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J. Biol. Chem., Vol. 283, Issue 8, 5148-5157, February 22, 2008

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Determination of the Escherichia coli S-Nitrosoglutathione Response Network Using Integrated Biochemical and Systems Analysis^*

From the Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095

During infection or denitrification, bacteria encounter reactive nitrogen species. Although the molecular targets of and defensive response against nitric oxide (NO) in Escherichia coli are well studied, the response elements specific to S-nitrosothiols are less clear. Previously, we employed an integrated systems biology approach to unravel the E. coli NO-response network. Here we use a similar approach to confirm that S-nitrosoglutathione (GSNO) primarily impacts the metabolic and regulatory programs of E. coli in minimal medium by reaction with homocysteine and cysteine and subsequent disruption of the methionine biosynthesis pathway. Targeting of homocysteine and cysteine results in altered regulatory activity of MetJ, MetR, and CysB, activation of the stringent response and growth inhibition. Deletion of metJ or supplementation with methionine strongly attenuated the effect of GSNO on growth and gene expression. Furthermore, GSNO inhibited the ArcAB two-component system. Consistent with the underlying nitrosative and thiol-oxidative chemistry, growth inhibition and the majority of the regulatory perturbations were dependent upon GSNO internalization by the Dpp dipeptide transporter. Contrastingly, perturbation of NsrR appeared to be a result of the submicromolar levels of NO released from GSNO and did not require GSNO internalization.

Received for publication, July 23, 2007 , and in revised form, December 10, 2007.

^* This work was supported in part by National Institutes of Health Grant NIH Grant # 1R01GM076143, National Science Foundation Grant CCF-0326605, and the University of California, Los Angeles (UCLA), Department of Energy Institute of Genomics and Proteomics. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S4.

¹ Both authors contributed equally to this work.

² Supported in part by the UCLA Chancellor's Dissertation Year Fellowship.

³ Supported in part by UCLA-National Science Foundation/Integrative Graduate Education and Research Trainseeship Program Award DGE-9987641.

⁴ To whom correspondence should be addressed: 5531 Boelter Hall, 420 Westwood Plaza, Los Angeles, CA 90095. E-mail: liaoj{at}ucla.edu.

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