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Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off Between Regulation and Enzymatic Activity

51 Pages Posted: 13 Apr 2018 Sneak Peek Status: Published

See all articles by Ed Reznik

Ed Reznik

Memorial Sloan Kettering Cancer Center - Marie-Josée and Henry R. Kravis Center for Molecular Oncology

Dimitris Christodoulou

ETH Zurich - Institute of Molecular Systems Biology (IMSB); ETH Zurich - Interdisciplinary PhD Program Systems Biology

Joshua E. Goldford

Boston University - Bioinformatics Programs

Emma Briars

Boston University - Bioinformatics Programs

Uwe Sauer

ETH Zurich - Institute of Molecular Systems Biology (IMSB)

Daniel Segrè

Boston University - Bioinformatics Programs; Boston University - Department of Biology; Boston University - Department of Biomedical Engineering

Elad Noor

ETH Zurich - Institute of Molecular Systems Biology (IMSB)

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Abstract

Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g. allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical difficulties have hindered the production of a genome-scale atlas of small molecule/enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. Generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.

Suggested Citation

Reznik, Ed and Christodoulou, Dimitris and Goldford, Joshua E. and Briars, Emma and Sauer, Uwe and Segrè, Daniel and Noor, Elad, Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off Between Regulation and Enzymatic Activity (2018). Available at SSRN: https://ssrn.com/abstract=3155788 or http://dx.doi.org/10.2139/ssrn.3155788
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ed Reznik

Memorial Sloan Kettering Cancer Center - Marie-Josée and Henry R. Kravis Center for Molecular Oncology ( email )

1275 York Avenue
New York, NY 10065
United States

Dimitris Christodoulou

ETH Zurich - Institute of Molecular Systems Biology (IMSB)

Building HPT
Auguste-Piccard-Hof 1
Zürich, 8093
Switzerland

ETH Zurich - Interdisciplinary PhD Program Systems Biology

Zürich, 8092
Switzerland

Joshua E. Goldford

Boston University - Bioinformatics Programs

Boston, MA 02215
United States

Emma Briars

Boston University - Bioinformatics Programs

Boston, MA 02215
United States

Uwe Sauer

ETH Zurich - Institute of Molecular Systems Biology (IMSB)

Building HPT
Auguste-Piccard-Hof 1
Zürich, 8093
Switzerland

Daniel Segrè

Boston University - Bioinformatics Programs

Boston, MA 02215
United States

Boston University - Department of Biology

United States

Boston University - Department of Biomedical Engineering

595 Commonwealth Avenue
Boston, MA 02215
United States

Elad Noor (Contact Author)

ETH Zurich - Institute of Molecular Systems Biology (IMSB) ( email )

Building HPT
Auguste-Piccard-Hof 1
Zürich, 8093
Switzerland

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