Leucine catabolic pathway

Ganesan B, P Dobrowski, BC Weimer (2006) Identification of the leucine-to-2-methylbutyric acid catabolic pathway of Lactococcus lactis. Appl Environ Microbiol 72 4264-4273. 

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 18-28 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... 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

Figure 11 The putative catabolic pathway of L-leucine and its implications for strain improvement. For a promising host strain, the pathway to be blocked is indicated with thick double lines and the pathways to be fortified are indicated with thick arrows. Abbreviations for enzymes participating in the L-leucine catabolism and the acylation of tylosin VDH, valine (branched-chain amino acid) dehydrogenase BCDFI, branched-chain a-keto acid dehydrogenase IVD (AcdH), isovaleryl-CoA dehydrogenase (acyl-CoA dehydrogenase) MCC, 3-methylcrotonyl-CoA carboxylase EH, enoyl-CoA hydratase AcyA, mac-rolide 3-O-acyltransferase AcyBl, macrolide 4"-(9-acyltransferase.

Poston (1984) showed that, in isolated rat tissues, about 5% of the catabolic flux of leucine was by way of aminomutase action to yield /S-leucine, and then isobutyryl CoA, with the remainder provided by the more conventional a-transamination pathway leading to the formation of isovaleryl CoA. In patients suffering from vitamin B12 deficiency, there is an elevation of plasma /S-leucine, suggesting that the aminomutase may act to metabolize /S -leucine arising from intestinal bacteria, rather than as a pathway for leucine catabolism. 

Leucine catabolism also occurs by a second, minor pathway. The first step in this pathway is catalyzed by leucine aminomutase (Poston, 1984). Leucine ami-nomutasc is one of the three vitamin Bjj-requiring enzymes in mammalian tissues. 

The Catabolic Pathways of Lysine, Tryptophan, Phenylalanine, "tyrosine, and Leucine. 

The following series of reactions, which has been derived from studies on vertebrates, shows the catabolic pathway from leucine to acetyl-CoA which can then enter the tricarboxylic acid cycle. 

More precise information on the pathway of leucine catabolism was obtained from studies on the formation of ketone bodies in liver slices incubated with and C Mabeled leucine and isovaleric acid. In these experiments it was found that leucine-3-C yielded acetoacetate in which the label was virtually all contained in the methyl and methylene carbons, and to approximately the same extent in each of these. Only a trace of radioactivity was found in the carboxyl carbon. On incubation with leucine-4-Ci the label occurred solely in the carbonyl group. This suggested that the isopropyl group of the amino acid had been directly converted to acetone. The over-all conclusion was that the isopropyl group forms acetone, and carbons 2 and 3 of the amino acid yield a 2-car-bon fragment which can condense to acetoacetate. The acetoacetate formed from leucine-4-C was not symmetrically labeled, the isotope being present only in the carbonyl carbon. 

Nemecek-Marshall M, Wojciechowsld C, Wagner WP, Fall R (1999) Acetone formation in the vibrio family a new pathway for bacterial leucine catabolism. J Bacteriol 181 7493... 

It has been noted that a greater amount of ketone bodies was produced from the D- or Dir-leucine than from the ir-isomer. Since both optical isomers yield the same products and follow the same catabolic pathway subsequent to their deamination it is to be inferred that the difference results from the fact that li-leucine is in part incorporated into the body protein, while the D-leucine is not. 

Later, it was concluded that isobutene was synthesised through decarboxylation of isovalerate that is produced in the catabolic pathway of L-leucine (Fukuda et al. 1985, 1994). The decarboxylation reaction is catalysed by a microsomal cytochrome P450 (cytochrome P450rm) in the presence of NADPH, O2 and cytochrome P450, which was an NADPH reductase (Fujii et al. 1988 Fukuda et al. 1994). The initial (and also the rate limiting) step of this reaction is the removal of the hydrogen atom at the p-carbon atom of isovalerate, which is then followed by decarboxylation. P450rm accepts electrons from the reductase and catalyses the formation of isobutene from isovalerate (Fukuda et al. 1994). 

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... 

A minor pathway of valine catabolism is concerned with its conversion to leucine. Because leucine is an essential amino acid, its synthesis from valine is clearly not sufficiently significant to meet the organism s daily demand for leucine. In this reaction, isobutyryl-CoA (see Figure 20.20) is condensed with a molecule of acetyl-CoA to give /3-ketoisocaproate, which is then transaminated to give (3-leucine. A mutase is then used to convert /3-leucine to leucine. This mutase... 

HMG-CoA lyase is normally present in the mitochondrial matrix.To understand the complexity of the metabolic problems of a patient with HMG-CoA lyase deficiency, it is necessary to consider the role of this enzyme in two very distinct metabolic pathways catabolism of leucine and ketogenesis. 

Leucine is a branched chain-amino acid that is essential or required in the diet. Mitochondrial catabolism of excess leucine occurs by the pathway shown in Figure 20-3. The initial transamination step (removal of the amino group) is followed by a decarboxylation reaction to produce isovaleric acid. It is this decarboxylation of the a-keto analogs of the three... 

Figure 20-3. Pathway for the catabolism of leucine. The last step in the pathway is catalyzed by 3-hydroxy-3methyl-CoA lyase, which is deficient in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

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