Interactive Regulatory Networks Controlling Metabolic Adjustments in de novo Pyrimidine Biosynthesis

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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.