iReMet-flux: constraint-based approach for integrating relative metabolite levels into a stoichiometric metabolic models
iReMet-flux: constraint-based approach for integrating relative metabolite levels into a stoichiometric metabolic models
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DOI：
10.1093/bioinformatics/btw465
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发表时间：
2016-09-01
期刊：
影响因子：
5.8
通讯作者：
Nikoloski, Zoran
中科院分区：
文献类型：
--
作者：
Sajitz-Hermstein, Max;Toepfer, Nadine;Nikoloski, Zoran
动机：了解扰动后代谢反应通量的重新路由有可能将细胞系统分子状态的变化与生长的改变联系起来。然而，在基因组水平上的差异通量分析仍然是系统生物学中最大的挑战之一。这是特别相关的植物，在自养生长的通量需要耗时的不稳定的标记实验和昂贵的计算，可行的小规模networks.Results：在这里，我们提出了一个计算和实验简便的方法，称为iReMet通量，它集成了相对的代谢模型中的代谢组学数据，以预测差异通量在基因组规模的水平。我们的方法及其变体补充了基于放射性示踪剂标记的通量估计方法。我们采用iReMet-Flux与植物可用的代谢谱来预测光自养生长的拟南芥和四个光呼吸突变体经历高到低CO2驯化的通量改变的反应和途径。我们还提供了有关反应和途径的预测，这些反应和途径在所研究的实验中受到最强烈的调控。针对iReMet-Flux配方定制的稳健性和变异性分析表明，研究结果提供了生物学相关信息，这些信息通过净CO2交换和生物质生产的外部测量进行了验证。因此，iReMet-Flux为在基因组尺度上对初级代谢和次级代谢途径之间的相互作用进行机械解剖铺平了道路。
Motivation: Understanding the rerouting of metabolic reaction fluxes upon perturbations has the potential to link changes in molecular state of a cellular system to alteration of growth. Yet, differential flux profiling on a genome-scale level remains one of the biggest challenges in systems biology. This is particularly relevant in plants, for which fluxes in autotrophic growth necessitate time-consuming instationary labeling experiments and costly computations, feasible for small-scale networks.Results: Here we present a computationally and experimentally facile approach, termed iReMet-Flux, which integrates relative metabolomics data in a metabolic model to predict differential fluxes at a genome-scale level. Our approach and its variants complement the flux estimation methods based on radioactive tracer labeling. We employ iReMet-Flux with publically available metabolic profiles to predict reactions and pathways with altered fluxes in photo-autotrophically grown Arabidopsis and four photorespiratory mutants undergoing high-to-low CO2 acclimation. We also provide predictions about reactions and pathways which are most strongly regulated in the investigated experiments. The robustness and variability analyses, tailored to the formulation of iReMet-Flux, demonstrate that the findings provide biologically relevant information that is validated with external measurements of net CO2 exchange and biomass production. Therefore, iReMet-Flux paves the wave for mechanistic dissection of the interplay between pathways of primary and secondary metabolisms at a genome-scale.