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Coordination of microbial metabolism

Key Points

  • All microorganisms have to coordinate common metabolic tasks, such as gathering nutrients, generating energy and synthesizing biomass.

  • Many different local regulators coordinate fluxes via individual metabolic pathways.

  • Global regulators report on the status of large metabolic modules.

  • Many metabolites that are positioned at key metabolic intersections have conserved their regulatory roles across vastly divergent species.

  • Whereas the molecular implementation of the regulatory circuits differs greatly among species, the logic by which they sense the metabolic state and coordinate the response to perturbations is typically conserved.

  • Deciphering regulatory circuits that rely on global metabolites enables intuitive understanding and monitoring of cellular decision-making processes.

Abstract

Beyond fuelling cellular activities with building blocks and energy, metabolism also integrates environmental conditions into intracellular signals. The underlying regulatory network is complex and multifaceted: it ranges from slow interactions, such as changing gene expression, to rapid ones, such as the modulation of protein activity via post-translational modification or the allosteric binding of small molecules. In this Review, we outline the coordination of common metabolic tasks, including nutrient uptake, central metabolism, the generation of energy, the supply of amino acids and protein synthesis. Increasingly, a set of key metabolites is recognized to control individual regulatory circuits, which carry out specific functions of information input and regulatory output. Such a modular view of microbial metabolism facilitates an intuitive understanding of the molecular mechanisms that underlie cellular decision making.

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Figure 1: Metabolic tasks and the regulation of metabolic fluxes.
Figure 2: Regulatory circuits that control carbon and energy metabolism in Escherichia coli.
Figure 3: Regulatory circuits that control nitrogen metabolism, amino acid metabolism and protein biosynthesis in Escherichia coli.
Figure 4: The high-level logic of Escherichia coli metabolic regulation.

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Acknowledgements

Partial financial support was provided by the YeastX project of the Swiss initiative for Systems Bbiology (see further information), evaluated by the Swiss National Science Foundation.

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Glossary

Regulatory circuits

Sets of molecular interactions that have defined information inputs and regulatory outputs.

Metabolic fluxes

The in vivo rates of metabolic reactions (or a series of consecutive reactions).

Central carbon metabolism

A core network of about 50 enzymatic reactions that convert carbon nutrients into 'building blocks'.

Regulatory logic

The mapping between the input and output of a regulatory circuit; its characterization can range from signs of interactions to the quantification of governing parameters.

Positive-feedback loop

A circuit in which a molecule induces its own production and/or represses its own consumption.

Diauxic growth

The strictly sequential consumption of carbon sources, typically with intermittent adaptation phases.

Catabolite repression

The reduction of alternative nutrient uptake as a result of the presence of a preferred nutrient.

Phosphotransferase system

(PTS). A common bacterial uptake system for sugars, with concomitant phosphorylation in which phosphoenolpyruvate (PEP) is the phosphate donor.

Inducer exclusion

The allosteric inhibition of alternative carbon transporters by the phosphotransferase system in the presence of glucose.

Catabolism

The degradation of complex molecules, such as nutrients, leading to the release of energy.

Anabolism

The energy-dependent formation of building blocks and macromolecules in a cell.

Negative-feedback loop

A circuit in which a molecule represses its own production and/or induces its own consumption.

Allosteric regulation

Regulation of protein activity by remote-site covalent protein modifications (for example, phosphorylation or acetylation) or non-covalent interactions with effector ligands, which change the functional site by the propagation of subtle conformational changes.

Glycolysis

The degradation of sugars to pyruvate, which results in the generation of ATP by substrate phosphorylation reactions.

Gluconeogenesis

The energy-dependent formation of sugars from trioses such as pyruvate.

Energy charge

A measure of the fraction of nucleotide pools in energetically charged (di- and tri-phosphate) states.

Transcriptional attenuators

RNA structures that cause transcriptional termination only in the presence of a metabolic end-product, such as an amino acid.

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Chubukov, V., Gerosa, L., Kochanowski, K. et al. Coordination of microbial metabolism. Nat Rev Microbiol 12, 327–340 (2014). https://doi.org/10.1038/nrmicro3238

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