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

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 limitations 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 we combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. By 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.
Authors:
 [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [5] ;  [4]
  1. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Center for Molecular Oncology and Dept. of Epidemiology and Biostatistics; Boston Univ., MA (United States). Dept. of Biomedical Engineering
  2. ETH Zurich, Zurich (Switzerland). Inst. of Molecular Systems Biology and Systems Biology Graduate School
  3. Boston Univ., MA (United States). Bioinformatics Program
  4. ETH Zurich, Zurich (Switzerland). Inst. of Molecular Systems Biology
  5. Boston Univ., MA (United States). Dept. of Biomedical Engineering and Bioinformatics Program and Dept. of Biology
Publication Date:
Grant/Contract Number:
SC0012627; W911NF-12-1-0390; R01GM121950; 1635070; RGP0020/2016; P30 CA008748
Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 20; Journal Issue: 11; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Research Org:
Boston Univ., MA (United States)
Sponsoring Org:
USDOE; Swiss Initiative in Systems Biology (SystemsX.ch); National Institutes of Health (NIH); National Science Foundation (NSF); Human Frontier Science Program (HFSP); Memorial Sloan Kettering Cancer Center, New York, NY (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; small molecule regulation; metabolism; trade-offs; enzyme kinetics; elasticity; regulatory network
OSTI Identifier:
1389689
Alternate Identifier(s):
OSTI ID: 1425649