Branch-chained amino acids oxidation

Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids 671... 

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). 

Insufficient thiamine significantly impairs glucose oxidation, causing highly aerobic tissues, such as brain and cardiac muscle, to fail first. In addition, branched-chain amino acids are sources of energy in brain and muscle. 

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... 

Figure 32-3. Schematic representation of fuel mobilization during fasting. Catabolism of muscle proteins provides alanine for gluconeogenesis and glutamine for utilization by the gut and kidney, while branched chain amino acids are primarily oxidized within the muscle. Breakdown of adipocyte triacylglycerols provides glycerol and free fatty acids (not shown) the free fatty acids provide fuel for liver, muscle and most other peripheral tissues. The liver utilizes both alanine and glycerol to synthesize glucose which is required for the brain and for red blood cells (not shown). Adapted from Besser and Thirner (2002).

Reviews by Ruderman (19) and Adibi (20,21) indicate that the branched-chain amino acids, particularly leucine, have an important role along with alanine in gluconeogenesis. Leucine and the other two branched-chain amino acids are catabolized in skeletal muscle. The nitrogen that is removed from the branched-chain amino acids in skeletal muscle is combined with pyruvate and returned to the liver as alanine. In the liver the nitrogen is removed for urea production and the carbon chain is utilized as substrate for synthesis of glucose. Adibi et al. (22) reported that during the catabolic conditions of starvation, oxidation of leucine and fatty acids increases in skeletal muscles. While glucose oxidation is reduced, the capacity for oxidation of the fatty acid palmltate more than doubled, and leucine oxidation increased by a factor of six. 

Aerobic exercise usually increases the percentage of muscle mass due to a decrease in body fat, but produces no absolute change in the amount of muscle. Aerobic exercise has been shown to alter protein metabolism including increases in amino acid oxidation with specific effects on the branched-chain amino acid leucine, increased urinary urea, and increased sweat nitrogen. 

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. 

Although alcaptonuria is a relatively harmless condition, such is not the case with other errors in amino acid metabolism. In maple syrup urine disease, the oxidative decarboxylation of a-ketoacids derived from valine, isoleucine, and leucine is blocked because the branched-chain dehydrogenase is missing or defective. Hence, the levels of these a-ketoacids and the branched-chain amino acids that give rise to them are markedly elevated in both blood and urine. Indeed, the urine of patients has the odor of maple syrup—hence the name of the disease (also called branched-chain ketoaciduria). Maple syrup urine disease usually leads to mental and physical retardation unless the patient is placed on a diet low in valine. 

Branched Chain Amino Acids valine (val), leucine (leu), and isoleucine (ilu). The metabolism of each of these three amino acids begins with the same theme transaminase DH Complex foeta-oxidation. Due to the irreversible nature of the DH Complex all three are essential. 

Net breakdown of muscle can occur with either exercise or prolonged fasting. The mechanisms that control the breakdown of the various types of protein found in muscle are not well understood. It has, however, been established that while the branched-chain amino acids (BCAAs) released tend to be oxidized for energy in the muscle cell, other released amino acids enter the bloodstream for catabolism, and perhaps gluconeogenesis, in the liver Examination of the amino acids released from skeletal muscle reveals an apparent anomaly alanine accounts for or ly about 6% of the amino acids of muscle, but for about 35% of the amino acids released from muscle during exerdse. 

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). 

The branched-chain amino acids are oxidized by muscle to produce energy. Some of the carbons are converted to glutamine and alanine. 

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. 

Thiamine pyrophosphate has two important coenzyme roles, both of which focus mostly on carbohydrate metabolism (Figs. 8.26 and 8.27). The active portion of the coen- rae is the thiazole ring. The first step in the oxidative decarboxylation of a-keto acids requires TPP. The two most common examples are pyruvate and a-ketoglutarate, oxidatively decarboxyatedto acetyl CoA and succinyl CoA, respectively. The same reaction is found in the metabolism of the branched-chain amino acids valine, isoleucine, leucine, and methionine. In all cases, TPP is a coenzyme in a mitochondrial multienzyme complex, consisting of TPP, lipoic acid, coenzyme A, FAD, and NAD. Note the number of vitamins required for the oxidative decarboxylation of a-keto acids thiamine (TPP), pantothenic acid (coenzyme A), riboflavin (FAD),and niacin (NAD). 

This mitochondrial reaction permits the final steps in the catabolism of the branched-chain amino acid leucine. The final products, acetoacetate and acetyl CoA, either are oxidative metabolized to carbon dioxide and water or enter other reactions in lipid metabolism. 

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). 

The a,-dehydrogenation is catalyzed by an FAD protein and is analogous to the dehydrogenation of straight-chain acyl-CoA thioesters in jd-oxidation of fatty acids (Chapter 18). Methylenecyclopropylacetyl-CoA derived from the plant toxin hypoglycin (Chapters 15 and 18), which inhibits this step in )S-oxidation, also inhibits it in the catabolism of branched-chain amino acids. 

---