BRANCHED CHAIN AMINO ACID METABOLISM

支链氨基酸(BCAA)，亮氨酸、异亮氨酸和缬氨酸被归类为必需氨基酸，因为我们不能合成它们的碳骨架，所以它们必须从饮食来源获得。对于必需氨基酸来说，严格控制它们的分解是必要的，以确保它们持续可用于蛋白质合成。从已知的支链氨基酸代谢紊乱患者的有害影响中可以清楚地看出，它们除了用作蛋白质构建块外，还有重要的作用。我们的假设是，这些其他功能对人类健康同样重要。分子(BCATm基因的调控)、结构(晶体结构)和免疫组织化学技术将被用来了解催化支链氨基酸分解途径的第一步--支链氨基转移酶同工酶(BCAT)--的精确生理功能。“代谢”线粒体同工酶，BCATm，是参与体内氮代谢的BCAT，而大脑的精确生理功能则是“专门化”胞浆同工酶(BCAT)。大脑“专门化”胞浆同工酶BCATC的“代谢”精确生理功能尚不清楚。最近的数据表明，阐明这些蛋白质的确切作用需要详细了解BCATm和BCATC在大脑和外周组织中的定位。免疫组织化学方法将被用来提供这些信息。为了了解BCATm基因在哺乳期大鼠的诱导表达以及BCATm在组织中的细胞特异性定位，需要确定代谢BCATm基因的结构和调控。最后，这些同工酶功能差异的分子基础，包括为什么神经活性药物和亮氨酸类似物加巴喷丁是BCATC的特异性抑制剂，而不是BCATm，将通过测定BCAT蛋白的三维结构来阐明。

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.