The biosynthesis of glutamate lies at the intersection of carbon and nitrogen metabolism, linking the Krebs citric acid cycle to nitrogen assimilation through glutamine synthetase. In Bacillus subtilis, the genes for glutamate synthesis and for the pathways leading to the precursors of glutamate are tightly regulated by a host of proteins that respond to a variety of metabolic signals. The long-term goal of this project is to unravel and understand the network of genes, enzymes, and regulatory proteins that allow the cell to maintain tight control over glutamate accumulation. Building on knowledge gained from previous work, this proposal aims to focus on the roles of two of these regulatory proteins, CcpC and GItC. Two aspects of CcpC function will be investigated: interaction with the inducer, citrate, and the role of multimerization in repression. For GItC, the metabolite or protein that regulates its activity will be identified, in addition, the broad role of GltC in gene regulation and its functional interaction with other regulatory proteins will be explored. One of the Krebs cycle enzymes, aconitase, may have a second, non-enzymatic activity, perhaps as an RNA binding protein. The putative secondary activity of aconitase will be tested by seeking targets of such a function and by creating mutants that retain enzymatic activity but have lost the non-enzymatic activity. The implications of this second activity for sporulation in B. subtilis will receive particular attention. Since B. subtilis is a model organism for the gram-positive branch of the bacterial world, the knowledge gained here will be applied to a related, pathogenic species, Listeria monocytogenes. Thus, this proposal seeks to take advantage of the apparent conservation of regulatory proteins, gene organization and regulatory sites between B. subtilis and L. monocytogenes and thereby make rapid progress in an unexplored aspect of the life of an important pathogen. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Program Officer
Anderson, James J
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Tufts University
Schools of Medicine
United States
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Mittal, Meghna; Pechter, Kieran B; Picossi, Silvia et al. (2013) Dual role of CcpC protein in regulation of aconitase gene expression in Listeria monocytogenes and Bacillus subtilis. Microbiology 159:68-76
Pechter, Kieran B; Meyer, Frederik M; Serio, Alisa W et al. (2013) Two roles for aconitase in the regulation of tricarboxylic acid branch gene expression in Bacillus subtilis. J Bacteriol 195:1525-37
Moses, Susanne; Sinner, Tatjana; Zaprasis, Adrienne et al. (2012) Proline utilization by Bacillus subtilis: uptake and catabolism. J Bacteriol 194:745-58
Belitsky, Boris R (2011) Indirect repression by Bacillus subtilis CodY via displacement of the activator of the proline utilization operon. J Mol Biol 413:321-36
Mittal, Meghna; Picossi, Silvia; Sonenshein, Abraham L (2009) CcpC-dependent regulation of citrate synthase gene expression in Listeria monocytogenes. J Bacteriol 191:862-72
Picossi, Silvia; Belitsky, Boris R; Sonenshein, Abraham L (2007) Molecular mechanism of the regulation of Bacillus subtilis gltAB expression by GltC. J Mol Biol 365:1298-313
Sonenshein, Abraham L (2007) Control of key metabolic intersections in Bacillus subtilis. Nat Rev Microbiol 5:917-27
Kim, Hyun-Jin; Mittal, Meghna; Sonenshein, Abraham L (2006) CcpC-dependent regulation of citB and lmo0847 in Listeria monocytogenes. J Bacteriol 188:179-90
Serio, Alisa W; Pechter, Kieran B; Sonenshein, Abraham L (2006) Bacillus subtilis aconitase is required for efficient late-sporulation gene expression. J Bacteriol 188:6396-405
Serio, Alisa W; Sonenshein, Abraham L (2006) Expression of yeast mitochondrial aconitase in Bacillus subtilis. J Bacteriol 188:6406-10

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