Prediction of metabolic fluxes by incorporating genomic context and flux-converging pattern analyses
Prediction of metabolic fluxes by incorporating genomic context and flux-converging pattern analyses
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DOI：
10.1073/pnas.1003740107
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发表时间：
2010-08-17
影响因子：
11.1
通讯作者：
Lee, Sang Yup
中科院分区：
文献类型：
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作者：
Park, Jong Myoung;Kim, Tae Yong;Lee, Sang Yup
基因组规模代谢模型的通量平衡分析 (FBA) 允许通过优化目标函数（例如在给定约束下最大化细胞生长）来计算细胞内通量，并在系统生物学和生物技术领域找到了众多应用。然而，由于系统的不确定性，它具有诸如通量预测不准确以及存在多个最优目标值解等局限性。在这里，我们报告了一种通过 FBA 结合系统和条件独立的约束来准确预测代谢通量的策略，这些约束通过基因组背景和通量收敛模式分析来限制分组反应可实现的通量范围。对三种类型的基因组环境、保守的基因组邻域、基因融合事件以及多个生物体中基因的共现进行了分析，以提出一组可能同时开启或关闭的通量。这些分组反应的通量范围受到通量收敛模式分析的限制。通过应用这些约束条件，在几种不同的基因型（pykF、zwf、ppc 和 suCA 突变体）和环境（改变的碳源）条件下对大肠杆菌基因组规模代谢模型进行 FBA，产生的通量值与实验测量的基于 C-13 的通量非常一致。因此，当实验确定困难时，该策略将有助于准确预测大型代谢网络的细胞内通量。
Flux balance analysis (FBA) of a genome-scale metabolic model allows calculation of intracellular fluxes by optimizing an objective function, such as maximization of cell growth, under given constraints, and has found numerous applications in the field of systems biology and biotechnology. Due to the underdetermined nature of the system, however, it has limitations such as inaccurate prediction of fluxes and existence of multiple solutions for an optimal objective value. Here, we report a strategy for accurate prediction of metabolic fluxes by FBA combined with systematic and condition-independent constraints that restrict the achievable flux ranges of grouped reactions by genomic context and flux-converging pattern analyses. Analyses of three types of genomic contexts, conserved genomic neighborhood, gene fusion events, and co-occurrence of genes across multiple organisms, were performed to suggest a group of fluxes that are likely on or off simultaneously. The flux ranges of these grouped reactions were constrained by flux-converging pattern analysis. FBA of the Escherichia coli genome-scale metabolic model was carried out under several different genotypic (pykF, zwf, ppc, and sucA mutants) and environmental (altered carbon source) conditions by applying these constraints, which resulted in flux values that were in good agreement with the experimentally measured C-13-based fluxes. Thus, this strategy will be useful for accurately predicting the intracellular fluxes of large metabolic networks when their experimental determination is difficult.