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Science 316 (5824): 593-597

Copyright © 2007 by the American Association for the Advancement of Science

Multiple High-Throughput Analyses Monitor the Response of E. coli to Perturbations

Nobuyoshi Ishii,1,2* Kenji Nakahigashi,1,2* Tomoya Baba,1,2,3* Martin Robert,1,2* Tomoyoshi Soga,1,2,6* Akio Kanai,1,2* Takashi Hirasawa,1,2* Miki Naba,1 Kenta Hirai,1 Aminul Hoque,1,2 Pei Yee Ho,5 Yuji Kakazu,1 Kaori Sugawara,1 Saori Igarashi,1 Satoshi Harada,1 Takeshi Masuda,1,2 Naoyuki Sugiyama,6 Takashi Togashi,1 Miki Hasegawa,1 Yuki Takai,1 Katsuyuki Yugi,1,2 Kazuharu Arakawa,1 Nayuta Iwata,1,2 Yoshihiro Toya,1,2 Yoichi Nakayama,1,2 Takaaki Nishioka,1,2,4 Kazuyuki Shimizu,1,2,5 Hirotada Mori,1,2,3 Masaru Tomita1,2,6{dagger}

Abstract: Analysis of cellular components at multiple levels of biological information can provide valuable functional insights. We performed multiple high-throughput measurements to study the response of Escherichia coli cells to genetic and environmental perturbations. Analysis of metabolic enzyme gene disruptants revealed unexpectedly small changes in messenger RNA and proteins for most disruptants. Overall, metabolite levels were also stable, reflecting the rerouting of fluxes in the metabolic network. In contrast, E. coli actively regulated enzyme levels to maintain a stable metabolic state in response to changes in growth rate. E. coli thus seems to use complementary strategies that result in a metabolic network robust against perturbations.

1 Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan.
2 Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa 252-8520, Japan.
3 Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
4 Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
5 Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka 820-8502, Japan.
6 Human Metabolome Technologies, Inc., Tsuruoka 997-0017, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: mt{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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