Development of an accurate kinetic model for the central carbon metabolism of Escherichia coli.
Development of an accurate kinetic model for the central carbon metabolism of Escherichia coli.
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DOI：
10.1186/s12934-016-0511-x
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发表时间：
2016-06-21
影响因子：
6.4
通讯作者：
Kurata H
中科院分区：
文献类型：
--
作者：
Jahan N;Maeda K;Matsuoka Y;Sugimoto Y;Kurata H
动力学模型提供了对生物系统的动态响应的见解，并预测其复杂的代谢和基因调控网络如何产生特定的功能。在许多生物系统中，大肠杆菌的代谢途径已经在酶和遗传水平上被广泛地建模，但是现有的模型不能准确地再现分批培养中的实验行为，这是由于对特定细胞生长速率的估计不足和大量的不可测量的参数。在本研究中，我们建立了一个详细的动力学模型的中心碳代谢的E。大肠杆菌的糖酵解途径、三羧酸循环、戊糖磷酸途径、Entner-Doudoroff途径、回补途径、乙醛酸分流、氧化磷酸化、磷酸转移酶系统（Pts）、非Pts以及cAMP受体、分解代谢物阻遏物/激活物、丙酮酸脱氢酶复合物阻遏物和异柠檬酸裂解酶调节因子对代谢基因的调控。在超级计算机上用约束优化方法估计了动力学参数。该模型基于反应动力学估计了比生长速率，并准确地再现了野生型E.大肠杆菌和多个遗传突变体的分批培养。该模型克服了现有分批培养动力学模型的固有局限性，预测了多层调控（变构效应物和基因表达）对中心碳代谢的影响，并提出了基于分子过程理解的合理设计的快速生长细胞。本文的在线版本（doi：10.1186/s12934-016-0511-x）包含补充材料，可供授权用户使用。
A kinetic model provides insights into the dynamic response of biological systems and predicts how their complex metabolic and gene regulatory networks generate particular functions. Of many biological systems, Escherichia coli metabolic pathways have been modeled extensively at the enzymatic and genetic levels, but existing models cannot accurately reproduce experimental behaviors in a batch culture, due to the inadequate estimation of a specific cell growth rate and a large number of unmeasured parameters. In this study, we developed a detailed kinetic model for the central carbon metabolism of E. coli in a batch culture, which includes the glycolytic pathway, tricarboxylic acid cycle, pentose phosphate pathway, Entner-Doudoroff pathway, anaplerotic pathway, glyoxylate shunt, oxidative phosphorylation, phosphotransferase system (Pts), non-Pts and metabolic gene regulations by four protein transcription factors: cAMP receptor, catabolite repressor/activator, pyruvate dehydrogenase complex repressor and isocitrate lyase regulator. The kinetic parameters were estimated by a constrained optimization method on a supercomputer. The model estimated a specific growth rate based on reaction kinetics and accurately reproduced the dynamics of wild-type E. coli and multiple genetic mutants in a batch culture. This model overcame the intrinsic limitations of existing kinetic models in a batch culture, predicted the effects of multilayer regulations (allosteric effectors and gene expression) on central carbon metabolism and proposed rationally designed fast-growing cells based on understandings of molecular processes. The online version of this article (doi:10.1186/s12934-016-0511-x) contains supplementary material, which is available to authorized users.