Dimerization and Bifunctionality Confer Robustness to the Isocitrate Dehydrogenase Regulatory System in Escherichia coli
Dimerization and Bifunctionality Confer Robustness to the Isocitrate Dehydrogenase Regulatory System in Escherichia coli
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DOI：
10.1074/jbc.m112.339226
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发表时间：
2013-02-22
影响因子：
4.8
通讯作者：
Gunawardena, Jeremy
中科院分区：
文献类型：
--
作者：
Dexter, Joseph P.;Gunawardena, Jeremy
系统生物学的一个重要目标是开发定量模型，解释特定的分子特征如何产生系统级的属性。从这个角度研究包含多功能蛋白质的代谢和调节途径特别有趣，因为它们经常被观察到表现出健壮性：即使其组成部分的水平发生变化，系统也能够执行其适当的功能。在这项研究中，我们使用广泛的生化数据和代数建模来开发和分析一个模型，该模型展示了大肠杆菌异柠檬酸脱氢酶(IDH)调控系统的稳健行为，该模型于1985年被实验证明具有稳健性。大肠杆菌IDH是由双功能异柠檬酸脱氢酶/磷酸酶(IDHKP)催化的可逆磷酸化来调节的，IDH的活性水平决定了碳流是通过乙醛旁路(用于在双碳基质上生长)还是通过完整的三羧酸循环来引导的。我们的模型结合了有关IDHKP的最新结构数据，确定了该系统的几个特定的生化特征(包括IDH的同源二聚化和IDHKP的双功能)，这为稳健性提供了潜在的解释。利用代数技术，我们得到了一个不变量，它概括了IDH的磷化形式之间的稳态关系。我们使用不变量结合IDHKP上的动力学数据来计算IDH在总IDH水平范围内的IDH活性，发现我们的模型预测了稳健性。我们的工作将IDH调控系统的许多已知生物化学统一到一个单一的量化框架中，并强调了在系统生物学中构建生物化学现实模型的重要性。
An important goal of systems biology is to develop quantitative models that explain how specific molecular features give rise to systems-level properties. Metabolic and regulatory pathways that contain multifunctional proteins are especially interesting to study from this perspective because they have frequently been observed to exhibit robustness: the ability for a system to perform its proper function even as levels of its components change. In this study, we use extensive biochemical data and algebraic modeling to develop and analyze a model that shows how robust behavior arises in the isocitrate dehydrogenase (IDH) regulatory system of Escherichia coli, which was shown in 1985 to experimentally exhibit robustness. E. coli IDH is regulated by reversible phosphorylation catalyzed by the bifunctional isocitrate dehydrogenase kinase/phosphatase (IDHKP), and the level of IDH activity determines whether carbon flux is directed through the glyoxylate bypass (for growth on two-carbon substrates) or the full tricarboxylic acid cycle. Our model, which incorporates recent structural data on IDHKP, identifies several specific biochemical features of the system (including homodimerization of IDH and bifunctionality of IDHKP) that provide a potential explanation for robustness. Using algebraic techniques, we derive an invariant that summarizes the steady-state relationship between the phospho-forms of IDH. We use the invariant in combination with kinetic data on IDHKP to calculate IDH activity at a range of total IDH levels and find that our model predicts robustness. Our work unifies much of the known biochemistry of the IDH regulatory system into a single quantitative framework and highlights the importance of constructing biochemically realistic models in systems biology.