Constraints-based models: Regulation of gene expression reduces the steady-state solution space
Constraints-based models: Regulation of gene expression reduces the steady-state solution space
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DOI：
10.1006/jtbi.2003.3071
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发表时间：
2003-04-07
影响因子：
2
通讯作者：
Palsson, BO
中科院分区：
文献类型：
--
作者：
Covert, MW;Palsson, BO
基于约束的模型已被有效地用于分析、解释和预测重建的基因组尺度代谢模型的功能。这些模型的第一代使用了与网络连通性、代谢反应的不可逆性和最大通量能力相关的“硬”不可调节约束。这些约束将网络的允许行为限制在一个凸数学解空间中，该空间的边是极端路径，可以用来描述在规定的性能标准下网络的最佳性能。本杂志发表的一篇配套论文描述了第二代基于约束的模型的发展，该模型结合了与基因表达调控相关的约束，使用通量平衡分析来生成生长和副产物分泌的时间过程，使用核心代谢的骨架表示。这些附加限制的施加阻止了来自“硬”约束的极端路径子集的使用，从而减少了解决方案空间并限制了允许的网络功能。在这里，我们使用极端路径分析来检查由于监管约束导致的解空间的减少。环境条件和调节机制的施加大大减少了活跃的极端途径的数量。这种方法已经在上面提到的骨骼系统中得到了证明，它有80个极端通路。由于对系统施加了监管约束，可行的极端路径数量减少到26 - 2个极端路径之间，减少了67.5% - 97.5%。这里开发的方法提供了一种方法来解释如何使用调节机制来约束网络功能，并从所有允许的网络功能中产生小范围的生理上有意义的行为。2003爱思唯尔科学有限公司版权所有。
Constraints-based models have been effectively used to analyse, interpret, and predict the function of reconstructed genome-scale metabolic models. The first generation of these models used "hard" non-adjustable constraints associated with network connectivity, irreversibility of metabolic reactions, and maximal flux capacities. These constraints restrict the allowable behaviors of a network to a convex mathematical solution space whose edges are extreme pathways that can be used to characterize the optimal performance of a network under a stated performance criterion. The development of a second generation of constraints-based models by incorporating constraints associated with regulation of gene expression was described in a companion paper published in this journal, using flux-balance analysis to generate time courses of growth and by-product secretion using a skeleton representation of core metabolism. The imposition of these additional restrictions prevents the use of a subset of the extreme pathways that are derived from the "hard" constraints, thus reducing the solution space and restricting allowable network functions. Here, we examine the reduction of the solution space due to regulatory constraints using extreme pathway analysis. The imposition of environmental conditions and regulatory mechanisms sharply reduces the number of active extreme pathways. This approach is demonstrated for the skeleton system mentioned above, which has 80 extreme pathways. As regulatory constraints are applied to the system, the number of feasible extreme pathways is reduced to between 26 and 2 extreme pathways, a reduction of between 67.5 and 97.5%. The method developed here provides a way to interpret how regulatory mechanisms are used to constrain network functions and produce a small range of physiologically meaningful behaviors from all allowable network functions. (C) 2003 Elsevier Science Ltd. All rights reserved.