Four Amino Acids Are Converted into Succinyl-CoA

The carbon skeletons of methionine, isoleucine, threonine, and valine are degraded by pathways that yield succinyl-CoA (Fig. 17-30), an intermediate of the citric acid cycle. Methionine donates its methyl group to one of several possible acceptors through S-adenosylmethionine, and three of the four remaining atoms of its carbon skeleton are converted into those of propionate as propionyl-CoA.

Isoleucine undergoes transamination, followed by oxidative decarboxylation of the resulting α-keto acid. The remaining five-carbon skeleton derived from isoleucine undergoes further oxidation, yielding acetyl-CoA and propionyl-CoA. In human tissues, threonine is also converted to propionyl-CoA. Propionyl-CoA derived from these three amino acids is converted to succinyl-CoA by the pathway described in Chapter 16 for propionate derived from the oxidation of fatty acids of uneven chain length: carboxylation to methylmalonyl-CoA, epimerization of the methylmalonyl-CoA, and finally its conversion to succinylCoA by the coenzyme B₁₂-dependent enzyme methylmalonyl-CoA mutase (see Fig. 16-12). A rare genetic defect that results in the absence of methylmalonyl-CoA mutase causes a serious genetic disease called methylmalonic acidemia (Table 17-2, Box 17-2).
The oxidation of valine follows a path similar to those for the other three amino acids in this group (Fig. 17-30). After transamination and decarboxylation of valine, a series of oxidation reactions converts the remaining four carbons into methylmalonyl-CoA, which is transformed into succinyl-CoA. Some parts of the valine and isoleucine degradative pathways closely parallel steps in fatty acid degradation (Chapter 16).

Branched-Chain Amino Acids Are Not Degraded in the Liver

Although much of the catabolism of amino acids occurs in liver, the three amino acids with branched side chains (leucine, isoleucine, and valine) are oxidized as fuels primarily in muscle, adipose, kidney, and brain tissue. These extrahepatic tissues contain a single aminotransferase not present in liver that acts on all three branched-chain amino acids to produce the corresponding α-keto acids
There is a relatively rare human genetic disease in which these three α-keto acids accumulate in the blood and "spill over" into the urine. This condition, which unless treated results in abnormal development of the brain, mental retardation, and death in early infancy, is called maple syrup urine disease because of the characteristic odor imparted to the urine by the α-keto acids. It is treated by rigid control over the diet to limit intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. All three α-keto acids derived from the branched-chain amino acids are acted on by a single enzyme, which is defective in patients with maple syrup urine disease. This explains why all three α-keto acids accumulate along with the corresponding amino acids (especially leucine) in affected individuals. This enzyme, the branched-chain a-keto acid dehydrogenase complex, catalyzes oxidative decarboxylation of each of the three a-keto acids, releasing the carboxyl group as CO₂ and producing the acyl-CoA derivative (Fig. 17-31).
This decarboxylation reaction is formally analogous to two others encountered in Chapter 15: the oxidation of pyruvate to acetyl-CoA by the pyruvate dehydrogenase complex (p. 450) and the oxidation of α-ketoglutarate to succinyl-CoA in the citric acid cycle by the α-ketoglutarate dehydrogenase complex (p. 455). In fact, all three enzymes are closely homologous in structure, and the reaction mechanism is essentially the same for all. Five cofactors (thiamine pyrophosphate, FAD, NAD, lipoate, and coenzyme A) participate, and the three proteins in each of the complexes catalyze homologous reactions. This is clearly a case in which enzymatic machinery that evolved to catalyze one reaction was "borrowed" by gene duplication and further evolved to catalyze similar reactions in other pathways.
The branched-chain α-keto acid dehydrogenase complex of the rat is regulated by covalent modification in response to the content of branched-chain amino acids in the diet. When there is little or no excess dietary intake of branched-chain amino acids, the enzyme complex is phosphorylated and thereby inactivated by a protein kinase. Addition of excess branched-chain amino acids to the diet results in dephosphorylation and consequent activation of the enzyme. Recall that the pyruvate dehydrogenase complex is subject to similar regulation by phosphorylation and dephosphorylation (p. 468).

Asparagine and Aspartate Are Degraded to Oxaloacetate

The carbon skeletons of asparagine and aspartate ultimately enter the citric acid cycle via oxaloacetate. The enzyme asparaginase catalyzes the hydrolysis of asparagine to yield aspartate, which undergoes a transamination reaction with α-ketoglutarate to yield glutamate and oxaloacetate (Fig. 17-32). The latter enters the citric acid cycle. We have now seen how the 20 different amino acids, after loss of their nitrogen atoms, are degraded by dehydrogenation, decarboxylation, and other reactions to yield portions of their carbon backbones in the form of five central metabolites that can enter the citric acid cycle. Here they are completely oxidized to carbon dioxide and water. During electron transfer, ATP is generated by oxidative phosphorylation, and in this way amino acids contribute to the total energy supply of the organism. Some Amino Acids Can Be Converted to Glucose, Others to Ketone Bodies Some carbon atoms from six of the amino acids (those that are degraded to acetoacetyl-CoA and/or acetyl-CoA: tryptophan, phenylalanine, tyrosine, isoleucine, leucine, and lysine) can yield ketone bodies in the liver, by conversion of acetoacetyl-CoA into acetone and β-hydroxybutyrate (see Fig. 16-16). These amino acids are ketogenic (Fig. 17-33). Their ability to form ketone bodies is particularly evident in untreated diabetes mellitus, in which large amounts of ketone bodies are produced by the liver, not only from fatty acids but from the ketogenic amino acids. Degradation of leucine, an exclusively ketogenic amino acid that is very common in proteins, makes a substantial contribution to ketosis during starvation. The amino acids that can be converted into pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate can be converted into glucose and glycogen by pathways described in Chapter 19. They are called glucogenic amino acids. The division between ketogenic and glucogenic amino acids is not sharp; four amino acids (tryptophan, phenylalanine, tyrosine, and isoleucine) are both ketogenic and glucogenic. Some of the amino acids that can be converted into pyruvate, particularly alanine, cysteine, and serine, can also potentially form acetoacetate via acetyl-CoA, especially in severe starvation and untreated diabetes mellitus