Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Coordination of microbial metabolism

Nature Reviews Microbiology volume 12, pages 327–340 (2014)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Gerosa, L. & Sauer, U. Regulation and control of metabolic fluxes in microbes. Curr. Opin. Biotechnol. 22, 566–575 (2011).

    CAS  PubMed  Google Scholar 

  2. Heinemann, M. & Sauer, U. Systems biology of microbial metabolism. Curr. Opin. Microbiol. 13, 343–337 (2010).

    Google Scholar 

  3. Karr, J. R. et al. A whole-cell computational model predicts phenotype from genotype. Cell 150, 389–401 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wall, M. E., Hlavacek, W. S. & Savageau, M. A. Design of gene circuits: lessons from bacteria. Nature Rev. Genet. 5, 34–42 (2004).

    CAS  PubMed  Google Scholar 

  5. Bochner, B. R., Gadzinski, P. & Panomitros, E. Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res. 11, 1246–1255 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Orth, J. D. et al. A comprehensive genome-scale reconstruction of Escherichia coli metabolism — 2011. Mol. Syst. Biol. 7, 535 (2011).

    PubMed  PubMed Central  Google Scholar 

  7. Mizuno, T. Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res. 4, 161–168 (1997).

    CAS  PubMed  Google Scholar 

  8. Laub, M. T. & Goulian, M. Specificity in two-component signal transduction pathways. Annu. Rev. Genet. 41, 121–145 (2007).

    CAS  PubMed  Google Scholar 

  9. Verhamme, D. T., Arents, J. C., Postma, P. W., Crielaard, W. & Hellingwerf, K. J. Glucose-6-phosphate-dependent phosphoryl flow through the Uhp two-component regulatory system. Microbiology 147, 3345–3352 (2001).

    CAS  PubMed  Google Scholar 

  10. Martinez-Antonio, A., Janga, S. C., Salgado, H. & Collado-Vides, J. Internal-sensing machinery directs the activity of the regulatory network in Escherichia coli. Trends Microbiol. 14, 22–27 (2006).

    CAS  PubMed  Google Scholar 

  11. Jobe, A. & Bourgeois, S. lac repressor–operator interaction: VI. The natural inducer of the lac operon. J. Mol. Biol. 69, 397–408 (1972).

    CAS  PubMed  Google Scholar 

  12. Ulrich, L. E., Koonin, E. V. & Zhulin, I. B. One-component systems dominate signal transduction in prokaryotes. Trends Microbiol. 13, 52–56 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Monod, J. Recherches sur la Croissance des Cultures Bacteriennes (in French) (Hermann, 1958).

    Google Scholar 

  14. Görke, B. & Stülke, J. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nature Rev. Microbiol. 6, 613–624 (2008). This is an excellent review on bacterial catabolite repression and the PTS.

    Google Scholar 

  15. Deutscher, J., Francke, C. & Postma, P. W. How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. Microbiol. Mol. Biol. Rev. 70, 939–1031 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shimada, T., Fujita, N., Yamamoto, K. & Ishihama, A. Novel roles of cAMP receptor protein (CRP) in regulation of transport and metabolism of carbon sources. PLoS ONE 6, e20081 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaplan, S., Bren, A., Zaslaver, A., Dekel, E. & Alon, U. Diverse two-dimensional input functions control bacterial sugar genes. Mol. Cell 29, 786–792 (2008). This paper shows the integration of regulation by Crp and carbon source-specific transcription factors in uptake systems.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bettenbrock, K. et al. Correlation between growth rates, EIIACrr phosphorylation, and intracellular cyclic AMP levels in Escherichia coli K-12. J. Bacteriol. 189, 6891–6900 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hogema, B. M. et al. Inducer exclusion in Escherichia coli by non-PTS substrates: the role of the PEP to pyruvate ratio in determining the phosphorylation state of enzyme IIAGlc. Mol. Microbiol. 30, 487–498 (1998).

    CAS  PubMed  Google Scholar 

  20. You, C. et al. Coordination of bacterial proteome with metabolism by cyclic AMP signalling. Nature 500, 301–306 (2013). This is groundbreaking work that unravels the regulatory logic of Crp-dependent catabolite repression in E. coli.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Goyal, S., Yuan, J., Chen, T., Rabinowitz, J. D. & Wingreen, N. S. Achieving optimal growth through product feedback inhibition in metabolism. PLoS Comput. Biol. 6, e1000802 (2010).

    PubMed  PubMed Central  Google Scholar 

  22. Lorca, G. L. et al. Catabolite repression and activation in Bacillus subtilis: dependency on CcpA, HPr, and HprK. J. Bacteriol. 187, 7826–7839 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Singh, K. D., Schmalisch, M. H., Stülke, J. & Görke, B. Carbon catabolite repression in Bacillus subtilis: quantitative analysis of repression exerted by different carbon sources. J. Bacteriol. 190, 7275–7284 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jault, J.-M. et al. The HPr kinase from Bacillus subtilis is a homo-oligomeric enzyme which exhibits strong positive cooperativity for nucleotide and fructose 1,6-bisphosphate binding. J. Biol. Chem. 275, 1773–1780 (2000).

    CAS  PubMed  Google Scholar 

  25. Chubukov, V. et al. Transcriptional regulation is insufficient to explain substrate-induced flux changes in Bacillus subtilis. Mol. Syst. Biol. 9, 709 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Meijer, M. M. C., Boonstra, J., Verkleij, A. J. & Verrips, C. T. Glucose repression in Saccharomyces cerevisiae is related to the glucose concentration rather than the glucose flux. J. Biol. Chem. 273, 24102–24107 (1998).

    CAS  PubMed  Google Scholar 

  27. Santangelo, G. M. Glucose signaling in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 70, 253–282 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Youk, H. & van Oudenaarden, A. Growth landscape formed by perception and import of glucose in yeast. Nature 462, 875–879 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Levy, S. & Barkai, N. Coordination of gene expression with growth rate: a feedback or a feed-forward strategy? FEBS Lett. 583, 3974–3978 (2009). This paper brings forwards the distinction between feedforward and feedback strategies of growth regulation.

    CAS  PubMed  Google Scholar 

  30. Kochanowski, K., Sauer, U. & Chubukov, V. Somewhat in control — the role of transcription in regulating microbial metabolic fluxes. Curr. Opin. Biotechnol. 24, 987–993 (2013).

    CAS  PubMed  Google Scholar 

  31. Oliveira, A. P. et al. Regulation of yeast central metabolism by enzyme phosphorylation. Mol. Syst. Biol. 8, 623 (2012).

    PubMed  PubMed Central  Google Scholar 

  32. Wang, Q. et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327, 1004–1007 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Link, H., Kochanowski, K. & Sauer, U. Systematic identification of allosteric protein–metabolite interactions that control enzyme activity in vivo. Nature Biotech. 31, 357–361 (2013). This paper outlines an approach to systematically map relevant allosteric interactions.

    CAS  Google Scholar 

  34. Yuan, J., Fowler, W. U., Kimball, E., Lu, W. & Rabinowitz, J. D. Kinetic flux profiling of nitrogen assimilation in Escherichia coli. Nature Chem. Biol. 2, 529–530 (2006).

    CAS  Google Scholar 

  35. Ramseier, T. M. Cra and the control of carbon flux via metabolic pathways. Res. Microbiol. 147, 489–493 (1996).

    CAS  PubMed  Google Scholar 

  36. Shimada, T., Yamamoto, K. & Ishihama, A. Novel members of the Cra regulon involved in carbon metabolism in Escherichia coli. J Bacteriol. 193, 649–659 (2011).

    CAS  PubMed  Google Scholar 

  37. Kochanowski, K. et al. Functioning of a metabolic flux sensor in Escherichia coli. Proc. Natl Acad. Sci. USA 110, 1130–1135 (2013). This study experimentally demonstrates the potential of FBP to report glycolytic flux in E. coli.

    CAS  PubMed  Google Scholar 

  38. Waygood, E. B., Mort, J. S. & Sanwal, B. D. The control of pyruvate kinase of Escherichia coli. Binding of substrate and allosteric effectors to the enzyme activated by fructose 1,6-bisphosphate. Biochemistry 15, 277–282 (1976).

    CAS  PubMed  Google Scholar 

  39. Xu, Y.-F., Amador-Noguez, D., Reaves, M. L., Feng, X.-J. & Rabinowitz, J. D. Ultrasensitive regulation of anapleurosis via allosteric activation of PEP carboxylase. Nature Chem. Biol. 8, 562–568 (2012).

    CAS  Google Scholar 

  40. Baldazzi, V. et al. The carbon assimilation network in Escherichia coli is densely connected and largely sign-determined by directions of metabolic fluxes. PLoS Comput. Biol. 6, e1000812 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. Daniels, B. C., Chen, Y. J., Sethna, J. P., Gutenkunst, R. N. & Myers, C. R. Sloppiness, robustness, and evolvability in systems biology. Curr. Opin. Biotechnol. 19, 389–395 (2008).

    CAS  PubMed  Google Scholar 

  42. Carminatti, H., Asúa, L. J. de, Recondo, E., Passeron, S. & Rozengurt, E. Some kinetic properties of liver pyruvate kinase (Type L). J. Biol. Chem. 243, 3051–3056 (1968).

    CAS  PubMed  Google Scholar 

  43. Jurica, M. S. et al. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 6, 195–210 (1998).

    CAS  PubMed  Google Scholar 

  44. Diesterhaft, M. & Freese, E. Pyruvate kinase of Bacillus subtilis. Biochim. Biophys. Acta 268, 373–380 (1972).

    CAS  PubMed  Google Scholar 

  45. Deutscher, J. et al. Protein kinase-dependent HPr/CcpA interaction links glycolytic activity to carbon catabolite repression in Gram-positive bacteria. Mol. Microbiol. 15, 1049–1053 (1995).

    CAS  PubMed  Google Scholar 

  46. Doan, T. & Aymerich, S. Regulation of the central glycolytic genes in Bacillus subtilis: binding of the repressor CggR to its single DNA target sequence is modulated by fructose-1,6-bisphosphate. Mol. Microbiol. 47, 1709–1721 (2003).

    CAS  PubMed  Google Scholar 

  47. Sauer, U. & Eikmanns, B. J. The PEP–pyruvate–oxaloacetate node as the switch point for carbon flux distribution in bacteria. FEMS Microbiol. Rev. 29, 765–794 (2005).

    CAS  PubMed  Google Scholar 

  48. Christen, S. & Sauer, U. Intracellular characterization of aerobic glucose metabolism in seven yeast species by 13C flux analysis and metabolomics. FEMS Yeast Res. 11, 263–272 (2011).

    CAS  PubMed  Google Scholar 

  49. Huberts, D. H. E. W., Niebel, B. & Heinemann, M. A flux-sensing mechanism could regulate the switch between respiration and fermentation. FEMS Yeast Res. 12, 118–128 (2011).

    PubMed  Google Scholar 

  50. Xu, Y.-F. et al. Regulation of yeast pyruvate kinase by ultrasensitive allostery independent of phosphorylation. Mol. Cell 48, 52–62 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Díaz-Ruiz, R. et al. Mitochondrial oxidative phosphorylation is regulated by fructose 1,6-bisphosphate. A possible role in crabtree effect induction? J. Biol. Chem. 283, 26948–26955 (2008).

    PubMed  Google Scholar 

  52. Brauer, M. J. et al. Conservation of the metabolomic response to starvation across two divergent microbes. Proc. Natl Acad. Sci. USA 103, 19302–19307 (2006).

    CAS  PubMed  Google Scholar 

  53. Voit, E., Neves, A. R. & Santos, H. The intricate side of systems biology. Proc. Natl Acad. Sci. USA 103, 9452–9457 (2006).

    CAS  PubMed  Google Scholar 

  54. Grüning, N.M. et al. Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell. Metab. 14, 415–427 (2011). This paper identifies the regulatory circuit in yeast that is responsible for the allosteric upregulation of NAPDH production in the pentose phosphate pathway following oxidative stress.

    PubMed  PubMed Central  Google Scholar 

  55. Keseler, I. M. et al. EcoCyc: fusing model organism databases with systems biology. Nucleic Acids Res. 41, D605–D612 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. Lorca, G. L. et al. Glyoxylate and pyruvate are antagonistic effectors of the Escherichia coli IclR transcriptional regulator. J. Biol. Chem. 282, 16476–16491 (2007).

    CAS  PubMed  Google Scholar 

  57. Göhler, A.-K. et al. More than just a metabolic regulator — elucidation and validation of new targets of PdhR in Escherichia coli. BMC Syst. Biol. 5, 197 (2011).

    PubMed  PubMed Central  Google Scholar 

  58. Schuetz, R., Kuepfer, L. & Sauer, U. Systematic evaluation of objective functions for predicting intracellular fluxes in Escherichia coli. Mol. Syst. Biol. 3, 119 (2007).

    PubMed  PubMed Central  Google Scholar 

  59. Price, N. D., Reed, J. L. & Palsson, B. Genome-scale models of microbial cells: evaluating the consequences of constraints. Nature Rev. Microbiol. 2, 886–897 (2004).

    CAS  Google Scholar 

  60. Yuan, J. et al. Metabolomics-driven quantitative analysis of ammonia assimilation in E. coli. Mol. Syst. Biol. 5, 302 (2009).

    PubMed  PubMed Central  Google Scholar 

  61. Gallego, O. et al. A systematic screen for protein–lipid interactions in Saccharomyces cerevisiae. Mol. Syst. Biol. 6, 430 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Li, X., Gianoulis, T. A., Yip, K. Y., Gerstein, M. & Snyder, M. Extensive in vivo metabolite–protein interactions revealed by large-scale systematic analyses. Cell 143, 639–50 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Rabinowitz, J. D. et al. Dissecting enzyme regulation by multiple allosteric effectors: nucleotide regulation of aspartate transcarbamoylase. Biochemistry 47, 5881–5888 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gottschalk, G. Bacterial Metabolism (Springer, 1986).

    Google Scholar 

  65. Koebmann, B. J., Westerhoff, H. V., Snoep, J. L., Nilsson, D. & Jensen, P. R. The glycolytic flux in Escherichia coli is controlled by the demand for ATP. J. Bacteriol. 184, 3909 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Holm, A. K. et al. Metabolic and transcriptional response to cofactor perturbations in Escherichia coli. J. Biol. Chem. 285, 17498–17506 (2010). References 65 and 66 provide experimental evidence that glycolysis may be controlled by ATP demand.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mensonides, F. I. C. et al. A new regulatory principle for in vivo biochemistry: pleiotropic low affinity regulation by the adenine nucleotides — illustrated for the glycolytic enzymes of Saccharomyces cerevisiae. FEBS Lett. 587, 2860–2867 (2013).

    CAS  PubMed  Google Scholar 

  68. Kotlarz, D. & Buc, H. Regulatory properties of phosphofructokinase 2 from Escherichia coli. Eur. J. Biochem. 117, 569–574 (1981).

    CAS  PubMed  Google Scholar 

  69. Babul, J. & Guixé, V. Fructose bisphosphatase from Escherichia coli. Purification and characterization. Arch. Biochem. Biophys. 225, 944–949 (1983).

    CAS  PubMed  Google Scholar 

  70. Berg, J. M., Tymoczko, J. L. & Stryer, L. in Biochemistry (W H Freeman, 2002).

    Google Scholar 

  71. Petersen, C. & Møller, L. B. Invariance of the nucleoside triphosphate pools of Escherichia coli with growth rate. J. Biol. Chem. 275, 3931–3935 (2000).

    CAS  PubMed  Google Scholar 

  72. Schneider, D. A. & Gourse, R. L. Relationship between growth rate and ATP concentration in Escherichia coli: a bioassay for available cellular ATP. J. Biol. Chem. 279, 8262–8268 (2004).

    CAS  PubMed  Google Scholar 

  73. Gunsalus, R. & Park, S. Aerobic–anaerobic gene regulation in Escherichia coli: control by the ArcAB and Fnr regulons. Res. Microbiol. 145, 437–450 (1994).

    CAS  PubMed  Google Scholar 

  74. Unden, G. & Bongaerts, J. Alternative respiratory pathways of Escherichia coli: energetics and transcriptional regulation in response to electron acceptors. Biochim. Biophys. Acta 1320, 217–234 (1997).

    CAS  PubMed  Google Scholar 

  75. Unden, G. & Schirawski, J. The oxygen-responsive transcriptional regulator FNR of Escherichia coli: the search for signals and reactions. Mol. Microbiol. 25, 205–210 (1997).

    CAS  PubMed  Google Scholar 

  76. Green, J., Crack, J. C., Thomson, A. J. & LeBrun, N. E. Bacterial sensors of oxygen. Curr. Opin. Microbiol. 12, 145–151 (2009).

    CAS  PubMed  Google Scholar 

  77. Georgellis, D., Kwon, O. & Lin, E. C. Quinones as the redox signal for the arc two-component system of bacteria. Science 292, 2314–2316 (2001).

    CAS  PubMed  Google Scholar 

  78. Bekker, M. et al. Changes in the redox state and composition of the quinone pool of Escherichia coli during aerobic batch-culture growth. Microbiology 153, 1974–1980 (2007).

    CAS  PubMed  Google Scholar 

  79. Nanchen, A., Schicker, A. & Sauer, U. Nonlinear dependency of intracellular fluxes on growth rate in miniaturized continuous cultures of Escherichia coli. Appl. Environ. Microbiol. 72, 1164–1172 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Anderson, D. H. & Duckworth, H. W. In vitro mutagenesis of Escherichia coli citrate synthase to clarify the locations of ligand binding sites. J. Biol. Chem. 263, 2163–2169 (1988).

    CAS  PubMed  Google Scholar 

  81. Daran-Lapujade, P. et al. The fluxes through glycolytic enzymes in Saccharomyces cerevisiae are predominantly regulated at posttranscriptional levels. Proc. Natl Acad. Sci. 104, 15753–15758 (2007).

    CAS  PubMed  Google Scholar 

  82. Fendt, S.-M. & Sauer, U. Transcriptional regulation of respiration in yeast metabolizing differently repressive carbon substrates. BMC Syst. Biol. 4, 12 (2010).

    PubMed  PubMed Central  Google Scholar 

  83. Scott, M., Gunderson, C. W., Mateescu, E. M., Zhang, Z. & Hwa, T. Interdependence of cell growth and gene expression: origins and consequences. Science 330, 1099–1102 (2010).

    CAS  PubMed  Google Scholar 

  84. Molenaar, D., van Berlo, R., de Ridder, D. & Teusink, B. Shifts in growth strategies reflect tradeoffs in cellular economics. Mol. Syst. Biol. 5, 323 (2009).

    PubMed  PubMed Central  Google Scholar 

  85. Valgepea, K. et al. Systems biology approach reveals that overflow metabolism of acetate in Escherichia coli is triggered by carbon catabolite repression of acetyl-CoA synthetase. BMC Syst. Biol. 4, 166 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Reitzer, L. Nitrogen assimilation and global regulation in Escherichia coli. Annu. Rev. Microbiol. 57, 155–176 (2003).

    CAS  PubMed  Google Scholar 

  87. Kurihara, S. et al. A novel putrescine utilization pathway involves γ-glutamylated intermediates of Escherichia coli K-12. J. Biol. Chem. 280, 4602–4608 (2005).

    CAS  PubMed  Google Scholar 

  88. Sohanpal, B. K., El-Labany, S., Lahooti, M., Plumbridge, J. A. & Blomfield, I. C. Integrated regulatory responses of fimB to N-acetylneuraminic (sialic) acid and GlcNAc in Escherichia coli K-12. Proc. Natl Acad. Sci. USA 101, 16322–16327 (2004).

    CAS  PubMed  Google Scholar 

  89. Leigh, J. A. & Dodsworth, J. A. Nitrogen regulation in bacteria and archaea. Annu. Rev. Microbiol. 61, 349–377 (2007).

    CAS  PubMed  Google Scholar 

  90. Heeswijk, W. C. van, Westerhoff, H. V. & Boogerd, F. C. Nitrogen assimilation in Escherichia coli: putting molecular data into a systems perspective. Microbiol. Mol. Biol. Rev. 77, 628–695 (2013).

    PubMed  PubMed Central  Google Scholar 

  91. Jiang, P. & Ninfa, A. J. α-ketoglutarate controls the ability of the Escherichia coli PII signal transduction protein to regulate the activities of NRII (NtrB) but does not control the binding of PII to NRII. Biochemistry 48, 11514–11521 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Schumacher, J. et al. Nitrogen and carbon status are integrated at the transcriptional level by the nitrogen regulator NtrC in vivo. mBio 4, e00881-13 (2013).

    PubMed  PubMed Central  Google Scholar 

  93. Ninfa, A. J. & Jiang, P. PII signal transduction proteins: sensors of α-ketoglutarate that regulate nitrogen metabolism. Curr. Opin. Microbiol. 8, 168–173 (2005).

    CAS  PubMed  Google Scholar 

  94. Jiang, P., Mayo, A. E. & Ninfa, A. J. Escherichia coli gutamine synthetase adenylyltransferase (ATase, EC 2.7.7.49): kinetic characterization of regulation by PII, PII-UMP, glutamine, and α-Ketoglutarate. Biochemistry 46, 4133–4146 (2007).

    CAS  PubMed  Google Scholar 

  95. Doucette, C. D., Schwab, D. J., Wingreen, N. S. & Rabinowitz, J. D. α-Ketoglutarate coordinates carbon and nitrogen utilization via enzyme I inhibition. Nature Chem. Biol. 7, 894–901 (2011).

    CAS  Google Scholar 

  96. Radchenko, M. V., Thornton, J. & Merrick, M. Control of AmtB–GlnK complex formation by intracellular levels of ATP, ADP, and 2-Oxoglutarate. J. Biol. Chem. 285, 31037–31045 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kim, M. et al. Need-based activation of ammonium uptake in Escherichia coli. Mol. Syst. Biol. 8, 616 (2012). This study shows how E. coli prevents the wasteful uptake of ammonium in presence of ample external ammonium.

    PubMed  PubMed Central  Google Scholar 

  98. Wray, L. V. J., Zalieckas, J. M. & Fisher, S. H. Bacillus subtilis glutamine synthetase controls gene expression through a protein–protein interaction with transcription factor TnrA. Cell 107, 427–435 (2001).

    CAS  PubMed  Google Scholar 

  99. Magasanik, B. & Kaiser, C. A. Nitrogen regulation in Saccharomyces cerevisiae. Gene 290, 1–18 (2002).

    CAS  PubMed  Google Scholar 

  100. Ter Schure, E. G., van Riel, N. A. & Verrips, C. T. The role of ammonia metabolism in nitrogen catabolite repression in Saccharomyces cerevisiae. FEMS Microbiol. Rev. 24, 67–83 (2000).

    CAS  PubMed  Google Scholar 

  101. Radchenko, M. V., Thornton, J. & Merrick, M. PII signal transduction proteins are ATPases whose activity is regulated by 2-oxoglutarate. Proc. Natl Acad. Sci. 110, 12948–12953 (2013).

    CAS  PubMed  Google Scholar 

  102. Alves, R. & Savageau, M. A. Effect of overall feedback inhibition in unbranched biosynthetic pathways. Biophys. J. 79, 2290–2304 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Pardee, A. Beginnings of feedback inhibition, allostery, and multi-protein complexes. Gene 321, 17–23 (2003).

    CAS  PubMed  Google Scholar 

  104. Cho, B.-K., Federowicz, S., Park, Y.-S., Zengler, K. & Palsson, B. Deciphering the transcriptional regulatory logic of amino acid metabolism. Nature Chem. Biol. 8, 65–71 (2012).

    CAS  Google Scholar 

  105. Yanofsky, C. Attenuation in the control of expression of bacterial operons. Nature 289, 751–758 (1981).

    CAS  PubMed  Google Scholar 

  106. Chubukov, V., Zuleta, I. A. & Li, H. Regulatory architecture determines optimal regulation of gene expression in metabolic pathways. Proc. Natl Acad. Sci. USA 109, 5127–5132 (2012).

    CAS  PubMed  Google Scholar 

  107. Gerosa, L., Kochanowski, K., Heinemann, M. & Sauer, U. Dissecting specific and global transcriptional regulation of bacterial gene expression. Mol. Syst. Biol. 9, 658 (2013). This paper unravels the regulatory logic of the arginine biosynthesis pathway in E. coli by combining experimental and computational efforts.

    PubMed  PubMed Central  Google Scholar 

  108. Kiupakis, A. K. & Reitzer, L. ArgR-independent induction and ArgR-dependent superinduction of the astCADBE operon in Escherichia coli. J. Bacteriol. 184, 2940–2950 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. De Felice, M., Levinthal, M., Iaccarino, M. & Guardiola, J. Growth inhibition as a consequence of antagonism between related amino acids: effect of valine in Escherichia coli K-12. Microbiol. Rev. 43, 42–58 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Calvo, J. M. & Matthews, R. G. The leucine-responsive regulatory protein, a global regulator of metabolism in Escherichia coli. Microbiol. Rev. 58, 466–490 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cho, B.-K., Barrett, C. L., Knight, E. M., Park, Y. S. & Palsson, B. Genome-scale reconstruction of the Lrp regulatory network in Escherichia coli. Proc. Natl Acad. Sci. USA 105, 19462–19467 (2008).

    CAS  PubMed  Google Scholar 

  112. Shivers, R. P. & Sonenshein, A. L. Activation of the Bacillus subtilis global regulator CodY by direct interaction with branched-chain amino acids. Mol. Microbiol. 53, 599–611 (2004).

    CAS  PubMed  Google Scholar 

  113. Binda, M. et al. The Vam6 GEF controls TORC1 by activating the EGO Complex. Mol. Cell 35, 563–573 (2009).

    CAS  PubMed  Google Scholar 

  114. Bremer, H. & Dennis, P. P. in Escherichia coli and Salmonella typhimurium: cellular and molecular biology (eds Neidhardt F. C. et al.) (ASM Press, 1996).

    Google Scholar 

  115. Warner, J. R. The economics of ribosome biosynthesis in yeast. Trends Biochem. Sci. 24, 437–440 (1999).

    CAS  PubMed  Google Scholar 

  116. Schneider, D. a, Gaal, T. & Gourse, R. L. NTP-sensing by rRNA promoters in Escherichia coli is direct. Proc. Natl Acad. Sci. USA 99, 8602–8607 (2002). This paper demonstrates the regulation of rRNA expression by nucleotide triphosphates in E. coli.

    CAS  PubMed  Google Scholar 

  117. Peterson, C. N., Levchenko, I., Rabinowitz, J. D., Baker, T. A & Silhavy, T. J. RpoS proteolysis is controlled directly by ATP levels in Escherichia coli. Genes Dev. 26, 548–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Potrykus, K. & Cashel, M. (p)ppGpp: still magical? Annu. Rev. Microbiol. 62, 35–51 (2008).

    CAS  PubMed  Google Scholar 

  119. Barker, M. M., Gaal, T., Josaitis, C. A. & Gourse, R. L. Mechanism of regulation of transcription initiation by ppGpp. I. Effects of ppGpp on transcription initiation in vivo and in vitro. J. Mol. Biol. 305, 673–688 (2001).

    CAS  PubMed  Google Scholar 

  120. Rutherford, S. T., Villers, C. L., Lee, J. H., Ross, W. & Gourse, R. L. Allosteric control of Escherichia coli rRNA promoter complexes by DksA. Genes Dev. 23, 236–248 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lemke, J. J. et al. Direct regulation of Escherichia coli ribosomal protein promoters by the transcription factors ppGpp and DksA. Proc. Natl Acad. Sci. USA 108, 5712–5717 (2011).

    CAS  PubMed  Google Scholar 

  122. Lopez, J. M., Dromerick, A. & Freese, E. Response of guanosine 5′-triphosphate concentration to nutritional changes and its significance for Bacillus subtilis sporulation. J. Bacteriol. 146, 605–613 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kriel, A. et al. Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance. Mol. Cell 48, 231–241 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Krásný, L. & Gourse, R. L. An alternative strategy for bacterial ribosome synthesis: Bacillus subtilis rRNA transcription regulation. EMBO J. 23, 4473–4483 (2004).

    PubMed  PubMed Central  Google Scholar 

  125. Zhang, S. & Haldenwang, W. G. Contributions of ATP, GTP, and redox state to nutritional stress activation of the Bacillus subtilis σB transcription factor. J. Bacteriol. 187, 7554–7560 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Hinnebusch, A. G. Translational regulation of Gcn4 and the general amino acid control of yeast. Annu. Rev. Microbiol. 59, 407–450 (2005).

    CAS  PubMed  Google Scholar 

  127. Slattery, M. G., Liko, D. & Heideman, W. Protein kinase A, TOR, and glucose transport control the response to nutrient repletion in Saccharomyces cerevisiae. Eukaryot. Cell 7, 358–367 (2008).

    CAS  PubMed  Google Scholar 

  128. Loewith, R. & Hall, M. N. Target of Rapamycin (TOR) in nutrient signaling and growth control. Genetics 189, 1177–1201 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Rolland, F. et al. Glucose-induced cAMP signalling in yeast requires both a G-protein coupled receptor system for extracellular glucose detection and a separable hexose kinase-dependent sensing process. Mol. Microbiol. 38, 348–358 (2000).

    CAS  PubMed  Google Scholar 

  130. Ishihama, Y. et al. Protein abundance profiling of the Escherichia coli cytosol. BMC Genomics 9, 102 (2008).

    PubMed  PubMed Central  Google Scholar 

  131. Babu, M. M. & Teichmann, S. A. Evolution of transcription factors and the gene regulatory network in Escherichia coli. Nucleic Acids Res. 31, 1234–1244 (2003).

    Google Scholar 

  132. Goelzer, A. et al. Reconstruction and analysis of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis. BMC Syst. Biol. 2, 20 (2008).

    PubMed  PubMed Central  Google Scholar 

  133. Sellick, C. A. & Reece, R. J. Eukaryotic transcription factors as direct nutrient sensors. Trends Biochem. Sci. 30, 405–412 (2005).

    CAS  PubMed  Google Scholar 

  134. Dechant, R. & Peter, M. Nutrient signals driving cell growth. Curr. Opin. Cell Biol. 20, 678–687 (2008).

    CAS  PubMed  Google Scholar 

  135. Brauer, M. J. et al. Coordination of growth rate, cell cycle, stress response, and metabolic activity in yeast. Mol. Biol. Cell 19, 352–367 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Airoldi, E. M. et al. Predicting cellular growth from gene expression signatures. PLoS Comput. Biol. 5, e1000257 (2009).

    PubMed  PubMed Central  Google Scholar 

  137. Berthoumieux, S. et al. Shared control of gene expression in bacteria by transcription factors and global physiology of the cell. Mol. Syst. Biol. 9, 634 (2013).

    PubMed  PubMed Central  Google Scholar 

  138. Keren, L. et al. Promoters maintain their relative activity levels under different growth conditions. Mol. Syst. Biol. 9, 701 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Schellenberger, J. et al. Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0. Nature Protoc. 6, 1290–1307 (2011).

    CAS  Google Scholar 

  140. Zamboni, N., Fendt, S.-M., Rühl, M. & Sauer, U. 13C-based metabolic flux analysis. Nature Protoc. 4, 878–892 (2009).

    CAS  Google Scholar 

  141. Yuan, J., Bennett, B. D. & Rabinowitz, J. D. Kinetic flux profiling for quantitation of cellular metabolic fluxes. Nature Protoc. 3, 1328–1340 (2008).

    CAS  Google Scholar 

  142. Buescher, J. M., Moco, S., Sauer, U., Zamboni, N. & Chemistry, A. Ultra-high performance liquid chromatography-tandem mass spectrometry method for fast and robust quantification of anionic and aromatic metabolites. Anal. Chem. 82, 4403–4412 (2010).

    CAS  PubMed  Google Scholar 

  143. Fuhrer, T., Heer, D., Begemann, B. & Zamboni, N. High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry. Anal. Chem. 83, 7074–7080 (2011).

    CAS  PubMed  Google Scholar 

  144. Bermejo, C., Haerizadeh, F., Takanaga, H., Chermak, D. & Frommer, W. B. Optical sensors for measuring dynamic changes of cytosolic metabolite levels in yeast. Nature Protoc. 6, 1806–1817 (2011).

    CAS  Google Scholar 

  145. Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nature Rev. Genet. 10, 57–63 (2009).

    CAS  PubMed  Google Scholar 

  146. Ingolia, N. T., Brar, G. a, Rouskin, S., McGeachy, A. M. & Weissman, J. S. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nature Protoc. 7, 1534–1550 (2012).

    CAS  Google Scholar 

  147. Zaslaver, A. et al. A comprehensive library of fluorescent transcriptional reporters for Escherichia coli. Nature Methods 3, 623–628 (2006).

    CAS  PubMed  Google Scholar 

  148. Ahrens, C. H., Brunner, E., Qeli, E., Basler, K. & Aebersold, R. Generating and navigating proteome maps using mass spectrometry. Nature Rev. Mol. Cell. Biol. 11, 789–801 (2010).

    CAS  Google Scholar 

  149. Otto, A., Bernhardt, J., Hecker, M. & Becher, D. Global relative and absolute quantitation in microbial proteomics. Curr. Opin. Microbiol. 15, 364–372 (2012).

    CAS  PubMed  Google Scholar 

  150. Furey, T. S. ChIP–seq and beyond: new and improved methodologies to detect and characterize protein–DNA interactions. Nature Rev. Genet. 13, 840–852 (2012).

    CAS  PubMed  Google Scholar 

  151. Ptacek, J. et al. Global analysis of protein phosphorylation in yeast. Nature 438, 679–684 (2005).

    CAS  PubMed  Google Scholar 

  152. Zhang, K., Zheng, S., Yang, J. S., Chen, Y. & Cheng, Z. Comprehensive profiling of protein lysine acetylation in Escherichia coli. J. Proteome Res. 12, 844–851 (2013).

    CAS  PubMed  Google Scholar 

  153. Weinert, B. T. et al. Acetyl-phosphate is a critical determinant of lysine acetylation in E. coli. Mol. Cell 51, 265–272 (2013).

    CAS  PubMed  Google Scholar 

  154. Moellering, R. E. & Cravatt, B. F. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science 341, 549–553 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Kotte, O., Zaugg, J. B. & Heinemann, M. Bacterial adaptation through distributed sensing of metabolic fluxes. Mol. Syst. Biol. 6, 355 (2010).

    PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Author notes

  1. Victor Chubukov, Luca Gerosa and Karl Kochanowski: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zurich (ETH-Zurich), Zurich, 8092, Switzerland

    Victor Chubukov, Luca Gerosa, Karl Kochanowski & Uwe Sauer

Authors
  1. Victor Chubukov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Gerosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karl Kochanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Uwe Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uwe Sauer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3238

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology