Integrated network analysis identifies nitric oxide response networks and dihydroxyacid dehydratase as a crucial target in Escherichia coli

Edited by Susan Gottesman, National Institutes of Health, Bethesda, MD, and approved March 26, 2007
May 15, 2007
104 (20) 8484-8489

Abstract

Nitric oxide (NO) is used by mammalian immune systems to counter microbial invasions and is produced by bacteria during denitrification. As a defense, microorganisms possess a complex network to cope with NO. Here we report a combined transcriptomic, chemical, and phenotypic approach to identify direct NO targets and construct the biochemical response network. In particular, network component analysis was used to identify transcription factors that are perturbed by NO. Such information was screened with potential NO reaction mechanisms and phenotypic data from genetic knockouts to identify active chemistry and direct NO targets in Escherichia coli. This approach identified the comprehensive E. coli NO response network and evinced that NO halts bacterial growth via inhibition of the branched-chain amino acid biosynthesis enzyme dihydroxyacid dehydratase. Because mammals do not synthesize branched-chain amino acids, inhibition of dihydroxyacid dehydratase may have served to foster the role of NO in the immune arsenal.

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Acknowledgments

We thank Jon M. Fukuto for insightful discussions during the course of this work and assistance in preparing the 2,3-dihydroxyisovalerate and Alice Lee for assistance with experimental analysis. This work was supported by National Institutes of Health Grant 2R01HL065741, National Science Foundation Grant CCF-0326605, and the University of California, Los Angeles (UCLA)–Department of Energy Institute of Genomics and Proteomics. L.M.T. was supported in part by UCLA–National Science Foundation/Integrative Graduate Education and Research Traineeship Program Award DGE-9987641. L.R.J. was supported in part by the UCLA Chancellor's Dissertation Year Fellowship.

Supporting Information

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 104 | No. 20
May 15, 2007
PubMed: 17494765

Classifications

Submission history

Received: December 7, 2006
Published online: May 15, 2007
Published in issue: May 15, 2007

Keywords

  1. systems biology
  2. chemoinformatics

Acknowledgments

We thank Jon M. Fukuto for insightful discussions during the course of this work and assistance in preparing the 2,3-dihydroxyisovalerate and Alice Lee for assistance with experimental analysis. This work was supported by National Institutes of Health Grant 2R01HL065741, National Science Foundation Grant CCF-0326605, and the University of California, Los Angeles (UCLA)–Department of Energy Institute of Genomics and Proteomics. L.M.T. was supported in part by UCLA–National Science Foundation/Integrative Graduate Education and Research Traineeship Program Award DGE-9987641. L.R.J. was supported in part by the UCLA Chancellor's Dissertation Year Fellowship.

Notes

This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0610888104/DC1.

Authors

Affiliations

Daniel R. Hyduke
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095
Laura R. Jarboe
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095
Linh M. Tran
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095
Katherine J. Y. Chou
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095
James C. Liao [email protected]
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095

Notes

*To whom correspondence should be addressed at: 5531 Boelter Hall, 420 Westwood Plaza, Los Angeles, CA 90095. E-mail: [email protected]
Author contributions: D.R.H. and L.R.J. contributed equally to this work; D.R.H., L.R.J., and J.C.L. designed research; D.R.H., L.R.J., K.J.Y.C., and J.C.L. performed research; D.R.H., L.R.J., L.M.T., and J.C.L. analyzed data; and D.R.H., L.R.J., and J.C.L. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Integrated network analysis identifies nitric oxide response networks and dihydroxyacid dehydratase as a crucial target in Escherichia coli
    Proceedings of the National Academy of Sciences
    • Vol. 104
    • No. 20
    • pp. 8197-8561

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