MODELING OF BRANCHED CHAIN AMINO ACID METABOLISM

支链氨基酸在肌动蛋白的调节中发挥作用 蛋白质周转、碳水化合物和肌肉能量 新陈代谢。生理和病理条件，如 食物剥夺糖尿病、创伤和氯贝特治疗 增加肌肉中支链氨基酸的氧化。 这些观察结果的潜在重要性通过以下几点得到了强调 临床结果显示支链氨基酸输注 在遭受创伤或烧伤的患者中显著减少 负氮平衡。支链酮酸 脱氢酶(BCKD)被认为是一种主要的速率控制因子 参与支链氨基酸的降解。 然而，它实际决定通量的程度 这种途径可能因代谢状态的不同而不同。 以及涉及的组织。分枝的生理调节剂 链氨基酸的代谢也是未知的。因此，总体上 这项提案的目标是创建一个监管的模式 BCKD通过变构调节剂的活性及其变化 磷酸化状态，并评价其在细胞周期调控中的作用 支链氨基酸降解。 这项提议的主要创新是使用新陈代谢 控制理论和计算机仿真技术作为一种手段 提出和检验假说。一种数学模型 BCKD的调控机制是发展起来的，然后代谢 运用控制理论对监管意义进行评价 不同的调节剂和这种酶控制通量的潜力 在各种组织中。为了执行这一计划，潜在的 BCKD和ITS的调节剂和动力学特性 相互转换酶、BCKD磷酸酶和BCKD激酶 必须下定决心。计算机模拟与代谢控制 理论将被用来对系统进行建模，以预测 在各种调节剂存在下的BCKD复合体。模型 将使用在培养基中孵化的线粒体进行测试 特定的调制剂浓度是受控制的。这个系统 也将被用来检查BCKD对通量的控制。vbl.使用 计算机模拟以做出定量预测，同时 模型参数的实验验证，将是可能的 在复杂(现实)中验证即使是微妙的监管机制 细胞内的代谢途径。这些实验将导致 监管的量化模型将能够识别 速率控制步骤和主要的调节调节器 降解支链氨基酸的组织及其如何 会因创伤和疾病而改变。

The branched chain amino acids play a role in the regulation of protein turnover, and carbohydrate and muscle energy metabolism. Physiological and pathological conditions such as food deprivation diabetes, trauma, and clofibrate treatment increase oxidation of the branched chain amino acids in muscle. The potential importance of these observations is underscored by clinical results which show that branched chain amino acid infusin in patients suffering from trauma or burns markedly reduces negative nitrogen balance. Branched chain ketoacid dehydrogenase (BCKD) is thought to be a major rate-controlling step in the degradation of the branched chain amino acids. However, the extent to which it actually determines flux through this pathway probably varies depending upon the metabolic state and the tissue involved. The physiological modulators of branched chain amino acid metabolism are also not known. Thus the overall goal of this proposal is to create of a model for the regulation of BCKD activity via allosteric modulators and changes in phosphorylation state and to evaluate its role in the regulation of branched chain amino acid degradation. The major innovations in this proposal are the use of metabolic control theory and computer simulation techniques as a means of both formulating and testing hypotheses. a mathematical model of the regulation of BCKD is developed and then metabolic control theory is applied to evaluate the regulatory significance of various modulators and potential of this enzyme to control flux in various tissues. In order to carryout this plan, the potential modulators and kinetic characteristics of BCKD and its interconverting enzymes, BCKD phosphatase and BCKD kinase must be determined. Computer simulation and metabolic control theory will be used to model the system to predict the behavior of BCKD complex in the presence of various modulators. The model will be tested using mitochondria incubated in media in which the particular modulator concentrations are controlled. This system will also be used to examine the control of flux by BCKD. Using computer simulation to make quantitative predictions along with experimental verification of model parameters, it will be possible to verify even subtle regulatory mechanisms in complex (realistic) metabolic pathways in the cell. These experiments will result in a quantitative model of regulation which will be able to identify the rate-controlling steps and major regulatory modulators in the tissues which degrade branched chain amino acids and how they are altered by trauma and disease.