Dissecting the nitrogen regulation system of streptomycetes

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This grant seeks to elucidate the mechanisms whereby streptomycetes respond to the availability of fixed nitrogen compounds in their environment and thereby control those metabolic pathways that are related to nitrogen metabolism. These processes relate both to the primary metabolism (synthesis and catabolism) of nitrogen compounds and to the control of synthesis of secondary metabolites. Whilst a number of nitrogen control proteins have been identified in streptomycetes, their interactions and the signal transduction pathways that regulate their expression or activities are unknown. Furthermore although synthesis of many antibiotics, is regulated by nitrogen sources in the growth medium, the links between nitrogen control and secondary metabolite synthesis are not understood. We will use Streptomyces venezuelae as our model system owing to its dispersed and rapid growth in liquid culture. The S. venezuelae genome sequence is complete and we will use transcriptomics to determine the spectrum of nitrogen-controlled genes and proteomic analysis to examine the role of covalent modification in responding rapidly to nitrogen nutritional shifts. Previous data from studies in S. coelicolor and in other bacteria suggest that the GlnR, GlnRII, GlnK and AmtB proteins are likely to be major components of the nitrogen control system. We will combine our transcriptomic and proteomic studies with analysis of mutants of the structural genes for each of these proteins to determine the roles of each of these potentially key components. In particular we will seek to identify the major targets for regulation by GlnK and to dissect the way in which the activities of GlnR and GlnRII are controlled. Finally we will study the regulation of two well understood secondary metabolite pathways, those for chloramphenicol and actinorhodin production, to investigate the links between nitrogen control and the synthesis of these antibiotics.

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