Pathways of Amino Acid Degradation:- Branched-Chain Amino Acids Are Not Degraded in the Liver
Although much of the catabolism of amino acids takes place in the 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 an amino transferase, absent in liver, that acts on all three branched-chain amino acids to produce the correspon ding α-keto acids (Fig. 18–28). The branched-chain-keto acid dehydrogenase complexthen catalyzes oxidative decarboxylation of all three α-keto acids, in each case releasing the carboxyl group as CO2 and producing the acyl-CoA derivative. This reaction is formally analogous to two other oxidative decarboxylations encountered in Chapter 16: oxidation of pyruvate to acetyl-CoA by the pyruvate dehydrogenase complex and oxidation of -ketoglutarate to succinyl-CoA by the α-ketoglutarate dehydrogenase complex. In fact, all three enzyme complexes are similar in structure and share essentially the same reaction mechanism. Five cofactors (thiamine pyro phosphate, FAD, NAD, lipoate, and coenzyme A) participate, and the three proteins in each complex catalyze homologous reactions. This is clearly a case in which enzymatic machinery that evolved to catalyze
FIGURE 18–28 Catabolic pathways for the three branched-chain amino acids: valine, isoleucine, and leucine. The three pathways, which occur in extrahepatic tissues, share the first two enzymes, as shown here. The branched-chain -keto acid dehydrogenase complex is analogous to the pyruvate and -ketoglutarate dehydrogenase complexes and requires the same five cofactors (some not shown here). This enzyme is defective in people with maple syrup urine disease.
One reaction was “borrowed” by gene duplication and further evolved to catalyze similar reactions in other pathways. Experiments with rats have shown that the branched-chain -keto acid dehydrogenase complex is regulated by covalent modification in response to the content of branched-chain amino acids in the diet. With 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 en zyme. Recall that the pyruvate dehydrogenase complex is subject to similar regulation by phosphorylation and dephosphorylation (p. 621). There is a relatively rare genetic disease in which the three branched-chain -keto acids (as well as their precursor amino acids, especially leucine) ac cumulate in the blood and “spill over” into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the -keto acids, results from a defective branched chain -keto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth.
