Branch-chained amino acids transamination

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 8.11 Five near-equilibrium reactions involved in transamination of five different amino adds. Three enzymes are involved in these reactions (1) alanine aminotransferase (2) aspartate aminotransferase (3) branched-chain amino acid aminotransferase, i.e. one enzyme catalyses the three reactions. (The branched-chain amino acids are essential.)...

Figure 8.17 The metabolism of branched-chain amino acids in muscle and the fate of the nitrogen and oxoacids. The a-NH2 group is transferred to form glutamate which is then aminated to form glutamine. The ammonia required for aminab on arises from glutamate via glutamate dehydrogenase, but originally from the transamination of the branded chain amino acids. Hence, they provide both nitrogen atoms for glutamine formation.

The amino acids, aspartate and glutamate, are not taken up from the blood but are synthesised in the brain. This requires nitrogen (for the -NH2 groups) which is obtained from branched-chain amino acids via transamination, as in other tissues. 

In the branched-chain amino acids (Val, Leu, He) and also tyrosine and ornithine, degradation starts with a transamination. For alanine and aspartate, this is actually the only degradation step. The mechanism of transamination is discussed in detail on p. 178. 

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.

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... 

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... 

The effects of exercise on branched-chain amino acids may be unique. The branched-chain amino acids are essential in the diet and are uniquely catabolized in skeletal muscles. These amino acids may provide an energy source for muscles or may serve an intermediate role in maintaining blood glucose through production of alanine via transamination with pyruvate in muscles (19). 

The liver is responsible for modifying blood protein and Aa composition, which it performs by a series of enzymatic process including transamination, deamination and reamination. The essential aromatic amino acids are degraded in the liver, whereas the branched-chain amino acids are passed to the periphery, where they are metabolised exclusively by skeletal muscle. Non-essential amino acids may be metabolised hepatically or in skeletal muscle. 

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. 

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. 

Degradation of all three branched-chain amino acids begins with a transamination followed by an oxidative decarboxylation catalyzed by the branched-chain a-keto acid dehydrogenase complex. This enzyme, like a-ketoglutarate dehydrogenase, requires thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD+ (Figure 7-11). 

In maple syrup urine disease, the enzyme complex that decarboxy-lates the transamination products of the branched-chain amino acids is defective (see Figure 7-11). Valine, isoleucine, and leucine accumulate. Urine has the odor of maple syrup. Mental retardation occurs. 

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... 

C. In maple syrup urine disease, the branched-chain amino acids (valine, leucine, and isoleucine) can be transaminated but not oxidatively decarboxylated because the a-keto acid dehydrogenase is defective. 

D. The branched-chain amino acids (valine, isoleucine, and leucine) are transaminated and then oxidatively decarboxylated by an enzyme that requires thiamine, lipoic add, coenzyme A, FAD, and NAD. 

In a similar way, other a-keto acids, e.g., a-ketoglutarate (in the TCA cycle see below) and branched-chain cc-keto acids derived by transamination from the branched-chain amino acids valine, leucine, and isoleucine (Chapter 17), undergo decarboxylation and dehydrogenation catalyzed by enzyme complexes. These enzyme complexes differ in specificity of Ei and E2, but all contain the same E3 (the dihydrolipoyl dehydrogenase). 

The branched-chain amino acids are degraded by reactions that we have already encountered in the citric acid cycle and fatty acid oxidation. Leucine is transaminated to the corresponding a-ketoacid, a-ketoisocaproate. This a-ketoacid is oxidatively decarhoxylated to isovaleryl CoA by the branched-chain a-ketoacid dehydrogenase complex. 

Leucine. Leucine, one of the branched chain amino acids, is converted to HMG-CoA in a series of reactions that include a transamination, two oxidations, a carboxylation, and a hydration. HMG-CoA is then converted to acetyl-CoA and acetoacetate by HMG-CoA lyase. 

In laboratory-scale experiments, solutions containing 200-600 mM keto acid were transaminated to the corresponding branched-chain L-amino acid, with a concentration of L-glutamate between 50 mM and 100 mM and a 1.1 molar excess of l-aspartate. Yields obtained for the branched-chain amino acids have typically been in the range of 80-90 % based on starting with a 2-keto acid [10l... 

There are three branched-chain amino acids leucine, isoleucine, and valine. These are all essential for higher animals, including humans, since they cannot be formed de novo. They can transaminate and, therefore, both the D- (after the action of D-amino acid oxidase) and keto amino acid derivatives can be utilized to form the L-amino... 

This would cause a deficiency of branched-chain amino acids. This deficiency is avoided by having transamination occur in the muscle, where the oxidative decarboxylation is less active. 

Isoleucine is a good example of branched-chain amino acids for a semi-in-depth examination. Unique aspects of the metabolism of valine and leucine are highlighted. After transamination and oxidative decarboxylation to form the branched-chain fatty-acyl CoA, a double bond is formed between a and b carbons utilizing FAD then water is added to form a b hydroxy derivative (Fig. 18.4). Then a NAD+-dependent dehydrogenase produces a keto derivative of the branched-chain fatty-acyl CoA. The similarity to straight-chain fatty-acid oxidation should be noted. This keto fragment is cleaved with participation of coenzyme A to form acetyl CoA, which ei-... 

In this disease, the a-keto derivatives for all three branched-chain amino acids are found in the urine. The transamination of the amino acids is normal, but the enzyme related to the oxidation of the a-keto acid derivatives (branched-chain a-keto acid dehydrogenase) is genetically defective or missing. Thus, there is an accumulation of the branched-chain amino acids and keto... 

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