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

Publication date: 12 September 2017
Source:Cell Reports, Volume 20, Issue 11
Author(s): Ed Reznik, Dimitris Christodoulou, Joshua E. Goldford, Emma Briars, Uwe Sauer, Daniel Segrè, Elad Noor
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. 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.

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Teaser

Reznik et al. report a computational pipeline for the genome-scale reconstruction of metabolic small molecule regulatory networks. They describe general design principles underlying small molecule regulation, and they prove a fundamental trade-off between the activity of a metabolic enzyme and the extent to which it is regulated.


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