Regulation of Branched-Chain Amino Acid Catabolism Robert A. Harris (Indiana University School of Medicine, Indianapolis) The branched chain amino acids (BCAAs) are essential amino acids and therefore must be continuously supplied in the diet for protein synthesis. Leucine is special among these amino acids because it promotes protein accretion by signaling an increase in protein translation, promoting insulin release, and inhibiting protein degradation. However, leucine promotes its own disposal as well as the other BCAAs by the catabolic pathway for BCAA oxidation, thereby limiting its positive effects on body protein accretion. A strong case can therefore be made that keeping the proper leucine concentration in the various organs of the body is critically important for maintaining body protein levels beyond the simply need of this essential amino acid for protein synthesis. Catabolism of leucine and the other BCAAs is regulated primarily at the level of the branched-chain b-keto acid dehydrogenase complex (BCKDC). BCKDC is controlled by covalent modification of its E1b subunits by a specific kinase (BDK) causing inactivation and dephosphorylation by a specific phosphatase (BDP) causing activation. The importance of regulation of BCKDC to growth and maintenance of body protein has become our primary interest. We hypothesize that proper regulation of the activity state of BCKDC by its kinase and phosphatase is critically important for body growth, tissue repair, and maintenance of body protein. Indeed, knocking out BDK creates mice that grow poorly, have rough hair coats, and suffer spontaneous seizures. We conclude that stringent regulation of BCKDC by its kinase is required for body protein accretion and normal neurological activity.