Biochemistry - The Chemical Reactions of Living Cells, Volume 3 - D. Metzler 1980

Metabolism of Nitrogenous Compounds
Alanine and Branched-Chain Amino Acids
Catabolism

The breakdown of Amino Acids most frequently begins with Transamination into the corresponding a-keto acid, which subsequently undergoes oxidative decarboxylation (reaction sequence 7B, Fig. 8-19). This is precisely how Alanine, valine, leucine, and isoleucine are metabolized in the animal body. Alanine directly yields Pyruvate and acetyl-CoA, whereas Other Amino Acids yield acyl-CoA derivatives whose degradation proceeds via the ß-Oxidation pathway (Fig. 14-11). In this process, certain deviations from the standard sequence of ß-oxidation stages characteristic of Fatty acids are observed (Fig. 9-1); for example, in the case of valine, this reaction sequence is adhered to only up to the stage of Water addition resulting in The formation of a ß-hydroxy derivative. The latter is converted into free 3-hydroxyisobutyrate, the further oxidation of which to methylmalonate semialdehyde completes the ß-oxidation process. Methylmalonate semialdehyde is decarboxylated and converted into propionate [66], which subsequently passes into propionyl-CoA, which in turn is carboxylated to form S-methylmalonyl-CoA. The further metabolic pathway is illustrated in Fig. 9-6.

During the breakdown of isoleucine, ß-oxidation proceeds to completion in the conventional manner, yielding acetyl-CoA and propionyl-CoA. However, in the course of leucine catabolism, following the dehydrogenation that initiates ß-oxidation, Carbon dioxide is added through the action of a biotinyl enzyme (Chap. 8, Sec. B). The double bond conjugated with the thioester carbonyl renders this carboxylation similar to the standard ß-carboxylation reaction. Why is this extra CO₂ necessary? The methyl group in the ß-position blocks complete ß-oxidation, yet an aldol Cleavage remains possible, leading to the Formation of Acetyl-CoA and acetone. Subsequent METABOLISM of acetone presents certain difficulties. When CO₂ is added, the product is acetoacetate, the catabolism of which is readily driven to completion via its conversion into acetyl-CoA.

Supplement 14-B

Maple Syrup Urine Disease and Jamaican Vomiting Sickness

Over 50 cases of a rare autosomal recessive disorder (discovered in 1954) have been described, in which the patient's urine and exhaled breath carry the odor of maple syrup^a. High concentrations of branched-chain a-keto acids, formed via the transamination of valine, leucine, and isoleucine, are detected in the urine. This characteristic odor is caused by the breakdown products of these acids. The biochemical defect lies in the enzyme that catalyzes The oxidative decarboxylation of keto acids, as indicated in Fig. 14-11.

Maple syrup urine disease (affecting approximately one in 200,000 individuals) results in death in early infancy if left untreated. Patients can survive if placed on a low-protein diet (gelatin diet) supplemented with Essential Amino Acids. However, Treatment is challenging, and sudden relapses can prove fatal.

Interestingly, a similar biochemical defect has been observed in a mutant strain of Bacillus subtilis^b. The Cell walls of these Bacteria must contain Branched-Chain Fatty Acids (Chap. 5, Sec. A, 4), and CoA derivatives of branched-chain fatty acids serve as starting Materials for their synthesis (Chap. 12, Sec. D). If the Oxidative Decarboxylation of the required keto acids is blocked, these mutants can grow only in a medium supplemented with branched-chain fatty acids.

A rare disorder of leucine catabolism is isovaleric acidemia, which is the inability to oxidize isovaleryl-CoA. The symptoms of this disease are observed in Jamaican vomiting sickness, a condition caused by poisoning from unripe ackee fruit. These fruits contain toxic hypoglycin A, which has the following Structure^c,d:

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This compound acts as a specific inhibitor of isovaleryl-CoA dehydrogenase, causing an accumulation of isovaleric acid in the Blood. It has been suggested that the presence of isovaleric acid in the blood exerts a depressing effect on the Central Nervous system, thereby accounting for certain symptoms. Nevertheless, it is generally accepted that in particularly severe cases of this vomiting sickness, death results from developing hypoglycemia. Blood glucose levels can drop to 0.5 mM, which is one-tenth of the normal concentration.

^a Dancis J., Levits M., in: The Metabolic Basis of Inherited Disease (J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, eds.), 3rd ed., pp. 426–439, McGraw-Hill, New York, 1972.

^b Willecke K., Pardee A. B., JBC, 246, 5264–5272 (1971).

^c Tanaka K., Isselbacher K. J., Shin V., Science, 175, 69–71 (1972).

^d Tanaka K., JBC, 247, 7465–7478 (1972).