EXCEED THE SPACE PROVIDED. The long-term goal of this project is to understand the mechanisms that regulate bacterial membrane lipid biosynthesis and explore the structure, function and diversity of the enzymes involved in this pathway. The study of Escherichia collhas historically served as the paradigm for bacterial lipid metabolism. The evolution of lipid biosynthesis as a focal point for the development of novel therapeutics and the availability of a wealth of genomic sequences has stimulated our exploration of these pathways in important pathogens. The discovery of two novel reductases, two new pathways for unsaturated fatty acid synthesis and two new transcriptional regulators during the last grant period highlights the importance of this avenue of research. Our multidisciplinary attack on this important problem will incorporate biochemistry, genetics, bioinformatics, chemical biology and structural biology into all facets of the research. The research plan builds on the important discoveries made during the last grant period and is organized into two broad subject areas. The first theme is global control of fatty acid synthesis and bacterial diversity. This will focus on the understanding the transcriptional regulation of gene expression of the fatty acid biosynthetic genes. The jumping off point for this work will be to follow our discovery of the FabR transcription factor in the E. coli model organism and the FabT factor in S. pneumoniae. Of particular importance will be to identify the ligands that control the DMA binding activity of the factors. The second theme is regulation and mechanism of individual fatty acid biosynthetic enzymes. The work in this section will focus on the detailed understanding of the structure, mechanism and regulation of the individual pathway enzymes. Of particular interest will be the elongation class of condensing enzymes since these proteins catalyze a unique Claison condensation reaction and have been clearly validated as important targets for antibacterial drug discovery. We will also emphasize FabG in order to understand the role of the large conformational changes that occur during catalysis in regulating its activity and to determine if this essential and widely-expressed protein is a suitable target for drug discovery. The results of these investigations will provide important new information on the structure, function, diversity and regulation of fatty acid biosynthesis that will contribute to the basic understanding of bacterial physiology and complement the development of novel antibacterial therapeutics.
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