Leucine transamination

What a-keto acid is formed on transamination of leucine ... 

The biological importance of transamination was confirmed using 15N-labeling experiments (Tannenbaum and Shemin, 1950). 15N-leucine incubated with pig heart muscle gave highly labelled 15N-glutamate, evidence that leucine could be transaminated. Isotope experiments were then extended to the whole range of amino acids. 

In a muscle at rest, most of the 2-oxo acids produced from transamination of branched chain amino acids are transported to the liver and become subject to oxidation in reactions catalysed by branched-chain 2-oxo acid dehydrogenase complex. During periods of exercise, however, the skeletal muscle itself is able to utilize the oxo-acids by conversion into either acetyl-CoA (leucine and isoleucine) or succinyl-CoA (valine and isoleucine). 

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.

Problem 21.5 (a) What is the relationship between reactants and products in the transamination reaction (b) Which ketoacid is needed to give (i) alanine (ii) leucine (iii) serine (iv) glutamine (c) Which amino acids cannot be made by transamination 4... 

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... 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

A further method to induce chirality in the pyridoxamine-mediated transamination reactions was developed by Kuzuhara et al. [13]. They synthesized optically resolved pyridinophanes (21, 22) having a nonbranched ansa chain" between the 2 - and 5 -positions of pyridoxamine. With the five-carbon chain in 21 and 22, the two isomers do not interconvert readily. In the presence of zinc(n) in organic solvents such as methanol, tert-butanol, acetonitrile, and nitromethane, they observed stereoselective transamination between pyridinophanes and keto acids. The highest ee%s are 95 % for d-and L-leucine by reaction of the corresponding a-keto acid with (S)- and (R)- 22, respectively. On the basis of kinetic analysis of the transamination reactions, Kuzuhara et al. originally proposed a mechanism for the asymmetric induction through kinetically controlled stereoselective protonation to the carboanion attached to an octahedral Zn(n) chelate intermediate. However, they subsequently raised some questions about this proposal [14]. 

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... 

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... 

Position leucine and a-ketoglutarate so that the groups to be exchanged are aligned. This arrangement makes it easy to predict the products of transamination reactions. 

E. coli (107, 125). The complexes have recently been reviewed (126). It is possible that lipoamide dehydrogenase also functions in the complexes that oxidatively decarboxylate the a-keto acids resulting from the transamination of valine, isoleucine, and leucine but these have proved difficult to resolve (127). Lipoamide dehydrogenase also functions in the pyridoxal phosphate and tetrahydrofolate-dependent oxidative decarboxylation of glycine in the anaerobic bacterium Peptococcus glyci-nophilus. The reaction in which the protein-bound lipoic acid is reduced is very complex and not yet fully understood the ultimate electron acceptor is NAD+ (112,113,128). 

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. 

Oxo-isovalerate may be formed by the transamination of valine it is also the immediate precursor of valine biosynthesis and an intermediate in the synthesis of leucine (both are essential amino acids in mammals). Oxo-lso-valerate undergoes a hydroxymethyl transfer reaction, in which the donor is... 

Branched-Chain Oxo-acid Decarboxylase and Maple Syrup Urine Disease The third oxo-add dehydrogenase catalyzes the oxidative decarboxylation of the branched-chain oxo-acids that arise from the transamination of the branched-chain amino acids, leucine, isoleuctne, emd vtdine. It has a similEU subunit composition to pyruvate and 2-oxoglutarate dehydrogenases, and the E3 subunit (dihydrolipoyl dehydrogenase) is the stune protein as in the other two multienzyme complexes. Genetic lack of this enzyme causes maple syrup urine disease, so-called because the bremched-chain oxo-acids that are excreted in the urine have a smell reminiscent of maple syrup. 

Elongation of amino acid side chains prior to glucosinolate biosynthesis has been studied in several plants. The mechanisms involved are believed to be similar to the formation of leucine from valine and acetate (Fig. 3.13). Through transamination, the amino acid is converted to the corresponding... 

Aldehydes related to common amino acids (3-methylbutanal from leucine, 2-methylpropanal from valine, phenylacetaldehyde from phenylalanine) are formed by enzymatic decarboxylation of the corresponding keto acids, which in turn are reversibly related to the amino acids by transamination [i.e., the keto acids are both degradation products of amino acids 147, 148) and intermediates in their synthesis 149). A third possibility—non-enzymatic oxidation of amino acids to aldehydes by enzymatically produced o-quinones—is established 150, 151) but is not discussed here. 

The production of aldehydes and alcohols from the hydrophobic amino acids has been studied primarily in yeast (147,148,149,154) since the fusel oils produced are significant secondary products of alcoholic fermentation (149). Also important are the studies of Morgan and coworkers on the malty flavor defect in milk which is produced by Streptococcus lactis var. maltigenes (155-161). This flavor is principally caused by 3-methylbutanal (155) which is produced by transamination of leucine to a-ketoisocaproate and decarboxylation (157). Labeling experiments showed that this compound is produced from leucine by tomato extract (9, 162, 163). The corresponding 3-methylbutanol and 3-methylbutyl acetate are produced similarly in banana (145, 163). Similar transformations of valine and phenylalanine are also carried out by banana slices (145). 

The degradation of the hranched-chain amino acids employs reactions that we have encountered previously in the citric acid cycle and fatty acid oxidation. Leucine is transaminated to the corresponding a-ketoacid, a-ketoisocaproate. This a-ketoacid is oxidatively decarboxylated to isovaleryl CoA by the branched-chain a-ketoacid dehydrogenase complex. 

The degradative pathways of valine and isoleucine resemble that of leucine. After transamination and oxidative decarboxylation to yield a CoA derivative, the subsequent reactions are like those of fatty acid oxidation. Isoleucine yields acetyl CoA and propionyl CoA, whereas valine yields CO2 and propionyl CoA. The degradation of leucine, valine, and isoleucine validate a point made earlier (Chapter 14) the number of reactions in metabolism is large, but the number of kinds of reactions is relatively small. The degradation of leucine, valine, and isoleucine provides a striking illustration of the underlying simplicity and elegance of metabolism. 

The liver also plays an essential role in dietary amino acid metabolism. The liver absorbs the majority of amino acids, leaving some in the blood for peripheral tissues. The priority use of amino acids is for protein synthesis rather than catabolism. By what means are amino acids directed to protein synthesis in preference to use as a fuel The K jyj value for the aminoacyl-tRNA synthetases is lower than that of the enzymes taking part in amino acid catabolism. Thus, amino acids are used to synthesize aminoacyl-tRNAs before they are catabolized. When catabolism does take place, the first step is the removal of nitrogen, which is subsequently processed to urea. The liver secretes from 20 to 30 g of urea a day. The a-ketoacids are then used for gluconeogenesis or fatty acid synthesis. Interestingly, the liver cannot remove nitrogen from the branch-chain amino acids (leucine, isoleucine, and valine). Transamination takes place in the muscle. 

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