Trends in Biochemical Sciences
ReviewRegulatory crosstalk of the metabolic network
Section snippets
Evolution of the metabolic network and its structure
Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid- or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.
As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent
The metabolic network is modular and robust
The metabolic network can be subdivided into several small, highly connected functional units, termed metabolic modules 6, 7. Delineation of modular structures is biased by scope and experimental conditions, but genome-scale network reconstructions facilitate the integration of multiple hierarchical layers; they refine module borders 8, 9. Network size markedly determines modular organisation; the larger the network, the greater the modularity [10]. Moreover, modularity is a driving force for
Metabolic modules are connected to regulatory processes
Under steady state conditions of an idealised metabolic network, different interconnected modules operate at varying concentrations and kinetics (Figure 1). When the conditions change, a reconfiguration of the network might be required. For instance, when cells are environmentally deprived of an amino acid, such as leucine, the endogenous synthesis pathway must be activated. The relevant module then undergoes a transition to increase activity. Such metabolic transitions require the cooperation
Reporter metabolites crosstalk with the cellular regulome
Patil and Nielsen identified reporter metabolites based on an enrichment analysis of transcriptional changes; they are nodes balanced by the transcriptome 4, 5. This definition can be extended, as more recent studies show that the metabolic flux is often controlled purely on a post-translational basis 20, 24. The balance of metabolite concentrations requires their constant monitoring by cellular regulatory components. However, differences can be observed, depending on whether the monitored
The importance of self-regulation and transitions in central carbohydrate metabolism
Pathways of central carbohydrate metabolism, glycolysis in particular, are well-studied examples of highly flexible metabolic systems. The intermediates and side reactions of these pathways are involved in a variety of regulatory processes (Figure 5). Feedback regulation has been extensively studied in Bacillus subtilis, which monitors its dextrose supply through fructose-1,6-bisphosphate (F16BP). F16BP levels increase rapidly upon glucose uptake, thereby antagonising a transcriptional
Concluding remarks
In this review, we have highlighted the role of the metabolic network as a fundamental part of the cellular regulome. Its unique modular structure facilitates participation in both system-wide and pathway-specific regulatory processes. Global regulation is often mediated through enzymatic cofactors or general substrates which are responsible for most of the interconnectivity of the metabolic network, whereas specific responses are controlled by specialised intermediates.
Changes in the flux of a
Competing interests
We declare that no competing interests exist.
Acknowledgments
We regret that many important scientific findings could not be discussed in this review. We thank our colleagues for interesting discussions and the Max Planck Society for funding.
Glossary
- Biochemical pathway
- sequence of enzymatic reactions that convert a starting molecule to an end product
- Metabolic flux
- amount/rate of molecules converted through a metabolic pathway
- Metabolic network
- Set and topology of metabolic biochemical reactions within a cell
- Metabolic switch
- enzyme at the boundary between metabolic modules; a change in the activity of the switch redistributes the metabolic flux
- Metabolic transition
- change in a module's activity, or a switch of the flux from one module to another
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