Quantitative Assignment of Reaction Directionality in a Multicompartmental Human Metabolic Reconstruction
Quantitative Assignment of Reaction Directionality in a Multicompartmental Human Metabolic Reconstruction
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DOI：
10.1016/j.bpj.2012.02.032
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发表时间：
2012-04-18
影响因子：
3.4
通讯作者：
Fleming, R. M. T.
中科院分区：
文献类型：
--
作者：
Haraldsdottir, H. S.;Thiele, I.;Fleming, R. M. T.
反应的方向性是基因组尺度代谢网络建模中的一个关键约束。我们通过计算体内标准转化反应吉布斯能作为细胞特异性pH值、电势和离子强度的函数，在人体代谢的多室基因组尺度模型Recon 1中热力学约束了反应的指向性。我们发现区室pH值是热力学决定反应方向性的重要决定因素。pH值对传递反应热力学的影响只有在代谢物被表示为多个质子化物质的假异构体基团时才能充分体现出来。我们准确地预测了387个反应的不可逆性，在输入数据中详细传播不确定性，并手动整理文献以解决相互冲突的方向性分配。在至少一半的病例中，可逆反应方向性的预测是由于缺乏室特异性定量代谢组学数据，其余病例是由于标准反应吉布斯能估计的不确定性。本研究指出迫切需要1)，定量代谢组学数据，2)，实验测量人体代谢物的热化学性质。
Reaction directionality is a key constraint in the modeling of genome-scale metabolic networks. We thermodynamically constrained reaction directionality in a multicompartmental genome-scale model of human metabolism, Recon 1, by calculating, in vivo, standard transformed reaction Gibbs energy as a function of compartment-specific pH, electrical potential, and ionic strength. We show that compartmental pH is an important determinant of thermodynamically determined reaction directionality. The effects of pH on transport reaction thermodynamics are only seen to their full extent when metabolites are represented as pseudoisomer groups of multiple protonated species. We accurately predict the irreversibility of 387 reactions, with detailed propagation of uncertainty in input data, and manually curate the literature to resolve conflicting directionality assignments. In at least half of all cases, a prediction of a reversible reaction directionality is due to the paucity of compartment-specific quantitative metabolomic data, with remaining cases due to uncertainty in estimation of standard reaction Gibbs energy. This study points to the pressing need for 1), quantitative metabolomic data, and 2), experimental measurement of thermochemical properties for human metabolites.