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J. Biol. Chem., Vol. 281, Issue 35, 25097-25109, September 1, 2006

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Regulation of Glutamine and Glutamate Metabolism by GlnR and GlnA in Streptococcus pneumoniae^*

Tomas G. Kloosterman¹, Wouter T. Hendriksen, Jetta J. E. Bijlsma¹, Hester J. Bootsma^¶1, Sacha A. F. T. van Hijum, Jan Kok, Peter W. M. Hermans^¶, and Oscar P. Kuipers²

From the Department of Molecular Genetics, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, P.O. Box 14, 9750 AA Haren, The Netherlands, the Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, 3000 DR Rotterdam, The Netherlands, and the ^¶Department of Pediatrics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands

Several genes involved in nitrogen metabolism are known to contribute to the virulence of pathogenic bacteria. Here, we studied the function of the nitrogen regulatory protein GlnR in the Gram-positive human pathogen Streptococcus pneumoniae. We demonstrate that GlnR mediates transcriptional repression of genes involved in glutamine synthesis and uptake (glnA and glnPQ), glutamate synthesis (gdhA), and the gene encoding the pentose phosphate pathway enzyme Zwf, which forms an operon with glnPQ. Moreover, the expression of gdhA is also repressed by the pleiotropic regulator CodY. The GlnR-dependent regulation occurs through a conserved operator sequence and is responsive to the concentration of glutamate, glutamine, and ammonium in the growth medium. By means of in vitro binding studies and transcriptional analyses, we show that the regulatory function of GlnR is dependent on GlnA. Mutants of glnA and glnP displayed significantly reduced adhesion to Detroit 562 human pharyngeal epithelial cells, suggesting a role for these genes in the colonization of the host by S. pneumoniae. Thus, our results provide a thorough insight into the regulation of glutamine and glutamate metabolism of S. pneumoniae mediated by both GlnR and GlnA.

Received for publication, February 22, 2006 , and in revised form, June 16, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Innovatie-gericht Onderzoeks Programma (IOP) Grant IGE03002.

² To whom correspondence should be addressed. Tel.: 31-50-363-2093; Fax: 31-50-363-2348; E-mail: o.p.kuipers{at}rug.nl.

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