Knorr Andrea L, Jain Rishi, Srivastava Ranjan
Department of Chemical, Materials and Biomolecular Engineering, University of Connecticut, 191 Auditorium Road U3222, Storrs, CT 06269-3222, USA.
Bioinformatics. 2007 Feb 1;23(3):351-7. doi: 10.1093/bioinformatics/btl619. Epub 2006 Dec 6.
A critical component of in silico analysis of underdetermined metabolic systems is the identification of the appropriate objective function. A common assumption is that the objective of the cell is to maximize growth. This objective function has been shown to be consistent in a few limited experimental cases, but may not be universally appropriate. Here a method is presented to quantitatively determine the most probable objective function.
The genome-scale metabolism of Escherichia coli growing on succinate was used as a case-study for analysis. Five different objective functions, including maximization of growth rate, were chosen based on biological plausibility. A combination of flux balance analysis and linear programming was used to simulate cellular metabolism, which was then compared to independent experimental data using a Bayesian objective function discrimination technique. After comparing rates of oxygen uptake and acetate production, minimization of the production rate of redox potential was determined to be the most probable objective function. Given the appropriate reaction network and experimental data, the discrimination technique can be applied to any bacterium to test a variety of different possible objective functions.
Additional files, code and a program for carrying out model discrimination are available at http://www.engr.uconn.edu/~srivasta/modisc.html.
对欠定代谢系统进行计算机模拟分析的一个关键组成部分是确定合适的目标函数。一个常见的假设是细胞的目标是实现生长最大化。在一些有限的实验案例中，这个目标函数已被证明是一致的，但可能并非普遍适用。本文提出了一种定量确定最可能的目标函数的方法。
以在琥珀酸盐上生长的大肠杆菌的基因组规模代谢作为分析的案例研究。基于生物学合理性选择了五个不同的目标函数，包括生长速率最大化。通量平衡分析和线性规划相结合用于模拟细胞代谢，然后使用贝叶斯目标函数判别技术将其与独立的实验数据进行比较。在比较氧气摄取速率和乙酸盐产生速率后，确定氧化还原电位产生速率最小化是最可能的目标函数。给定适当的反应网络和实验数据，该判别技术可应用于任何细菌，以测试各种不同的可能目标函数。
可在http://www.engr.uconn.edu/~srivasta/modisc.html获取用于进行模型判别的附加文件、代码和程序。
