1887

Abstract

Increasing the throughput of systems biology-based experimental characterization of -designed strains has great potential for accelerating the development of cell factories. For this, analysis of metabolism in the steady state is essential as only this enables the unequivocal definition of the physiological state of cells, which is needed for the complete description and reconstruction of their phenotypes. In this review, we show that for a systems microbiology approach, high-resolution characterization of metabolism in the steady state – growth space analysis (GSA) – can be achieved by using advanced continuous cultivation methods termed changestats. In changestats, an environmental parameter is continuously changed at a constant rate within one experiment whilst maintaining cells in the physiological steady state similar to chemostats. This increases the resolution and throughput of GSA compared with chemostats, and, moreover, enables following of the dynamics of metabolism and detection of metabolic switch-points and optimal growth conditions. We also describe the concept, challenge and necessary criteria of the systematic analysis of steady-state metabolism. Finally, we propose that such systematic characterization of the steady-state growth space of cells using changestats has value not only for fundamental studies of metabolism, but also for systems biology-based metabolic engineering of cell factories.

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2015-09-01
2021-10-20
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References

  1. Adamberg K., Kask S., Laht T. M., Paalme T. 2003; The effect of temperature and pH on the growth of lactic acid bacteria: a pH-auxostat study. Int J Food Microbiol 85:171–183 [View Article][PubMed]
    [Google Scholar]
  2. Adamberg K., Adamberg S., Laht T. M., Ardö Y., Paalme T. 2006; Study of cheese associated lactic acid bacteria under carbohydrate-limited conditions using D-Stat cultivation. Food Biotechnol 20:143–160 [View Article]
    [Google Scholar]
  3. Adamberg K., Lahtvee P.-J., Valgepea K., Abner K., Vilu R. 2009; Quasi steady state growth of Lactococcus lactis in glucose-limited acceleration stat (A-stat) cultures. Antonie van Leeuwenhoek 95:219–226 [View Article][PubMed]
    [Google Scholar]
  4. Adamberg K., Seiman A., Vilu R. 2012; Increased biomass yield of Lactococcus lactis by reduced overconsumption of amino acids and increased catalytic activities of enzymes. PLoS One 7:e48223 [View Article][PubMed]
    [Google Scholar]
  5. Albergaria H., Duarte L. C., Amaral-Collaço M. T., Gírio F. M. 2000; Study of Saccharomyces uvarum CCMI 885 physiology under fed-batch, chemostat and accelerostat cultivation techniques. Food Technol Biotechnol 38:33–38
    [Google Scholar]
  6. Albergaria H., Torrão A. R., Hogg T., Gírio F. M. 2003; Physiological behaviour of Hanseniaspora guilliermondii in aerobic glucose-limited continuous cultures. FEMS Yeast Res 3:211–216 [View Article][PubMed]
    [Google Scholar]
  7. Arike L., Valgepea K., Peil L., Nahku R., Adamberg K., Vilu R. 2012; Comparison and applications of label-free absolute proteome quantification methods on Escherichia coli . J Proteomics 75:5437–5448 [View Article][PubMed]
    [Google Scholar]
  8. Barbosa M. J., Hoogakker J., Wijffels R. H. 2003; Optimisation of cultivation parameters in photobioreactors for microalgae cultivation using the A-stat technique. Biomol Eng 20:115–123 [View Article][PubMed]
    [Google Scholar]
  9. Barbosa M. J., Zijffers J.-W.F., Nisworo A., Vaes W., van Schoonhoven J., Wijffels R. H. 2005; Optimization of biomass, vitamins, and carotenoid yield on light energy in a flat-panel reactor using the A-stat technique. Biotechnol Bioeng 89:233–242 [View Article][PubMed]
    [Google Scholar]
  10. Becker J., Zelder O., Häfner S., Schröder H., Wittmann C. 2011; From zero to hero - design-based systems metabolic engineering of Corynebacterium glutamicum for l-lysine production. Metab Eng 13:159–168 [View Article][PubMed]
    [Google Scholar]
  11. Bordbar A., Monk J. M., King Z. A., Palsson B. Ø. 2014; Constraint-based models predict metabolic and associated cellular functions. Nat Rev Genet 15:107–120 [View Article][PubMed]
    [Google Scholar]
  12. Bryson V., Szybalski W. 1952; Microbial selection. Science 116:45–51 [View Article]
    [Google Scholar]
  13. Bull A. T. 2010; The renaissance of continuous culture in the post-genomics age. J Ind Microbiol Biotechnol 37:993–1021 [View Article][PubMed]
    [Google Scholar]
  14. De Deken R. H. 1966; The Crabtree effect: a regulatory system in yeast. J Gen Microbiol 44:149–156 [View Article][PubMed]
    [Google Scholar]
  15. Dénervaud N., Becker J., Delgado-Gonzalo R., Damay P., Rajkumar A. S., Unser M., Shore D., Naef F., Maerkl S. J. 2013; A chemostat array enables the spatio-temporal analysis of the yeast proteome. Proc Natl Acad Sci U S A 110:15842–15847 [View Article][PubMed]
    [Google Scholar]
  16. Erm S., Adamberg K., Vilu R. 2014; Multiplying steady-state culture in multi-reactor system. Bioprocess Biosyst Eng 37:2361–2370 [View Article][PubMed]
    [Google Scholar]
  17. Esquerré T., Laguerre S., Turlan C., Carpousis A. J., Girbal L., Cocaign-Bousquet M. 2014; Dual role of transcription and transcript stability in the regulation of gene expression in Escherichia coli cells cultured on glucose at different growth rates. Nucleic Acids Res 42:2460–2472 [View Article][PubMed]
    [Google Scholar]
  18. Ferenci T. 2007; Bacterial physiology, regulation and mutational adaptation in a chemostat environment. Adv Microb Physiol 53:169–229 [View Article][PubMed]
    [Google Scholar]
  19. Girbal L., Rols J.-L., Lindley N. D. 2000; Growth rate influences reductive biodegradation of the organophosphorus pesticide demeton by Corynebacterium glutamicum . Biodegradation 11:371–376 [View Article][PubMed]
    [Google Scholar]
  20. Gresham D., Hong J. 2015; The functional basis of adaptive evolution in chemostats. FEMS Microbiol Rev 39:2–16[PubMed]
    [Google Scholar]
  21. Harder W., Kuenen J. G., Matin A. 1977; A review. Microbial selection in continuous culture. J Appl Bacteriol 43:1–24 [View Article][PubMed]
    [Google Scholar]
  22. Helling R. B., Vargas C. N., Adams J. 1987; Evolution of Escherichia coli during growth in a constant environment. Genetics 116:349–358
    [Google Scholar]
  23. Herwig C., Marison I., von Stockar U. 2001; On-line stoichiometry and identification of metabolic state under dynamic process conditions. Biotechnol Bioeng 75:345–354 [View Article][PubMed]
    [Google Scholar]
  24. Hoekema S., Douma R. D., Janssen M., Tramper J., Wijffels R. H. 2006; Controlling light-use by Rhodobacter capsulatus continuous cultures in a flat-panel photobioreactor. Biotechnol Bioeng 95:613–626 [View Article][PubMed]
    [Google Scholar]
  25. Hoekema S., Rinzema A., Tramper J., Wijffels R. H., Janssen M. 2014; Deceleration-stats save much time during phototrophic culture optimization. Biotechnol Bioeng 111:792–802 [View Article][PubMed]
    [Google Scholar]
  26. Hoskisson P. A., Hobbs G. 2005; Continuous culture - making a comeback?. Microbiology 151:3153–3159 [View Article][PubMed]
    [Google Scholar]
  27. Huang C.-J., Lin H., Yang X. 2012; Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements. J Ind Microbiol Biotechnol 39:383–399 [View Article][PubMed]
    [Google Scholar]
  28. Ishii N., Nakahigashi K., Baba T., Robert M., Soga T., Kanai A., Hirasawa T., Naba M., Hirai K., other authors. 2007; Multiple high-throughput analyses monitor the response of E. coli to perturbations. Science 316:593–597 [View Article][PubMed]
    [Google Scholar]
  29. Jantama K., Zhang X., Moore J. C., Shanmugam K. T., Svoronos S. A., Ingram L. O. 2008; Eliminating side products and increasing succinate yields in engineered strains of Escherichia coli C. Biotechnol Bioeng 101:881–893 [View Article][PubMed]
    [Google Scholar]
  30. Kasemets K., Drews M., Nisamedtinov I., Adamberg K., Paalme T. 2003; Modification of A-stat for the characterization of microorganisms. J Microbiol Methods 55:187–200 [View Article][PubMed]
    [Google Scholar]
  31. Kasemets K., Kahru A., Laht T.-M., Paalme T. 2006; Study of the toxic effect of short- and medium-chain monocarboxylic acids on the growth of Saccharomyces cerevisiae using the CO2-auxo-accelerostat fermentation system. Int J Food Microbiol 111:206–215 [View Article][PubMed]
    [Google Scholar]
  32. Kasemets K., Nisamedtinov I., Laht T.-M., Abner K., Paalme T. 2007; Growth characteristics of Saccharomyces cerevisiae S288C in changing environmental conditions: auxo-accelerostat study. Antonie van Leeuwenhoek 92:109–128 [View Article][PubMed]
    [Google Scholar]
  33. Kask S., Laht T.-M., Pall T., Paalme T. 1999; A study on growth characteristics and nutrient consumption of Lactobacillus plantarum in A-stat culture. Antonie van Leeuwenhoek 75:309–320 [View Article][PubMed]
    [Google Scholar]
  34. Klein C. J. L., Rasmussen J. J., Rønnow B., Olsson L., Nielsen J. 1999; Investigation of the impact of MIG1 and MIG2 on the physiology of Saccharomyces cerevisiae . J Biotechnol 68:197–212 [View Article][PubMed]
    [Google Scholar]
  35. Konstantinov K. B., Cooney C. L. 2014; White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Symposium. J Pharm Sci 104:813–820 [CrossRef]
    [Google Scholar]
  36. Koseki S. 2009; Microbial Responses Viewer (MRV): a new ComBase-derived database of microbial responses to food environments. Int J Food Microbiol 134:75–82 [View Article][PubMed]
    [Google Scholar]
  37. Laht T.-M., Kask S., Elias P., Adamberg K., Paalme T. 2002; Role of arginine in the development of secondary microflora in Swiss-type cheese. Int Dairy J 12:831–840 [View Article]
    [Google Scholar]
  38. Lahtvee P.-J., Valgepea K., Nahku R., Abner K., Adamberg K., Vilu R. 2009; Steady state growth space study of Lactococcus lactis in D-stat cultures. Antonie van Leeuwenhoek 96:487–496 [View Article][PubMed]
    [Google Scholar]
  39. Lahtvee P.-J., Adamberg K., Arike L., Nahku R., Aller K., Vilu R. 2011; Multi-omics approach to study the growth efficiency and amino acid metabolism in Lactococcus lactis at various specific growth rates. Microb Cell Fact 10:12 [View Article][PubMed]
    [Google Scholar]
  40. Le Marc Y., Pin C., Baranyi J. 2005; Methods to determine the growth domain in a multidimensional environmental space. Int J Food Microbiol 100:3–12 [View Article][PubMed]
    [Google Scholar]
  41. Lee J. W., Na D., Park J. M., Lee J., Choi S., Lee S. Y. 2012; Systems metabolic engineering of microorganisms for natural and non-natural chemicals. Nat Chem Biol 8:536–546 [View Article][PubMed]
    [Google Scholar]
  42. Long Z., Nugent E., Javer A., Cicuta P., Sclavi B., Cosentino Lagomarsino M., Dorfman K. D. 2013; Microfluidic chemostat for measuring single cell dynamics in bacteria. Lab Chip 13:947–954 [View Article][PubMed]
    [Google Scholar]
  43. Málek I. 1958; The physiological state of microorganisms during continuous culture. In Continuous Culture of Microorganisms: A Symposium pp. 21 Prague: Publishing House ASCR;
    [Google Scholar]
  44. Marc J., Feria-Gervasio D., Mouret J.-R., Guillouet S. E. 2013; Impact of oleic acid as co-substrate of glucose on short and long-term Crabtree effect in Saccharomyces cerevisiae . Microb Cell Fact 12:83 [View Article][PubMed]
    [Google Scholar]
  45. Markx G. H., Davey C. L., Kell D. B. 1991; The permittistat: a novel type of turbidostat. J Gen Microbiol 137:735–743 [View Article]
    [Google Scholar]
  46. Martin G. A., Hempfling W. P. 1976; A method for the regulation of microbial population density during continuous culture at high growth rates. Arch Microbiol 107:41–47 [View Article][PubMed]
    [Google Scholar]
  47. McCloskey D., Palsson B. Ø., Feist A. M. 2013; Basic and applied uses of genome-scale metabolic network reconstructions of Escherichia coli . Mol Syst Biol 9:661 [View Article][PubMed]
    [Google Scholar]
  48. Moffitt J. R., Lee J. B., Cluzel P. 2012; The single-cell chemostat: an agarose-based, microfluidic device for high-throughput, single-cell studies of bacteria and bacterial communities. Lab Chip 12:1487–1494 [View Article][PubMed]
    [Google Scholar]
  49. Monod J. 1950; [The technique of continuous culture, theory and applications]. Ann Inst Pasteur (Paris) 79:390–410 (in French)
    [Google Scholar]
  50. Nahku R. 2012 Validation of Critical Factors for the Quantitative Characterization of Bacterial Physiology in Accelerostat Cultures Tallinn: TUT Press;
    [Google Scholar]
  51. Nahku R., Valgepea K., Lahtvee P.-J., Erm S., Abner K., Adamberg K., Vilu R. 2010; Specific growth rate dependent transcriptome profiling of Escherichia coli K12 MG1655 in accelerostat cultures. J Biotechnol 145:60–65 [View Article][PubMed]
    [Google Scholar]
  52. Nahku R., Peebo K., Valgepea K., Barrick J. E., Adamberg K., Vilu R. 2011; Stock culture heterogeneity rather than new mutational variation complicates short-term cell physiology studies of Escherichia coli K-12 MG1655 in continuous culture. Microbiology 157:2604–2610 [View Article][PubMed]
    [Google Scholar]
  53. Nakamura C. E., Whited G. M. 2003; Metabolic engineering for the microbial production of 1,3-propanediol. Curr Opin Biotechnol 14:454–459 [View Article][PubMed]
    [Google Scholar]
  54. Nisamedtinov I., Lindsey G. G., Karreman R., Orumets K., Koplimaa M., Kevvai K., Paalme T. 2008; The response of the yeast Saccharomyces cerevisiae to sudden vs. gradual changes in environmental stress monitored by expression of the stress response protein Hsp12p. FEMS Yeast Res 8:829–838 [View Article][PubMed]
    [Google Scholar]
  55. Novick A., Szilard L. 1950; Description of the chemostat. Science 112:715–716 [View Article][PubMed]
    [Google Scholar]
  56. Ochoa-Estopier A., Guillouet S. E. 2014; D-stat culture for studying the metabolic shifts from oxidative metabolism to lipid accumulation and citric acid production in Yarrowia lipolytica . J Biotechnol 170:35–41 [View Article][PubMed]
    [Google Scholar]
  57. Paalme T., Kahru A., Elken R., Vanatalu K., Tiisma K., Vilu R. 1995; The computer-controlled continuous culture of Escherichia coli with smooth change of dilution rate (A-stat). J Microbiol Methods 24:145–153 [View Article]
    [Google Scholar]
  58. Paalme T., Elken R., Vilu R., Korhola M. 1997a; Growth efficiency of Saccharomyces cerevisiae on glucose/ethanol media with a smooth change in the dilution rate (A-stat). Enzyme Microb Technol 20:174–181 [View Article]
    [Google Scholar]
  59. Paalme T., Elken R., Kahru A., Vanatalu K., Vilu R. 1997b; The growth rate control in Escherichia coli at near to maximum growth rates: the A-stat approach. Antonie van Leeuwenhoek 71:217–230 [View Article][PubMed]
    [Google Scholar]
  60. Paddon C. J., Westfall P. J., Pitera D. J., Benjamin K., Fisher K., McPhee D., Leavell M. D., Tai A., Main A., other authors. 2013; High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496:528–532 [View Article][PubMed]
    [Google Scholar]
  61. Peebo K., Valgepea K., Nahku R., Riis G., Õun M., Adamberg K., Vilu R. 2014; Coordinated activation of PTA-ACS and TCA cycles strongly reduces overflow metabolism of acetate in Escherichia coli . Appl Microbiol Biotechnol 98:5131–5143 [View Article][PubMed]
    [Google Scholar]
  62. Postma E., Verduyn C., Scheffers W. A., Van Dijken J. P. 1989; Enzymic analysis of the crabtree effect in glucose-limited chemostat cultures of Saccharomyces cerevisiae . Appl Environ Microbiol 55:468–477
    [Google Scholar]
  63. Stephanopoulos G., Misra J., Hwang D., Schmitt W., Alevizos I., Silva S., Gill R. 2002 Defining biological states and related genes, proteins and patterns US Patent US 2002/0169562 A1
  64. Stouthamer A. H. 1973; A theoretical study on the amount of ATP required for synthesis of microbial cell material. Antonie van Leeuwenhoek 39:545–565 [View Article][PubMed]
    [Google Scholar]
  65. Sun J., Alper H. S. 2015; Metabolic engineering of strains: from industrial-scale to lab-scale chemical production. J Ind Microbiol Biotechnol 42:423–436 [View Article][PubMed]
    [Google Scholar]
  66. Teich A., Meyer S., Lin H. Y., Andersson L., Enfors S., Neubauer P. 1999; Growth rate related concentration changes of the starvation response regulators sigmaS and ppGpp in glucose-limited fed-batch and continuous cultures of Escherichia coli . Biotechnol Prog 15:123–129 [View Article][PubMed]
    [Google Scholar]
  67. Tomson K., Barber J., Vanatalu K. 2006; Adaptastat – a new method for optimising of bacterial growth conditions in continuous culture: Interactive substrate limitation based on dissolved oxygen measurement. J Microbiol Methods 64:380–390 [View Article][PubMed]
    [Google Scholar]
  68. Valgepea K., Adamberg K., Nahku R., Lahtvee P.-J., Arike L., Vilu R. 2010; 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 [View Article][PubMed]
    [Google Scholar]
  69. Valgepea K., Adamberg K., Vilu R. 2011; Decrease of energy spilling in Escherichia coli continuous cultures with rising specific growth rate and carbon wasting. BMC Syst Biol 5:106 [View Article][PubMed]
    [Google Scholar]
  70. Valgepea K., Adamberg K., Seiman A., Vilu R. 2013; Escherichia coli achieves faster growth by increasing catalytic and translation rates of proteins. Mol Biosyst 9:2344–2358 [View Article][PubMed]
    [Google Scholar]
  71. van der Sluis C., Westerink B. H., Dijkstal M. M., Castelein S. J., van Boxtel A. J., Giuseppin M. L., Tramper J., Wijffels R. H. 2001; Estimation of steady-state culture characteristics during acceleration-stats with yeasts. Biotechnol Bioeng 75:267–275 [View Article][PubMed]
    [Google Scholar]
  72. van der Sluis C., Rahardjo Y. S. P., Smit B. A., Kroon P. J., Hartmans S., Ter Schure E. G., Tramper J., Wijffels R. 2002; Concomitant extracellular accumulation of alpha-keto acids and higher alcohols by Zygosaccharomyces rouxii . J Biosci Bioeng 93:117–124 [View Article][PubMed]
    [Google Scholar]
  73. Van Dien S. 2013; From the first drop to the first truckload: commercialization of microbial processes for renewable chemicals. Curr Opin Biotechnol 24:1061–1068 [View Article][PubMed]
    [Google Scholar]
  74. van Dijken J. P., Bauer J., Brambilla L., Duboc P., Francois J. M., Gancedo C., Giuseppin M. L. F., Heijnen J. J., Hoare M., other authors. 2000; An interlaboratory comparison of physiological and genetic properties of four Saccharomyces cerevisiae strains. Enzyme Microb Technol 26:706–714 [View Article][PubMed]
    [Google Scholar]
  75. Watson T. G. 1969; Steady state operation of a continuous culture at maximum growth rate by control of carbon dioxide production. J Gen Microbiol 59:83–89 [View Article][PubMed]
    [Google Scholar]
  76. Yim H., Haselbeck R., Niu W., Pujol-Baxley C., Burgard A., Boldt J., Khandurina J., Trawick J. D., Osterhout R. E., other authors. 2011; Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. Nat Chem Biol 7:445–452 [View Article][PubMed]
    [Google Scholar]
  77. Zijffers J.-W.F., Schippers K. J., Zheng K., Janssen M., Tramper J., Wijffels R. H. 2010; Maximum photosynthetic yield of green microalgae in photobioreactors. Mar Biotechnol (NY) 12:708–718 [View Article][PubMed]
    [Google Scholar]
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