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Biological analysis and mathematical modeling of glucose metabolism and the aspartate and pyruvate family amino acid biosyntheses in Escherichia coli K12.

机译：大肠杆菌K12中葡萄糖代谢以及天冬氨酸和丙酮酸家族氨基酸生物合成的生物学分析和数学建模。

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摘要

To elucidate the systems biology of the model organism, Escherichia coli, mathematical models to simulate carbon flow through the pathways of central metabolism, and pyruvate and aspartate family amino acid biosynthesis are developed. A "bottom-up" approach is elected to incorporate detailed enzyme kinetic and pathway-specific regulatory mechanisms from experimental data into the models. To achieve this goal, kMech and Cellerator packages in Mathematica(TM) are used to automatically convert models for enzyme mechanisms and regulation patterns into association-dissociation reactions, and then into differential equations. These equations are solved by Mathematica(TM) to simulate each model and to generate graphical outputs. In addition to simplifying the underlining mathematics of writing differential equations, this approach allows the examination of the biochemical behavior of metabolites and enzyme states in the pathway with great detail.; Models to simulate the behavior of more complex enzymes in an overall simulation of central metabolic and amino acid biosynthesis pathways also are described. A more flexible model in Cellerator, which generalizes the Monod, Wyman, Changeux (MWC) model for enzyme allosteric regulation is used to allow for multiple substrate, activator and inhibitor binding sites. This model expands the ability to simulate the behavior of allosteric enzymes and their feedback inhibition mechanisms and allows the generation of a more accurate simulation of allosteric effects in biosynthetic pathways. A random steady state model is used to describe catalysis by large enzyme complexes such as pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in the TCA cycle. This model incorporates the rate of the overall cycles of reactions in the complex with the random nature of the structural organization of component enzymes.; To verify the simulations and models for enzyme mechanisms, the models' behavior is tested under conditions of metabolic and genetic perturbations, and the results are compared with experimental data from the literature. The overall effect of cellular growth on an alternative carbon source such as acetate on the central pathways of metabolism and how well this shift correlates with the simulations is also explored. In all cases, the simulations are consistent with experimental results and data in the literature.
机译：为了阐明模型生物大肠杆菌的系统生物学，开发了模拟碳通过中枢代谢途径流动以及丙酮酸和天冬氨酸家族氨基酸生物合成的数学模型。选择了一种“自下而上”的方法，将来自实验数据的详细酶动力学和特定于途径的调节机制纳入模型。为了实现该目标，使用Mathematica（TM）中的kMech和Cellerator程序包将酶机制和调控模式的模型自动转换为缔合-解离反应，然后转换为微分方程。这些方程由Mathematica（TM）求解，以模拟每个模型并生成图形输出。除了简化编写微分方程的基本数学外，这种方法还可以更详细地检查通路中代谢物和酶态的生化行为。还描述了在中央代谢和氨基酸生物合成途径的整体模拟中模拟更复杂酶的行为的模型。在Cellerator中，一种更灵活的模型适用于酶变构调节的一般化Monod，Wyman，Changeux（MWC）模型，可用于多个底物，激活剂和抑制剂结合位点。该模型扩展了模拟变构酶行为及其反馈抑制机制的能力，并允许在生物合成途径中生成更精确的变构效应模拟。在TCA循环中，使用随机稳态模型描述大型酶复合物（例如丙酮酸脱氢酶和α-酮戊二酸脱氢酶）的催化作用。该模型将复合物中反应总循环的速率与组分酶结构组织的随机性质结合在一起。为了验证酶机制的仿真和模型，在代谢和遗传扰动的条件下测试了模型的行为，并将结果与​​文献中的实验数据进行了比较。还探讨了细胞生长对替代碳源（例如乙酸盐）在代谢的主要途径上的总体影响以及这种变化与模拟的相关程度。在所有情况下，仿真结果均与实验结果和文献数据一致。

著录项

  • 作者

    Najdi, Tarek Samih.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Biology Molecular.; Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 132 p.
  • 总页数 132
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;微生物学;
  • 关键词

  • 入库时间 2022-08-17 11:39:02

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