar cheese, is formed from the catabolism of methionine (Curtin and McSweeney, 2004 Weimer et al., 1999). Furthermore, bacterial lyases also metabolize methionine to a-ketobutyrate, methanethiol, and ammonia (Tanaka et al., 1985). On catabolism by aminotransferase, aromatic amino acids yield volatile flavor compounds such as benzalde-hyde, phenylacetate, phenylethanol, phenyllactate, etc. Deamination reactions also result in a-ketoacids and ammonia, which add to the flavor of... 

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