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Journal of Bacteriology, September 2008, p. 6178-6187, Vol. 190, No. 18
0021-9193/08/$08.00+0     doi:10.1128/JB.00552-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CcpN Controls Central Carbon Fluxes in Bacillus subtilis ^,

Simon Tännler,^1, Eliane Fischer,^1, Dominique Le Coq,^2,3,4 Thierry Doan,^2,3,4 Emmanuel Jamet,^2,3,4 Uwe Sauer,¹ and Stéphane Aymerich^2,3,4*

Institute of Molecular Systems Biology, ETH Zurich, CH-8093 Zurich, Switzerland,¹ INRA, UMR1238,² CNRS, UMR2585,³ AgroParisTech, Microbiologie et Génétique Moléculaire, F-78850 Thiverval-Grignon, France⁴

Received 22 April 2008/ Accepted 20 June 2008

The transcriptional regulator CcpN of Bacillus subtilis has been recently characterized as a repressor of two gluconeogenic genes, gapB and pckA, and of a small noncoding regulatory RNA, sr1, involved in arginine catabolism. Deletion of ccpN impairs growth on glucose and strongly alters the distribution of intracellular fluxes, rerouting the main glucose catabolism from glycolysis to the pentose phosphate (PP) pathway. Using transcriptome analysis, we show that during growth on glucose, gapB and pckA are the only protein-coding genes directly repressed by CcpN. By quantifying intracellular fluxes in deletion mutants, we demonstrate that derepression of pckA under glycolytic condition causes the growth defect observed in the ccpN mutant due to extensive futile cycling through the pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and pyruvate kinase. Beyond ATP dissipation via this cycle, PckA activity causes a drain on tricarboxylic acid cycle intermediates, which we show to be the main reason for the reduced growth of a ccpN mutant. The high flux through the PP pathway in the ccpN mutant is modulated by the flux through the alternative glyceraldehyde-3-phosphate dehydrogenases, GapA and GapB. Strongly increased concentrations of intermediates in upper glycolysis indicate that GapB overexpression causes a metabolic jamming of this pathway and, consequently, increases the relative flux through the PP pathway. In contrast, derepression of sr1, the third known target of CcpN, plays only a marginal role in ccpN mutant phenotypes.

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* Corresponding author. Mailing address: MGM, INRA-CNRS-AgroParisTech, F-78850 Thiverval-Grignon, France. Phone: 33 1 30 81 54 49. Fax: 33 1 30 81 54 57. E-mail: stephane.aymerich{at}grignon.inra.fr

Published ahead of print on 27 June 2008.

Supplemental material for this article may be found at http://jb.asm.org/.

S.T. and E.F. contributed equally to this study.

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Journal of Bacteriology, September 2008, p. 6178-6187, Vol. 190, No. 18
0021-9193/08/$08.00+0     doi:10.1128/JB.00552-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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