Elementary metabolite units (EMU): A novel framework for modeling isotopic distributions
Elementary metabolite units (EMU): A novel framework for modeling isotopic distributions
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DOI：
10.1016/j.ymben.2006.09.001
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发表时间：
2007-01-01
影响因子：
8.4
通讯作者：
Stephanopoulos, Gregory
中科院分区：
文献类型：
--
作者：
Antoniewicz, Maciek R.;Kelleher, Joanne K.;Stephanopoulos, Gregory
代谢通量分析(MFA)已成为代谢工程和哺乳动物生理学的重要工具。通过稳定同位素标记、GC/MS和核磁共振测量进行的MFA的一个重要限制是需要解决大量的同位素异构体或累积体方程，特别是当使用多个同位素示踪剂标记体系时。这一限制降低了MFA在阐明包含复杂生物反应网络的现实情况的生理学方面充分利用多个同位素示踪剂的能力。在这里，我们提出了一个新的框架，用于同位素标记系统的建模，它显著减少了系统变量的数量，而不会造成任何信息损失。元素代谢物单元(EMU)框架基于一种高效的分解方法，该方法利用网络反应中发生的原子跃迁的知识确定在反应网络内模拟同位素标记所需的最少信息量。分解算法生成的功能单元称为动车组，构成了生成描述通量和稳定同位素测量之间关系的系统方程的新基础。用EMU框架模拟的同分异构体丰度与用同分异构体和累积异构体方法得到的结果相同，但所需的计算时间要短得多。对于一个典型的C-13标记系统，需要求解的方程总数减少了一个数量级(100s动车组与1000s同位素异构体)。因此，EMU框架对于分析多个同位素示踪剂的标记是最有效的。例如，使用H-2、C-13和O-18示踪剂分析糖异生途径只需要354个EMU，相比之下，需要200多万个同位素异构体。(C)2006 Elsevier Inc.保留所有权利。
Metabolic flux analysis (MFA) has emerged as a tool of great significance for metabolic engineering and mammalian physiology. An important limitation of MFA, as carried out via stable isotope labeling and GC/MS and nuclear magnetic resonance (NMR) measurements, is the large number of isotopomer or cumomer equations that need to be solved, especially when multiple isotopic tracers are used for the labeling of the system. This restriction reduces the ability of MFA to fully utilize the power of multiple isotopic tracers in elucidating the physiology of realistic situations comprising complex bioreaction networks. Here, we present a novel framework for the modeling of isotopic labeling systems that significantly reduces the number of system variables without any loss of information. The elementary metabolite unit (EMU) framework is based on a highly efficient decomposition method that identifies the minimum amount of information needed to simulate isotopic labeling within a reaction network using the knowledge of atomic transitions occurring in the network reactions. The functional units generated by the decomposition algorithm, called EMUs, form the new basis for generating system equations that describe the relationship between fluxes and stable isotope measurements. Isotopomer abundances simulated using the EMU framework are identical to those obtained using the isotopomer and cumomer methods, however, require significantly less computation time. For a typical C-13-labeling system the total number of equations that needs to be solved is reduced by one order-of-magnitude (100s EMUs vs. 1000s isotopomers). As such, the EMU framework is most efficient for the analysis of labeling by multiple isotopic tracers. For example, analysis of the gluconeogenesis pathway with H-2, C-13, and O-18 tracers requires only 354 EMUs, compared to more than two million isotopomers. (C) 2006 Elsevier Inc. All rights reserved.