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，严格控制其分解是必要的，以确保其持续用于蛋白质合成。从已知BCAA代谢紊乱患者记录的有害作用中可以清楚地看出，它们除了作为蛋白质构建块之外还具有重要作用。我们的假设是，这些其他功能对人类健康同样重要。分子（BCATm基因的调节）、结构（晶体结构）和免疫组织化学技术将用于了解催化支链氨基酸分解途径第一步的酶的精确生理功能，即支链氨基转移酶同工酶（BCAT）。“代谢”线粒体同工酶，BCATm，是BCAT参与体内氮代谢，而大脑的精确生理功能的“专业化”胞质同工酶（BCAT）。脑“特化”胞质同工酶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在脑内和外周组织中的定位。将使用免疫组织化学方法提供该信息。将确定代谢BCATm基因的结构和调控，以了解泌乳大鼠中BCATm基因表达的诱导以及BCATm在组织中的细胞特异性定位。最后，这些同工酶的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，是一个特定的抑制剂BCATc，但不是BCATm，将阐明通过确定的三维结构的BCAT蛋白。

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.