Interactive Regulatory Networks Controlling Metabolic Adjustments in de novo Pyrimidine Biosynthesis

9723129 Wild通过对新生生物合成的调节来管理细胞内嘧啶池涉及细胞代谢中最微妙的生理平衡系统之一。虽然维持特定的核苷酸水平以维持RNA合成能力是必要的，但所有的核苷三磷酸池都是相互依赖的，并且需要耗费大量的能量来维持。为了应对这些基本需求，在基因表达和单个酶步骤的变构修饰水平上发展了一个复杂的协同控制网络。然而，正如在其他代谢途径中观察到的那样，对单个调控成分的详细描述并不能充分描述途径（更不用说有机体）水平上的代谢/生长反应。经典的主要调控控制点概念，对于嘧啶途径，传统上被认为是天冬氨酸转甲氨基酰基酶（ATCase），并不能充分预测途径对代谢扰动的反应。然而，丰富的信息和遗传结构的多样性，现在可用于嘧啶途径的大多数单个步骤，为开发其代谢作用的系统级理解铺平了道路。本项目研究了大肠杆菌中嘧啶核苷酸代谢调控的四个具体方面：1)评估精氨酸/嘧啶代谢在介导环境/营养变化反应中的遗传和代谢调控特征。2)整合各种控制过程，遗传和生化，通过体内研究与遗传结构，选择性地修改个别成分；3)生物调控网络分析中的通路建模。鉴于嘧啶生物合成在细胞代谢中的核心作用，以及该途径与其他中心途径的调节关系，从综合生理水平而不是孤立的机械水平来适当理解其调节逻辑是很重要的。核酸是生物体的“信息分子”，因此包含细胞生长和分裂所必需的信息。核酸是由一组较小的成分（核苷酸）构成的，这些成分在所有生物中都是相同的。这些核苷酸分为两类：嘌呤和嘧啶。该项目研究嘧啶核苷酸的生物化学和代谢，其细节对于理解DNA和RNA合成以及基因表达和细胞生长的调控至关重要。关于大肠杆菌嘧啶代谢单个步骤的遗传学和调控的丰富知识使其成为研究这些复杂问题的模型系统。随着知识从简单的细菌系统中获得，应用于真核系统中更复杂和相互交织的途径成为可能。

9723129 Wild The management of intracellular pyrimidine pools via the regulation of de novo biosynthesis involves one of the most delicate physiological balancing systems in cellular metabolism. While it is necessary to maintain specific nucleotide levels in order to sustain RNA synthetic capacity, all of the nucleoside triphosphate pools are interdependent and energetically costly to maintain. In response to these basic needs, there is an intricate, synergistic network of controls which have developed at the level of gene expression and allosteric modification of individual enzymatic steps. However, as has been observed with other metabolic pathways, the detailed description of individual regulatory components does not adequately describe metabolic/growth responses at the pathway (much less organismal) level. The classical concept of a primary regulatory control point, which for the pyrimidine pathway has traditionally been considered to be the aspartate transcarbamylase (ATCase), does not adequately predict pathway responses to metabolic perturbations. However, the wealth of information and the variety of genetic constructs which are now available for most of the individual steps of the pyrimidine pathway have prepared the way for development of a system-level understanding of its metabolic role. This project addresses four specific aspects of the regulation of pyrimidine nucleotide metabolism in Escherichia coli: 1) Evaluation of the genetic and metabolic regulatory features of arginine/pyrimidine metabolism in mediating responses to environmental/nutritional shifts. 2) Integration of the various control processes, genetic and biochemical, through in vivo studies with genetic constructs which selectively modify individual components; leading to 3) Pathway modeling in the analysis of the biological regulatory network. Given the central role that pyrimidine biosynthesis plays in cellular metabolism, and the regulatory relationship of this pathway with other central pathways, an appropriate un derstanding of the regulatory logic at an integrated physiological level rather than an isolated, mechanistic one is important. Nucleic acids are the "informational molecules" of living organisms and as such contain the information necessary for cell growth and division. Nucleic acids are constructed from a set of smaller components (nucleotides) which are identical in all living species. These nucleotides fall into two classes: purines and pyrimidines. This project studies the biochemistry and metabolism of the pyrimidine nucleotides, the details of which are critical for an understanding of DNA and RNA synthesis and regulation of gene expression and cell growth. The wealth of knowledge available on the genetics and regulation of the individual steps in pyrimidine metabolism in the bacterium E. coli makes it a model system for studying these complex issues. As knowledge is gained from the simpler, bacterial systems, application to the more complex and inter-woven pathways of eukaryotic systems becomes possible.