Reconstruction and functional characterization of the human mitochondrial metabolic network based on proteomic and biochemical data
Reconstruction and functional characterization of the human mitochondrial metabolic network based on proteomic and biochemical data
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DOI：
10.1074/jbc.m403782200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Palsson, BO
中科院分区：
文献类型：
--
作者：
Vo, TD;Greenberg, HJ;Palsson, BO
包括基因组学、蛋白质组学、同位素体和DNA序列变异在内的多种数据集正在成为人类线粒体的可用数据集。因此，有必要将这些数据整合到一个可以研究和分析线粒体生物学和相关疾病的计算机建模框架中。本文报道了基于蛋白质组学和生化数据的人类线粒体代谢网络的重建和表征。重构的189个反应都是元素平衡和电荷平衡的，并被分配到各自的细胞区室（线粒体、细胞质或细胞外）。重建的网络完成三种代谢功能（ATP产生、血红素合成和混合磷脂合成）的能力被确定。基于网络的线粒体能量转化过程分析表明，每葡萄糖的总ATP产量为31.5。通过通量变异性分析和对所有可能的最优通量分布的分析，评估了以反应通量允许变化为特征的网络灵活性。结果表明，该网络对血红素和磷脂的生物合成具有高度的灵活性，但对最大的ATP生产具有适度的灵活性。所有最优网络通量分布的一个子集，分别相对于三种代谢功能计算，被发现是高度相关的，这表明这一组可能包含生理上有意义的通量。对最佳通量分布的检查还确定了在网络中形成功能模块的相关反应集。
Diverse datasets including genomic, proteomic, isotopomer, and DNA sequence variation are becoming available for human mitochondria. Thus there is a need to integrate these data within an in silico modeling framework where mitochondrial biology and related disorders can be studied and analyzed. This paper reports a reconstruction and characterization of the human mitochondrial metabolic network based on proteomic and biochemical data. The 189 reactions included in this reconstruction are both elementally and charge-balanced and are assigned to their respective cellular compartments (mitochondrial, cytosol, or extracellular). The capabilities of the reconstructed network to fulfill three metabolic functions (ATP production, heme synthesis, and mixed phospholipid synthesis) were determined. Network-based analysis of the mitochondrial energy conversion process showed that the overall ATP yield per glucose is 31.5. Network flexibility, characterized by allowable variation in reaction fluxes, was evaluated using flux variability analysis and analysis of all of the possible optimal flux distributions. Results showed that the network has high flexibility for the biosynthesis of heme and phospholipids but modest flexibility for maximal ATP production. A subset of all of the optimal network flux distributions, computed with respect to the three metabolic functions individually, was found to be highly correlated, suggesting that this set may contain physiological meaningful fluxes. Examinations of optimal flux distributions also identified correlated reaction sets that form functional modules in the network.