BRANCH CHAIN AMINO ACIDS AND REGULATION OF BODY PROTEIN TURNOVER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的总体目标是更深入地了解人体体内氮代谢，特别关注必需氨基酸代谢与尿素合成之间的相互作用以及影响尿素循环的疾病，以及支链氨基酸代谢在枫糖浆尿病（MSUD）中的作用。具有影响尿素合成的遗传缺陷的患者可能在利用谷氨酰胺作为尿素氮源方面表现出部分障碍1。我们和其他人也表明，对这类患者的一种常见治疗方法（即，摄入苯基丁酸盐或苯乙酸盐，通常与苯甲酸酯结合）将氮从尿素合成转移到其他排泄途径（从而达到其治疗目的）。我们的研究表明，这种疗法对支链氨基酸代谢（BCAA）有实质性的影响。这导致BCAA浓度显著下降，尽管总蛋白质摄入量足够。这些药物作用的一个预测结果是抑制体内蛋白质的合成。丁苯对支链氨基酸代谢的影响也可能影响枫糖浆尿病（MSUD）的治疗。MSUD是一种影响三支链氨基酸（BCAA）亮氨酸、异亮氨酸和缬氨酸代谢的遗传性代谢性疾病。由于酶复合物支链酮酸脱氢酶（BCKD）的缺陷，MSUD患者支链氨基酸和支链酮酸升高。正是这些升高导致MSUD患者出现症状。我们过去的工作表明，苯基丁酸降低对照受试者和尿素循环障碍患者的BCAA和支链酮酸。如果在MSUD患者中也发现这种作用，则可能具有临床相关性，因为在这些患者中，苯基丁酸可用于治疗以降低BCAA水平及其副产物。因此，我们建议在正常受试者、患有尿素合成部分和/或严重缺陷的患者、MSUD患者以及导致尿素合成继发性缺陷的疾病中进行实验，以验证这些假设。这些发现将直接影响我们对这些疾病和其他疾病的营养管理，其中限制蛋白质摄入是主要的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to achieve a deeper understanding of in vivo nitrogen metabolism in human, with specific foci on interactions between essential amino acid metabolism and urea synthesis and on diseases affecting the urea cycle, and branched chain amino acid metabolism in Maple Syrup Urine Disease (MSUD). Patients with genetic defects affecting urea synthesis may exhibit a partial block in their ability to utilize glutamine as a urea nitrogen source1. We and others have also shown that a common therapy for such patients, (i.e., the ingestion of either phenylbutyrate or phenylacetate, often in combination with benzoate) diverts nitrogen from the urea synthesis to alternative routes of excretion (and hence achieves its therapeutic objective). Our studies suggest that this therapy has a substantial impact on branched chain amino acid metabolism (BCAA). This leads to a marked fall in BCAA concentrations in spite of adequate levels of total protein intake. One predicted outcome of the effect of these drugs is to inhibit body protein synthesis. The effect of buphenyl on branched chain amino acid metabolism may also affect the treatment of Maple Syrup Urine Disease (MSUD). MSUD is an inherited metabolic disorder which affects the metabolism of the three branched chain amino acids (BCAA) leucine, isoleucine and valine. MSUD patients have elevated branched chain amino acids and the branched chain keto acids due to a defect in the enzyme complex branched chain keto acid dehydrogenase (BCKD). It is these elevations that cause a patient with MSUD to be symptomatic. Our past work indicates that phenylbutyrate decreases BCAA and branched chain keto acids in control subjects and patients with urea cycle disorders. If this effect is also found in patients with MSUD, it may be clinically relevant as phenylbutyrate may be given therapeutically to decrease BCAA levels and their byproducts in these patients. Accordingly, we propose experiments in normal subjects and in patients suffering from partial and/or severe defects in urea synthesis, MSUD patients, as well as disorders leading to secondary defects in urea synthesis, to test these hypotheses. These findings should directly impact on our nutritional management of these and other disorders in which restriction of protein intake is a mainstay of therapy.