The branched chain amino acids (BCAA), leucine, isoleucine and valine, are classified as essential amino acids, because we cannot synthesize their carbon skeleton so they must be acquired from dietary sources. For essential amino acids tight control of their breakdown is necessary to assure their continuous availability for protein synthesis. As is clear from the deleterious effects documented in patients with known disorders of BCAA metabolism, they have essential roles in addition to their use as protein building blocks. It is our hypothesis that these other functions are equally important for human health. Molecular (regulation of the BCATm gene), structural (crystal structure) and immunohistochemical techniques will be used to understand the precise physiological function of he enzymes catalyzing the first step in the pathway of BCAA breakdown, the branched chain aminotransferase isoenzymes (BCAT). The """"""""metabolic"""""""" mitochondrial isoenzyme, BCATm, is the BCAT involved in body nitrogen metabolism while the precise physiological function of the brain """"""""specialized"""""""" cytosolic isoenzymes (BCAT). The """"""""metabolic"""""""" precise physiological function of the brain """"""""specialized"""""""" cytosolic isoenzyme, BCATc, is not yet understood. Recent data has made it apparent that elucidating the exact role of these protein requires a detailed knowledge of the localization of BCATm and BCATc within brain and in peripheral tissues. Immunohistochemical methods will be used to provide this information. Structure and regulation of the gene for the metabolic BCATm will be determined in order to understand the induction of BCATm gene expression in the lactating rat and cell specific localization of BCATm in tissues. Finally, the molecular basis for the functional differences in these isoenzymes, including why the neuroactive drug and leucine analog, gabapentin, is a specific inhibitor of BCATc but not BCATm, will be elucidate by determining the three dimensional structure of the BCAT proteins.
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