The Chemical Engineering Department is hosting a special graduate seminar on the regulation of metabolic flux by small molecules.
Metabolism is precisely coordinated around the goal of balancing fluxes to maintain robust growth. Hierarchical regulatory mechanisms for controlling metabolic fluxes, from transcriptional regulation of genes to direct modulation of enzyme activity by small-molecule regulation (SMR) have evolved to achieve this goal. While SMR is ubiquitous in metabolism, the organizational principles of the networks formed by SMR interactions and their generalized role in metabolic coordination is not well understood. Questions such as which metabolites are optimal regulators, which reactions are optimal targets of regulation, and what information is communicated via this form of regulation remain open. Systemic answers to these questions are required for forward engineering of metabolic systems. In this seminar, multi-omics and thermodynamic data from Escherichia coli and Saccharomyces cerevisiae are used to develop the hypothesis that substrates of thermodynamicall unfavourable reactions in metabolism are optimal regulators, because they carry information about upstream flux. A novel reconstruction of the genome-scale E.coli SMR network (SMRN) is then used to show that small-molecule regulators are most often substrates of at least one thermodynamically unfavourable reaction among multiple consumption pathways. Explanatory models of feedforward regulation are developed to demonstrate that such substrates optimally maintain metabolic control across steady states by ensuring that information about upstream flux is preserved and can therefore be used for such control. Finally the relevance of SMR to the stability of metabolic cycles is explored, with implications for the rational engineering of such cycles.
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