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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1527S-1530S, June 2005

4th Amino Acid Assessment Workshop

Overview of the Molecular and Biochemical Basis of Branched-Chain Amino Acid Catabolism1,2

Robert A. Harris3, Mandar Joshi, Nam Ho Jeoung and Mariko Obayashi

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202

3To whom correspondence should be addressed. E-mail: raharris{at}iupui.edu.

The branched-chain amino acids (BCAAs) are required for protein synthesis and neurotransmitter synthesis. The branched-chain {alpha}-ketoacid dehydrogenase complex (BCKDC) is the most important regulatory enzyme in the catabolic pathways of the BCAAs. Activity of the complex is controlled by covalent modification with phosphorylation of its branched-chain {alpha}-ketoacid dehydrogenase subunits by a specific kinase [branched-chain kinase (BDK)] causing inactivation and dephosphorylation by a specific phosphatase [branched-chain phosphatase (BDP)] causing activation. Tight control of BCKDC activity is important for conserving as well as disposing of BCAAs. Phosphorylation of the complex occurs when there is a need to conserve BCAAs for protein synthesis; dephosphorylation occurs when BCAAs are present in excess. The relative activities of BDK and BDP set the activity state of BCKDC. BDK activity is regulated by {alpha}-ketoisocaproate inhibition and altered level of expression. Less is known about BDP but a novel mitochondrial phosphatase was identified recently that may contribute to the regulation of BCKDC. Reduced capacity to oxidize BCAAs, as in maple syrup urine disease, results in excess BCAAs in the blood and profound neurological dysfunction and brain damage. In contrast, loss of control of BCAA oxidation results in growth impairment and epileptic-like seizures. These findings emphasize the importance of control of BCAA catabolism for normal neurological function. It is proposed that the safe upper limit of dietary BCAA intake could be established with a BCAA tolerance test and clamp protocol.

KEY WORDS: • leucine • branched-chain amino acids • branched-chain keto acids • branched-chain {alpha}-ketoacid dehydrogenase • branched-chain {alpha}-ketoacid dehydrogenase kinase




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