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.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000146
2015-09-01
2020-01-27
Loading full text...

Full text loading...

/deliver/fulltext/micro/161/9/1707.html?itemId=/content/journal/micro/10.1099/mic.0.000146&mimeType=html&fmt=ahah

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 Microbiol85:171–183 [CrossRef][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 Biotechnol20:143–160 [CrossRef]
    [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 Leeuwenhoek95:219–226 [CrossRef][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 One7:e48223 [CrossRef][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 Biotechnol38:33–38
    [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 Res3:211–216 [CrossRef][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 Proteomics75:5437–5448 [CrossRef][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 Eng20:115–123 [CrossRef][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 Bioeng89:233–242 [CrossRef][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 Eng13:159–168 [CrossRef][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 Genet15:107–120 [CrossRef][PubMed]
    [Google Scholar]
  12. Bryson V., Szybalski W.. 1952; Microbial selection. Science116:45–51 [CrossRef]
    [Google Scholar]
  13. Bull A. T.. 2010; The renaissance of continuous culture in the post-genomics age. J Ind Microbiol Biotechnol37:993–1021 [CrossRef][PubMed]
    [Google Scholar]
  14. De Deken R. H.. 1966; The Crabtree effect: a regulatory system in yeast. J Gen Microbiol44:149–156 [CrossRef][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 A110:15842–15847 [CrossRef][PubMed]
    [Google Scholar]
  16. Erm S., Adamberg K., Vilu R.. 2014; Multiplying steady-state culture in multi-reactor system. Bioprocess Biosyst Eng37:2361–2370 [CrossRef][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 Res42:2460–2472 [CrossRef][PubMed]
    [Google Scholar]
  18. Ferenci T.. 2007; Bacterial physiology, regulation and mutational adaptation in a chemostat environment. Adv Microb Physiol53:169–229 [CrossRef][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 . Biodegradation11:371–376 [CrossRef][PubMed]
    [Google Scholar]
  20. Gresham D., Hong J.. 2015; The functional basis of adaptive evolution in chemostats. FEMS Microbiol Rev39:2–16[PubMed]
    [Google Scholar]
  21. Harder W., Kuenen J. G., Matin A.. 1977; A review. Microbial selection in continuous culture. J Appl Bacteriol43:1–24 [CrossRef][PubMed]
    [Google Scholar]
  22. Helling R. B., Vargas C. N., Adams J.. 1987; Evolution of Escherichia coli during growth in a constant environment. Genetics116:349–358
    [Google Scholar]
  23. Herwig C., Marison I., von Stockar U.. 2001; On-line stoichiometry and identification of metabolic state under dynamic process conditions. Biotechnol Bioeng75:345–354 [CrossRef][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 Bioeng95:613–626 [CrossRef][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 Bioeng111:792–802 [CrossRef][PubMed]
    [Google Scholar]
  26. Hoskisson P. A., Hobbs G.. 2005; Continuous culture - making a comeback?. Microbiology151:3153–3159 [CrossRef][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 Biotechnol39:383–399 [CrossRef][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. Science316:593–597 [CrossRef][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 Bioeng101:881–893 [CrossRef][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 Methods55:187–200 [CrossRef][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 Microbiol111:206–215 [CrossRef][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 Leeuwenhoek92:109–128 [CrossRef][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 Leeuwenhoek75:309–320 [CrossRef][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 Biotechnol68:197–212 [CrossRef][PubMed]
    [Google Scholar]
  35. Konstantinov K. B., Cooney C. L.. 2014; White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Symposium. J Pharm Sci104:813–820[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 Microbiol134:75–82 [CrossRef][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 J12:831–840 [CrossRef]
    [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 Leeuwenhoek96:487–496 [CrossRef][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 Fact10:12 [CrossRef][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 Microbiol100:3–12 [CrossRef][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 Biol8:536–546 [CrossRef][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 Chip13:947–954 [CrossRef][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 Fact12:83 [CrossRef][PubMed]
    [Google Scholar]
  45. Markx G. H., Davey C. L., Kell D. B.. 1991; The permittistat: a novel type of turbidostat. J Gen Microbiol137:735–743 [CrossRef]
    [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 Microbiol107:41–47 [CrossRef][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 Biol9:661 [CrossRef][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 Chip12:1487–1494 [CrossRef][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 Biotechnol145:60–65 [CrossRef][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. Microbiology157:2604–2610 [CrossRef][PubMed]
    [Google Scholar]
  53. Nakamura C. E., Whited G. M.. 2003; Metabolic engineering for the microbial production of 1,3-propanediol. Curr Opin Biotechnol14:454–459 [CrossRef][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 Res8:829–838 [CrossRef][PubMed]
    [Google Scholar]
  55. Novick A., Szilard L.. 1950; Description of the chemostat. Science112:715–716 [CrossRef][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 Biotechnol170:35–41 [CrossRef][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 Methods24:145–153 [CrossRef]
    [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 Technol20:174–181 [CrossRef]
    [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 Leeuwenhoek71:217–230 [CrossRef][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. Nature496:528–532 [CrossRef][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 Biotechnol98:5131–5143 [CrossRef][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 Microbiol55:468–477
    [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 Leeuwenhoek39:545–565 [CrossRef][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 Biotechnol42:423–436 [CrossRef][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 Prog15:123–129 [CrossRef][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 Methods64:380–390 [CrossRef][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 Biol4:166 [CrossRef][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 Biol5:106 [CrossRef][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 Biosyst9:2344–2358 [CrossRef][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 Bioeng75:267–275 [CrossRef][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 Bioeng93:117–124 [CrossRef][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 Biotechnol24:1061–1068 [CrossRef][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 Technol26:706–714 [CrossRef][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 Microbiol59:83–89 [CrossRef][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 Biol7:445–452 [CrossRef][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 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000146
Loading
/content/journal/micro/10.1099/mic.0.000146
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error