The steady flow of metabolites through the living cell is accomplished by a complex interaction between many metabolic pathways. These interactions must be closely regulated to guarantee balanced growth of the cell. Regulation occurs on a variety of levels including gene expression, feedback inhibition and regulation of both metabolite pool sizes and their ratios. This regulation reflects the environmental stimuli affecting the cell. One such stimulus that is particularly relevant to this work is the amount of molecular oxygen available. I have uncovered a novel, anaerobically induced pathway for synthesis of the pryimidine moiety of thiamine (vitamin B1) in Salmonella typhimurium. This pathway is designated alternative pyrimidine biosynthesis or apb. The apb pathway appears to be required for synthesis of the pyrimidine moiety of thaimine in wild-type cells during anaerobic growth in medium containing high levels of purines. It is plausible that these growth conditions reflect those found by S. typhimurium in its natural habitat of the gut. Vitamin B1 is an essential vitamin required for both biosynthesis and energy generation. The biosynthesis of this vitamin has been studied in the past, however, many aspects of this pathway remain unexplored. S. typhimurium is a facultative anaerobe with a well established genetic system that we can use to explore the apb pathway which is clearly physiologically relevant to the anaerobic lifestyle of Salmonella typhimurium. We are interested not only in the apb pathway per se but also in the interactions it may have with other metabolic pathways both aerobically and anaerobically. A comprehensive study on the biochemical and genetic components of the apb pathway will be initiated. For this purpose modern chemical, biochemical, molecular biological and genetic techniques will be employed. This encompassing approach will allow us to gain insight in a number of areas related to this problem, such as: the metabolic origin of the atoms in the pyrimidine synthesized through the apb pathway, the number of gene products involves, the regulation of gene expression of this pathway at different levels and in the long run, to unravel the interactions between this and other pathways. We believe that the investigation of this pathway will contribute to our understanding of the global metabolic strategies that S. typhimurium uses to survive in its natural anaerobic environment by utilizing redundant pathways which are regulated differentially. In addition these studies will further our knowledge of genes whose expression is regulated by oxygen.
Showing the most recent 10 out of 71 publications
