An Integrated Model of Eicosanoid Metabolism and Signaling Based on Lipidomics Flux Analysis
An Integrated Model of Eicosanoid Metabolism and Signaling Based on Lipidomics Flux Analysis
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DOI：
10.1016/j.bpj.2009.03.011
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发表时间：
2009-06-03
影响因子：
3.4
通讯作者：
Subramaniam, Shankar
中科院分区：
文献类型：
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作者：
Gupta, Shakti;Maurya, Mano Ram;Subramaniam, Shankar
越来越多的证据表明，脂质在信号转导和细胞运输中起着重要而关键的作用，这促使了对脂质途径的大规模研究。脂质代谢产物和途径策略联盟正在积极研究哺乳动物细胞中的脂质代谢，并已获得巨噬细胞RAW 264.7细胞的kdo2 -脂质A（一种脂多糖类似物）治疗后各种脂质的时间过程数据。被称为类二十烷类的脂质在炎症中起着重要作用。我们基于KEGG通路数据库和文献重建了一个集成的类二十烷代谢和信号传导网络，并建立了一个动力学模型。采用基于矩阵的方法从实验数据中估计速率常数，并进一步采用广义约束非线性优化方法对其进行细化。所得模型与所有物种的实验数据拟合良好，模拟酶活性与文献值相近。我们开发的类二十烷代谢定量模型可用于设计实验研究，利用遗传和药理学扰动来探测脂质途径中的通量。
There is increasing evidence for a major and critical involvement of lipids in signal transduction and cellular trafficking, and this has motivated large-scale studies on lipid pathways. The Lipid Metabolites and Pathways Strategy consortium is actively investigating lipid metabolism in mammalian cells and has made available time-course data on various lipids in response to treatment with KDO2-lipid A (a lipopolysaccharide analog) of macrophage RAW 264.7 cells. The lipids known as eicosanoids play an important role in inflammation. We have reconstructed an integrated network of eicosanoid metabolism and signaling based on the KEGG pathway database and the literature and have developed a kinetic model. A matrix-based approach was used to estimate the rate constants from experimental data and these were further refined using generalized constrained nonlinear optimization. The resulting model fits the experimental data well for all species, and simulated enzyme activities were similar to their literature values. The quantitative model for eicosanoid metabolism that we have developed can be used to design experimental studies utilizing genetic and pharmacological perturbations to probe fluxes in lipid pathways.