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Branched-Chain Amino Acids: Metabolism, Physiological Function, and Application: Session II

Branched-Chain Amino Acid Catabolism in Exercise and Liver Disease^1–3,

Yoshiharu Shimomura⁴, Takashi Honda⁵, Makoto Shiraki⁶, Taro Murakami⁷, Juichi Sato^*, Hisamine Kobayashi, Kazunori Mawatari, Mariko Obayashi^** and Robert A. Harris^**

Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan; ^* Department of General Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan, Ajinomoto Co., Tokyo 104-8315, Japan; and ^** Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122

⁴ To whom correspondence should be addressed. E-mail: shimomura.yoshiharu{at}nitech.ac.jp.

ABSTRACT

Branched-chain -keto acid dehydrogenase (BCKDH) complex, the enzyme catalyst for the second step of the BCAA catabolic pathway, plays a central role in the regulation of BCAA catabolism. The activity of the complex is regulated by a covalent modification cycle in which phosphorylation by BCKDH kinase inactivates and dephosphorylation by BCKDH phosphatase activates the complex. Many studies suggest that control of the activity of the kinase is a primary determinant of the activity of the complex. The kinase exists at all times in the mitochondrial matrix space in two forms, with a large amount being free and a smaller amount bound rather tightly to the BCKDH complex. Only the bound form of the kinase appears to be catalytically active and, therefore, responsible for phosphorylation and inactivation of the complex. -Ketoisocaproate, the transamination product of leucine and the most important known physiological inhibitor of BCKDH kinase, promotes release of the kinase from the complex. -Chloroisocaproate, the analogue of leucine and the most potent known inhibitor of the kinase, is more effective than -ketoisocaproate in promoting release of BCKDH kinase from the complex. Exercise and chronic liver disease (liver cirrhosis) likewise decrease the amount of the kinase bound to the complex in rat liver. The resulting activation of the BCKDH complex appears responsible for the increase in BCAA catabolism caused by exercise and liver cirrhosis. Our findings support the use of BCAA supplements for patients with liver cirrhosis.

KEY WORDS: • branched-chain amino acids • BCKDH complex • BCKDH kinase • leucine, -ketoisocaproate • -chloroisocaproate • exercise • liver cirrhosis • TNF

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