Review
Regulatory crosstalk of the metabolic network

https://doi.org/10.1016/j.tibs.2009.12.001Get rights and content

The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.

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

References (74)

  • S. Mazurek

    Pyruvate kinase type M2 and its role in tumor growth and spreading

    Semin. Cancer Biol.

    (2005)
  • D. Bakowski et al.

    Regulation of store-operated calcium channels by the intermediary metabolite pyruvic acid

    Curr. Biol.

    (2007)
  • A. Yalcin

    Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer

    Exp. Mol. Pathol.

    (2009)
  • C. Godon

    The H2O2 stimulon in Saccharomyces cerevisiae

    J. Biol. Chem.

    (1998)
  • A. Wagner

    Robustness and Evolvability in Living Systems

    (2005)
  • J.R. Beckwith et al.

    The Lactose Operon

    (1970)
  • K.R. Patil et al.

    Uncovering transcriptional regulation of metabolism by using metabolic network topology

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • T. Cakir

    Integration of metabolome data with metabolic networks reveals reporter reactions

    Mol. Syst. Biol.

    (2006)
  • E. Ravasz

    Hierarchical organization of modularity in metabolic networks

    Science

    (2002)
  • S.S. Shen-Orr

    Network motifs in the transcriptional regulation network of Escherichia coli

    Nat. Genet.

    (2002)
  • A. Kreimer

    The evolution of modularity in bacterial metabolic networks

    Proc. Natl. Acad. Sci. U. S. A.

    (2008)
  • I.M. De La Fuente

    Global self-organization of the cellular metabolic structure

    PLoS One

    (2008)
  • C.J. Marx

    Flux analysis uncovers key role of functional redundancy in formaldehyde metabolism

    PLoS Biol.

    (2005)
  • N. Kashtan

    Varying environments can speed up evolution

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • M. Parter

    Environmental variability and modularity of bacterial metabolic networks

    BMC Evol. Biol.

    (2007)
  • L.M. Blank

    Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast

    Genome Biol.

    (2005)
  • N. Ishii

    Multiple high-throughput analyses monitor the response of E. coli to perturbations

    Science

    (2007)
  • L. Kuepfer

    Metabolic functions of duplicate genes in Saccharomyces cerevisiae

    Genome Res.

    (2005)
  • M.E. Hillenmeyer

    The chemical genomic portrait of yeast: uncovering a phenotype for all genes

    Science

    (2008)
  • P. Daran-Lapujade

    The fluxes through glycolytic enzymes in Saccharomyces cerevisiae are predominantly regulated at posttranscriptional levels

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • M.J. Brauer

    Homeostatic adjustment and metabolic remodeling in glucose-limited yeast cultures

    Mol. Biol. Cell

    (2005)
  • K.F. Jensen et al.

    Metabolic growth rate control in Escherichia coli may be a consequence of subsaturation of the macromolecular biosynthetic apparatus with substrates and catalytic components

    Microbiol. Rev.

    (1990)
  • J.I. Castrillo

    Growth control of the eukaryote cell: a systems biology study in yeast

    J. Biol.

    (2007)
  • M. Ralser

    Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response

    Nat. Biotechnol.

    (2009)
  • G.R. Steinberg et al.

    AMPK in Health and Disease

    Physiol. Rev.

    (2009)
  • G. Heeren

    The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back-signaling via TOR1

    Aging

    (2009)
  • D.N. Wilson et al.

    The weird and wonderful world of bacterial ribosome regulation

    Crit. Rev. Biochem. Mol. Biol.

    (2007)
  • Cited by (89)

    • Chemical reaction network decomposition technique for stability analysis

      2022, Automatica
      Citation Excerpt :

      They mainly use the information of the small parts to infer the properties of the large network synthesized by these parts. In particular, these contributions will promote the research on cross-talk (Decraene, Mitchell, & Mcmullin, 2009; Gruning, Lehrach, & Ralser, 2010; Lopezotin & Hunter, 2010), which refers to the situation where two or more signaling pathways with the same components affect each other, and shows great potential applications in medicine. The remaining part of the paper proceeds as follows.

    View all citing articles on Scopus
    View full text