Pillay Ché S, Hofmeyr Jan-Hendrik S, Rohwer Johann M
Discipline of Genetics, University of KwaZulu-Natal, South Africa, Carbis Road, Pietermaritzburg, 3201, South Africa.
BMC Syst Biol. 2011 Jan 25;5:15. doi: 10.1186/1752-0509-5-15.
The thioredoxin system consisting of NADP(H), thioredoxin reductase and thioredoxin provides reducing equivalents to a large and diverse array of cellular processes. Despite a great deal of information on the kinetics of individual thioredoxin-dependent reactions, the kinetic regulation of this system as an integrated whole is not known. We address this by using kinetic modeling to identify and describe kinetic behavioral motifs found within the system.
Analysis of a realistic computational model of the Escherichia coli thioredoxin system revealed several modes of kinetic regulation in the system. In keeping with published findings, the model showed that thioredoxin-dependent reactions were adaptable (i.e. changes to the thioredoxin system affected the kinetic profiles of these reactions). Further and in contrast to other systems-level descriptions, analysis of the model showed that apparently unrelated thioredoxin oxidation reactions can affect each other via their combined effects on the thioredoxin redox cycle. However, the scale of these effects depended on the kinetics of the individual thioredoxin oxidation reactions with some reactions more sensitive to changes in the thioredoxin cycle and others, such as the Tpx-dependent reduction of hydrogen peroxide, less sensitive to these changes. The coupling of the thioredoxin and Tpx redox cycles also allowed for ultrasensitive changes in the thioredoxin concentration in response to changes in the thioredoxin reductase concentration. We were able to describe the kinetic mechanisms underlying these behaviors precisely with analytical solutions and core models.
Using kinetic modeling we have revealed the logic that underlies the functional organization and kinetic behavior of the thioredoxin system. The thioredoxin redox cycle and associated reactions allows for a system that is adaptable, interconnected and able to display differential sensitivities to changes in this redox cycle. This work provides a theoretical, systems-biological basis for an experimental analysis of the thioredoxin system and its associated reactions.
由NADP(H)、硫氧还蛋白还原酶和硫氧还蛋白组成的硫氧还蛋白系统为大量多样的细胞过程提供还原当量。尽管有大量关于单个硫氧还蛋白依赖性反应动力学的信息，但该系统作为一个整体的动力学调节尚不清楚。我们通过使用动力学建模来识别和描述该系统中发现的动力学行为模式来解决这个问题。
对大肠杆菌硫氧还蛋白系统的一个现实计算模型的分析揭示了该系统中的几种动力学调节模式。与已发表的研究结果一致，该模型表明硫氧还蛋白依赖性反应是可适应的（即硫氧还蛋白系统的变化会影响这些反应的动力学谱）。此外，与其他系统水平的描述相反，对该模型的分析表明，明显不相关的硫氧还蛋白氧化反应可以通过它们对硫氧还蛋白氧化还原循环的综合影响相互作用。然而，这些影响的程度取决于单个硫氧还蛋白氧化反应的动力学，一些反应对硫氧还蛋白循环的变化更敏感，而其他反应，如Tpx依赖性的过氧化氢还原反应，对这些变化不太敏感。硫氧还蛋白和Tpx氧化还原循环的耦合也使得硫氧还蛋白浓度能够对硫氧还蛋白还原酶浓度的变化做出超敏感的变化。我们能够用解析解和核心模型精确描述这些行为背后的动力学机制。
使用动力学建模，我们揭示了硫氧还蛋白系统功能组织和动力学行为背后的逻辑。硫氧还蛋白氧化还原循环及相关反应使得该系统具有适应性、相互关联性，并能够对该氧化还原循环的变化表现出不同的敏感性。这项工作为硫氧还蛋白系统及其相关反应的实验分析提供了一个理论性的系统生物学基础。
