Robustness in glyoxylate bypass regulation.
Robustness in glyoxylate bypass regulation.
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DOI：
10.1371/journal.pcbi.1000297
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发表时间：
2009-03
影响因子：
4.3
通讯作者：
Alon U
中科院分区：
文献类型：
--
作者：
Shinar G;Rabinowitz JD;Alon U
乙醛酸旁路允许大肠杆菌在只有两个碳的碳源上生长，通过绕过三羧酸循环中作为CO2的碳损失。流向这条旁路的流量是由异柠檬酸脱氢酶（IDH）的磷酸化调节的，这种磷酸化是由一种称为IDHKP的双功能激酶-磷酸酶引起的。在该系统中，已经发现IDH活性相对于总IDH蛋白浓度的广泛变化是显著稳健的。在这里，我们研究可能的机制来解释这种鲁棒性。IDHKP同时作为一级激酶和具有单个IDH结合位点的零级磷酸酶起作用的解释被发现与稳健性不一致。相反，我们提出了一个强大的机制，两个基板结合的双功能酶，形成三元复合物。为了生长良好，细胞需要通过其代谢网络产生一套平衡的构建模块。当代谢物流过网络中的分支途径时，调节回路用于维持适当的通量。在这里，我们问这样的调节回路如何精确地工作，尽管它们是由蛋白质组成的，其水平在细胞与细胞之间以及在同一细胞中随时间而变化。我们使用了一个经过充分研究的回路，在一个关键的分支点称为乙醛酸旁路，作为一个模型系统。以前的实验表明，该系统对蛋白质水平的变化非常稳健。在这里，我们提出了一种机制来解释这种鲁棒性，基于催化两个相反反应的双功能酶。我们表明，一个简单的解释的基础上酶的饱和度是不一致的更严格的数学分析。我们提出的机制提出了几个实验验证的预测。它显示了系统级特征（鲁棒性）如何从看似无关的生化细节中产生。由于在不同生物体的其他系统中发现了双功能酶的类似设计，因此本机制可能适用更广泛。
The glyoxylate bypass allows Escherichia coli to grow on carbon sources with only two carbons by bypassing the loss of carbons as CO2 in the tricarboxylic acid cycle. The flux toward this bypass is regulated by the phosphorylation of the enzyme isocitrate dehydrogenase (IDH) by a bifunctional kinase–phosphatase called IDHKP. In this system, IDH activity has been found to be remarkably robust with respect to wide variations in the total IDH protein concentration. Here, we examine possible mechanisms to explain this robustness. Explanations in which IDHKP works simultaneously as a first-order kinase and as a zero-order phosphatase with a single IDH binding site are found to be inconsistent with robustness. Instead, we suggest a robust mechanism where both substrates bind the bifunctional enzyme to form a ternary complex. To grow well, the cell needs to produce a balanced set of building blocks by means of its metabolic network. Regulatory circuits are used to maintain appropriate fluxes as metabolites flow through the branching pathways in the network. Here, we asked how such regulatory circuits can work precisely, despite the fact that they are made of proteins whose levels vary from cell to cell and in the same cell over time. We used a well-studied circuit, at a key branch point called the glyoxylate bypass, as a model system. Previous experiments showed that this system is remarkably robust to changes in the levels of its proteins. Here, we propose a mechanism to explain this robustness, based on a bifunctional enzyme that catalyzes two opposing reactions. We show that a simple explanation based on enzyme saturation is inconsistent with more rigorous mathematical analysis. Our proposed mechanism suggests several experimentally testable predictions. It shows how a systems-level feature (robustness) may arise from seemingly unrelated biochemical details. Because analogous designs with bifunctional enzymes are found in other systems in different organisms, the present mechanism might apply more broadly.
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影响因子：
64.8
作者：
Alon, U;Surette, MG;Leibler, S
通讯作者：
Leibler, S
影响因子：
64.8
作者：
Barkai, N;Leibler, S
通讯作者：
Leibler, S
影响因子：
64.8
作者：
LAPORTE, DC;KOSHLAND, DE
通讯作者：
KOSHLAND, DE
影响因子：
16
作者：
Barkai, Naama;Shilo, Ben-Zion
通讯作者：
Shilo, Ben-Zion
DOI：
10.1099/00221287-65-1-57
发表时间：
1971-01-01
期刊：
JOURNAL OF GENERAL MICROBIOLOGY
影响因子：
--
作者：
HOLMS, WH;BENNETT, PM
通讯作者：
BENNETT, PM