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.
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