its tissue specificity have been studied intensively in rats. 2 The activities of key enzymes in the valine cata-
The first step in BCAA catabolism, which takes place largely bolic pathway -branched-chain aminotransferase, in extrahepatic tissues, is reversible transamination of the branched-chain a-keto acid dehydrogenase complex, BCAAs to produce the branched-chain a-keto acids catalyzed methacrylyl (MC)-coenzyme A (CoA) hydratase (croby the branched-chain aminotransferase (BCAT). The second tonase), and 3-hydroxyisobutyryl-CoA (HIB-CoA) hystep, which occurs largely in the liver, is irreversible oxidadrolase -were measured in normal and cirrhotic hutive decarboxylation of the a-keto acids to produce their coenman livers. Unlike rat liver, which does not contain zyme A (CoA) esters catalyzed by the branched-chain a-keto branched-chain aminotransferase, the aminotransacid dehydrogenase (BCKDH) complex (Fig. 1). The latter is ferase activity in the normal liver was measurable the committed step in the BCAA catabolism. After dehydrogeand is increased somewhat in cirrhosis of the human nation of CoA esters, each compound is metabolized individuliver. The total activity of branched-chain a-keto acid ally by a separate pathway. dehydrogenase complex in the normal human liver Among these pathways, valine catabolism is unique bewas Γ1% of that in rat liver, and 20% to 30% of the cause methacrylyl-CoA (MC-CoA), a potentially toxic comcomplex was in the active form in both normal and pound, is formed in the middle part of the pathway and is cirrhotic livers. Only the actual activity of the endetoxified in two steps by MC-CoA hydratase (crotonase) and zyme was significantly decreased by cirrhosis. These 3-hydroxyisobutyryl-CoA (HIB-CoA) hydrolase (Fig. 1). 3
MCresults suggest that human liver is less active than
CoA is a toxic compound because of its strong tendency to rat liver in the catabolism of branched-chain amino react with free thiol groups of proteins and glutathione. 4,5 and a-keto acids. Activities of MC-CoA hydratase and That it is toxic in vivo is supported by clinical findings in HIB-CoA hydrolase in human liver were very high an infant with an almost complete deficiency in HIB-CoA compared with that of branched-chain a-keto acid hydrolase. 5 This child had multiple congenital physical maldehydrogenase complex, suggesting an important formations, excreted large quantities of cysteine/cysteamine role for these enzymes in catabolism of a potentially conjugates of methacrylate, and died of a cardiac lesion at 3 toxic compound, MC-CoA, formed as an intermediate months.
in the catabolism of valine and isobutyrate. Cirrhosis
Formation of a monocarboxylic acid, ((S)-3-hydroxyisoburesulted in a significant decrease in HIB-CoA hytyric acid), which readily diffuses out of cells after being drolase activity but had no effect on the citrate formed by HIB-CoA hydrolase, is suggested to be physiologisynthase activity, suggesting that the decrease in cally important for protection of cells against the toxic effects HIB-CoA hydrolase activity does not reflect a general of MC-CoA. 3,5 Thus, hydrolysis of HIB-CoA may be an imdecrease in mitochondria but that it may contribute portant strategy for disposal of MC-CoA by cells. 3 In support to cellular damage that culminates in liver failure.
of this idea, the activities of MC-CoA hydratase and HIB-(HEPATOLOGY 1996; 24:1395-1398.)
CoA hydrolase are much greater than those of other enzymes of the valine pathway in both the rat 3 and the dog. 6 Branched-chain amino acids (BCAAs: valine, leucine, and Abnormal regulation of the amino acid metabolism occurs isoleucine) are indispensable amino acids for animals and in various pathological conditions such as cirrhosis and liver comprise approximately 35% of the indispensable amino failure. 7 BCAAs often are used to treat patients with hepatic acids in muscle proteins and 40% of the amino acids required encephalopathy, 7 but the basis for striking changes in plasma preformed by mammals. 1 The BCAA catabolic pathway and and tissue levels of BCAAs that occur under various pathological conditions are poorly understood. A proposed model for BCAA catabolism is based on data obtained in rats, but it is not clear whether the model is applicable to humans. 1 In Abbreviations: BCAA, branched-chain amino acid; BCAT, branched-chain aminotransferase; CoA, coenzyme A; BCKDH, branched-chain a-keto acid dehydrogenase; MC-CoA, addition, it is interesting from the viewpoint of physiological methacryryl-CoA; HIB-CoA, 3-hydroxyisobutyryl-CoA.