Metabolomics

, 14:43 | Cite as

Metabolite secretion in microorganisms: the theory of metabolic overflow put to the test

  • Farhana R. Pinu
  • Ninna Granucci
  • James Daniell
  • Ting-Li Han
  • Sonia Carneiro
  • Isabel Rocha
  • Jens Nielsen
  • Silas G. Villas-Boas
Review Article

Abstract

Introduction

Microbial cells secrete many metabolites during growth, including important intermediates of the central carbon metabolism. This has not been taken into account by researchers when modeling microbial metabolism for metabolic engineering and systems biology studies.

Materials and Methods

The uptake of metabolites by microorganisms is well studied, but our knowledge of how and why they secrete different intracellular compounds is poor. The secretion of metabolites by microbial cells has traditionally been regarded as a consequence of intracellular metabolic overflow.

Conclusions

Here, we provide evidence based on time-series metabolomics data that microbial cells eliminate some metabolites in response to environmental cues, independent of metabolic overflow. Moreover, we review the different mechanisms of metabolite secretion and explore how this knowledge can benefit metabolic modeling and engineering.

Keywords

Microbial metabolism Microorganisms Active efflux Secretion Metabolic engineering Metabolic modeling Systems biology 

Notes

Acknowledgements

The authors are thankful to Mia Jüllig for assistance with Fig. 2. Callaghan Innovation and Bioresource Processing Alliance provided PhD stipends for James Daniell and Ninna Granucci respectively.

Compliance with ethical standards

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary material

11306_2018_1339_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1168 KB)

References

  1. Agarwal, L., Isar, J., Meghwanshi, G. K., & Saxena, R. K. (2006). A cost effective fermentative production of succinic acid from cane molasses and corn steep liquor by Escherichia coli. Journal of Applied Microbiology, 100, 1348–1354.  https://doi.org/10.1111/j.1365-2672.2006.02894.x.PubMedCrossRefGoogle Scholar
  2. Airich, L. G., Tsyrenzhapova, I. S., Vorontsova, O. V., Feofanov, A. V., Doroshenko, V. G., & Mashko, S. V. (2010). Membrane topology analysis of the Escherichia coli aromatic amino acid efflux protein YDDG. Journal of Molecular Microbiology and Biotechnology, 19, 189–197.  https://doi.org/10.1159/000320699.PubMedCrossRefGoogle Scholar
  3. Ajinomoto. (2009). Fact Sheet: Amino Acids Business [online]. 2015. Retrieved August 19, 2002 from https://www.ajinomoto.com/en/. Accessed 10 Oct 2017.
  4. Allen, J., Davey, H.M., Broadhurst, D., Heald, J.K., Rowland, J.J., Oliver, S.G., et al. (2003). High-throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nature Biotechnology, 21, 692–696.PubMedCrossRefGoogle Scholar
  5. Aung, H. W., Henry, S. A., & Walker, L. P. (2013). Revising the representation of fatty acid, glycerolipid, and glycerophospholipid metabolism in the consensus model of yeast metabolism. Industrial Biotechnology, 9, 215–228.  https://doi.org/10.1007/s11306-014-0721-3.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Aurich, M. K., Paglia, G., Rolfsson, Ó, Hrafnsdóttir, S., Magnúsdóttir, M., Stefaniak, M. M., et al. (2014). Prediction of intracellular metabolic states from extracellular metabolomic data. Metabolomics, 11, 603–619.  https://doi.org/10.1007/s11306-014-0721-3.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bass, R. B., Strop, P., Barclay, M., & Rees, D. C. (2002). Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel. Science, 298, 1582–1587.  https://doi.org/10.1126/science.1077945.PubMedCrossRefGoogle Scholar
  8. Becker, M., Börngen, K., Nomura, T., Battle, A. R., Marin, K., Martinac, B., et al. (2013). Glutamate efflux mediated by Corynebacterium glutamicum MSCCG, Escherichia coli MSCS, and their derivatives. BBA-Biomembrane, 1828, 1230–1240.  https://doi.org/10.1016/j.bbamem.2013.01.001.CrossRefGoogle Scholar
  9. Beese-Sims, S. E., Lee, J., & Levin, D. E. (2011). Yeast Fps1 glycerol facilitator functions as a homotetramer. Yeast, 28, 815–819.  https://doi.org/10.1002/yea.1908.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Börngen, K., Battle, A. R., Möker, N., Morbach, S., Marin, K., Martinac, B., et al. (2010). The properties and contribution of the Corynebacterium glutamicum MSCS variant to fine-tuning of osmotic adaptation. BBA-Biomembrane, 1798, 2141–2149.  https://doi.org/10.1016/j.bbamem.2010.06.022.CrossRefGoogle Scholar
  11. Boudker, O., & Verdon, G. (2010). Structural perspectives on secondary active transporters. Trends in Pharmacological Science, 31, 418–426.  https://doi.org/10.1016/j.tips.2010.06.004.CrossRefGoogle Scholar
  12. Braga, R. M., Dourado, M. N., & Araujo, W. L. (2016). Microbial interactions: Ecology in a molecular perspective. Brazilian Journal of Microbiology, 47, 86–98.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Broda, P. (1968). Ribonucleic acid synthesis and glutamate excretion in Escherichia coli. Journal of Bacteriology, 96, 1528–1534.PubMedPubMedCentralGoogle Scholar
  14. Burkovski, A., & Krämer, R. (2002). Bacterial amino acid transport proteins: Occurrence, functions, and significance for biotechnological applications. Applied Microbiology and Biotechnology, 58, 265–274.  https://doi.org/10.1007/s00253-001-0869-4.PubMedCrossRefGoogle Scholar
  15. Carneiro, S., Villas-Bôas, S. G., Ferreira, E. C., & Rocha, I. (2011). Metabolic footprint analysis of recombinant Escherichia coli strains during fed-batch fermentations. Molecular Biosystems, 7, 899–910.  https://doi.org/10.1039/c0MB00143k.PubMedCrossRefGoogle Scholar
  16. Carneiro, S., Villas-Bôas, S. G., Ferreira, E. C., & Rocha, I. (2012). Influence of the RelA activity on E. coli metabolism by metabolite profiling of glucose-limited chemostat cultures. Metabolites, 2, 717–732.  https://doi.org/10.3390/metabo2040717.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chubukov, V., Gerosa, L., Kochanowski, K., & Sauer, U. (2014). Coordination of microbial metabolism. Nature Reviews Microbiology, 12, 327–340.  https://doi.org/10.1038/nrmicro3238.PubMedCrossRefGoogle Scholar
  18. Chumnanpuen, P., Hansen, M. A. E., Smedsgaard, J., & Nielsen, J. (2014). Dynamic metabolic footprinting reveals the key components of metabolic network in yeast Saccharomyces cerevisiae. International Journal of Genomics 2014: Article ID 894296.  https://doi.org/10.1155/2014/894296.PubMedPubMedCentralGoogle Scholar
  19. Cocaign-Bousquet, M., & Lindley, N. D. (1995). Pyruvate overflow and carbon flux within the central metabolic pathways of Corynebacterium glutamicum during growth on lactate. Enzyme and Microbial Technology, 17, 260–267.  https://doi.org/10.1016/0141-0229(94)00023-K.CrossRefGoogle Scholar
  20. Crabtree, H. G. (1929). Observations on the carbohydrate metabolism of tumours. Biochemical Journal, 23, 536–545.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Daßler, T., Maier, T., Winterhalter, C., & Böck, A. (2000). Identification of a major facilitator protein from Escherichia coli involved in efflux of metabolites of the cysteine pathway. Molecular Microbiology, 36, 1101–1112.PubMedCrossRefGoogle Scholar
  22. Dörries, K., & Lalk, M. (2013). Metabolic footprint analysis uncovers strain specific overflow metabolism and d-isoleucine production of Staphylococcus aureus COL and HG001. PLoS ONE.  https://doi.org/10.1371/journal.pone.0081500.PubMedPubMedCentralGoogle Scholar
  23. dos Santos, S. C., & Sa-Correia, I. (2011). A genome-wide screen identifies yeast genes required for protection against or enhanced cytotoxicity of the antimalarial drug quinine. Molecular Genetics and Genomics, 286, 333–346.PubMedCrossRefGoogle Scholar
  24. dos Santos, S. C., & Sa-Correia, I. (2015). Yeast toxicogenomics: Lessons from a eukaryotic cell model and cell factory. Current Opinion in Biotechnology, 33, 183–191.PubMedCrossRefGoogle Scholar
  25. dos Santos, S. C., Teixeira, M. C., Dias, P. J., & Sa-Correia, I. (2014). MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: Understanding their physiological function through post-genomic approaches. Frontiers in Physiology, 5, 180.PubMedPubMedCentralGoogle Scholar
  26. Driessen, A. J. M., & Konings, W.,N. (1990). Energetic problems of bacterial fermentations extrusion of metabolic end products. In T. A. Krulwich (Ed.), The bacteria: A treatise on structure and function. San Diego: Academic Press, Inc.Google Scholar
  27. Düring-Olsen, L., Regenberg, B., Gjermansen, C., Kielland-Brandt, M. C., & Hansen, J. (1999). Cysteine uptake by Saccharomyces cerevisiae is accomplished by multiple permeases. Current Genetics, 35, 609–617.PubMedCrossRefGoogle Scholar
  28. Eggeling, L., & Sahm, H. (2003). New ubiquitous translocators: Amino acid export by Corynebacterium glutamicum and Escherichia coli. Archives of Microbiology, 180, 155–160.  https://doi.org/10.1007/s00203-003-0581-0.PubMedCrossRefGoogle Scholar
  29. Fell, D. A. (1992). Metabolic control analysis—A survey of its theoretical and experimental development. Biochemical Journal, 286, 313–330.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Forrest, L. R., Krämer, R., & Ziegler, C. (2011). The structural basis of secondary active transport mechanisms. BBA-Bioenergetics, 1807, 167–188.  https://doi.org/10.1016/j.bbabio.2010.10.014.PubMedCrossRefGoogle Scholar
  31. Forsberg, H., & Ljungdahl, P. O. (2001). Sensors of extracellular nutrients in Saccharomyces cerevisiae. Current Genetics, 40, 91–109.  https://doi.org/10.1007/s002940100244.PubMedCrossRefGoogle Scholar
  32. Franke, S., Grass, G., Rensing, C., & Nies, D. H. (2003). Molecular analysis of the copper-transporting efflux system cuscfba of Escherichia coli. Journal of Bacteriology, 185, 3804–3812.  https://doi.org/10.1128/JB.185.13.3804-3812.2003.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Fu, Z., Verderame, T. D., Leighton, J. M., Sampey, B. P., Appelbaum, E. R., Patel, P. S., et al. (2014). Exometabolome analysis reveals hypoxia at the up-scaling of a Saccharomyces cerevisiae high-cell density fed-batch biopharmaceutical process. Microbial Cell Factories, 13, 32.  https://doi.org/10.1186/1475-2859-13-32.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Fukui, K., Koseki, C., Yamamoto, Y., Nakamura, J., Sasahara, A., Yuji, R., et al. (2011). Identification of succinate exporter in Corynebacterium glutamicum and its physiological roles under anaerobic conditions. Journal of Bacteriology, 154, 25–34.  https://doi.org/10.1016/j.jbiotec.2011.03.010.Google Scholar
  35. Geijer, C., Ahmadpour, D., Palmgren, M., Filipsson, C., Klein, D. M., et al. (2012). Yeast aquaglyceroporins use the transmembrane core to restrict glycerol transport. Journal of Biological Chemistry, 287, 23562–23570.  https://doi.org/10.1074/jbc.M112.353482.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Granucci, N., Pinu, F. R., Han, T. L., & Villas-Boas, S. G. (2015). Can we predict the intracellular metabolic state of a cell based in extracellular metabolite data? Molecular BioSystems, 11, 3297–3304.  https://doi.org/10.1039/C5MB00292C.PubMedCrossRefGoogle Scholar
  37. Guzmán, G. I., Utrilla, J., Nurk, S., Brunk, E., Monk, J. M., Ebrahim, A., et al. (2015). Model-driven discovery of underground metabolic functions in Escherichia coli. Proceedings of National Academy of Science of the United States of America 112, 929–934.  https://doi.org/10.1073/pnas.1414218112.CrossRefGoogle Scholar
  38. Hagman, A., Säll, T., & Piškur, J. (2014). Analysis of the yeast short-term crabtree effect and its origin. FEBS Journal, 281, 4805–4814.  https://doi.org/10.1111/febs.13019.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Han, T. L., Tumanov, S., Cannon, R. D., & Villas-Boas, S.,G. (2013). Metabolic response of Candida albicans to phenylethyl alcohol under hyphae-inducing conditions. PLoS ONE.  https://doi.org/10.1371/journal.pone.0071364.Google Scholar
  40. Hermann, T., & Krämer, R. (1996). Mechanism and regulation of isoleucine excretion in Corynebacterium glutamicum. Applied and Environmental Microbiology, 62, 3238–3244.PubMedPubMedCentralGoogle Scholar
  41. Hoffmann, T., Von Blohn, C., Stanek, A., Moses, S., Barzantny, H., & Bremer, E. (2012). Synthesis, release, and recapture of compatible solute proline by osmotically stressed Bacillus subtilis cells. Applied and Environmental Microbiology, 78, 5753–5762.  https://doi.org/10.1128/AEM.01040-12.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Holme, T. (1957). Continuous culture studies on glycogen synthesis in Escherichia coli B. Acta Chemica Scandenavica, 11, 763–775.CrossRefGoogle Scholar
  43. Ingram, L. O. (1976). Adaptation of membrane lipids to alcohols. Journal of Bacteriology, 125, 670–678.PubMedPubMedCentralGoogle Scholar
  44. Kell, D. B., Brown, M., Davey, H. M., Dunn, W. B., Spasic, I., & Oliver, S. G. (2005). Metabolic footprinting and systems biology: The medium is the message. Nature Reviews Microbiology, 3, 557–565.  https://doi.org/10.1038/nrmicro1177.PubMedCrossRefGoogle Scholar
  45. Kell, D. B., & Oliver, S. G. (2014). How drugs get into cells: Tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Frontiers in Pharmacology, 5, 231.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kell, D. B., Peck, M. W., Rodger, G., & Morris, J. G. (1981). On the permeability to weak acids and bases of the cytoplasmic membrane of Clostridium pasteurianum. Biochemical and Biophysical Research Communications, 99(1), 81–88.PubMedCrossRefGoogle Scholar
  47. Kell, D. B., Swainston, N., Pir, P., & Oliver, S. G. (2015). Membrane transporter engineering in industrial biotechnology and whole cell biocatalysis. Trends in Biotechnology, 33, 237–246.PubMedCrossRefGoogle Scholar
  48. Kell, D. B., & Westerhoff, H. V. (1986). Metabolic control-theory—Its role in microbiology and biotechnology. Fems Microbiology Letters, 39, 305–320.CrossRefGoogle Scholar
  49. Kiefer, P., Heinzle, E., Zelder, O., & Wittmann, C. (2004). Comparative metabolic flux analysis of lysine-producing Corynebacterium glutamicum cultured on glucose or fructose. Applied and Environmental Microbiology, 70, 229–239.  https://doi.org/10.1128/AEM.70.1.229-239.2004.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kinclova-Zimmermannova, O., & Sychrova, H. (2007). Plasma-membrane Cnh1 Na/H antiporter regulates potassium homeostasis in Candida albicans. Microbiology, 153, 2603–2612.  https://doi.org/10.1099/mic.0.2007/008011-0.PubMedCrossRefGoogle Scholar
  51. Konings, W. N., Poolman, B., & Driessen, A. M. (1992). Can the excretion of metabolites by bacteria be manipulated? FEMS Microbiology Letters, 88:, 93–108.  https://doi.org/10.1111/j.1574-6968.1992.tb04959.x.CrossRefGoogle Scholar
  52. Krämer, R. (1994). Secretion of amino acids by bacteria: Physiology and mechanism. FEMS Microbiology Reviews, 13, 75–94.  https://doi.org/10.1111/j.1574-6976.1994.tb00036.x.CrossRefGoogle Scholar
  53. Krämer, R. (1996). Analysis and modeling of substrate uptake and product release by prokaryotic and eukaryotic cells. Advances in Biochemical Engineering and Biotechnology, 54, 31–74.Google Scholar
  54. Krämer, R. (2004). Production of amino acids: Physiological and genetic approaches. Food Biotechnology, 18, 171–216.  https://doi.org/10.1081/FBT-200025664.CrossRefGoogle Scholar
  55. Kubicek, C. P. (1987). The role of the citric acid cycle in fungal organic acid fermentations. Biochemical Society Symposium, 54, 113–126.PubMedGoogle Scholar
  56. Lamark, T., Styrvold, O. B., & Strøm, A. R. (1992). Efflux of choline and glycine betaine from osmoregulating cells of Escherichia coli. FEMS Microbiology Letters, 96, 149–154.  https://doi.org/10.1016/0378-1097(92)90395-5.CrossRefGoogle Scholar
  57. Lee, D., Smallbone, K., Dunn, W.B., Murabito, E., Winder, C.L., Kell, D.B., et al. (2012). Improving metabolic flux predictions using absolute gene expression data. BMC Systems Biology, 6, 73.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Legiša, M., & Mattey, M. (2007). Changes in primary metabolism leading to citric acid overflow in Aspergillus niger. Biotechnology Letters, 29, 181–190.  https://doi.org/10.1007/s10529-006-9235-z.PubMedCrossRefGoogle Scholar
  59. Lepore, B. W., Indic, M., Pham, H., Hearn, E. M., Patel, D. R., & van den Berg, B. (2011). Ligand-gated diffusion across the bacterial outer membrane. Proceedings of the National Academy of Sciences of the United States of America, 108, 10121–10126.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Liang, L., Liu, R., Li, F., Wu, M., Chen, K., Ma, J., et al. (2013). Repetitive succinic acid production from lignocellulose hydrolysates by enhancement of atp supply in metabolically engineered Escherichia coli. Bio resource Technology, 143, 405–412.  https://doi.org/10.1016/j.biortech.2013.06.031.CrossRefGoogle Scholar
  61. Liu, J. Y., Miller, P. F., Willard, J., & Olson, E. R. (1999). Functional and biochemical characterization of Escherichia coli sugar efflux transporters. Journal of Biological Chemistry, 274, 22977–22984.  https://doi.org/10.1074/jbc.274.33.22977.PubMedCrossRefGoogle Scholar
  62. Livshits, V. A., Zakataeva, N. P., Aleshin, V. V., & Vitushkina, M. V. (2003). Identification and characterization of the new gene rhta involved in threonine and homoserine efflux in Escherichia coli. Research in Microbiology, 154, 123–135.  https://doi.org/10.1016/S0923-2508(03)00036-6.PubMedCrossRefGoogle Scholar
  63. Ljungdahl, P. O., & Daignan-Fornier, B. (2012). Regulation of amino acid, nucleotide, and phosphate metabolism in Saccharomyces cerevisiae. Genetics, 190, 885–929.  https://doi.org/10.1534/genetics.111.133306.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Magasanik, B., & Kaiser, C. A. (2002). Nitrogen regulation in Saccharomyces cerevisiae. Gene, 290, 1–18.  https://doi.org/10.1016/S0378-1119(02)00558-9.PubMedCrossRefGoogle Scholar
  65. Martín, J. F., Casqueiro, J., & Liras, P. (2005). Secretion systems for secondary metabolites: How producer cells send out messages of intercellular communication. Current Opinion on Microbiology, 8, 282–293.  https://doi.org/10.1016/j.mib.2005.04.009.CrossRefGoogle Scholar
  66. Mattey, M. (1992). The production of organic acids. Critical Reviews on Biotechnology, 12, 87–132.  https://doi.org/10.3109/07388559209069189.CrossRefGoogle Scholar
  67. Mccloskey, D., Palsson, B. O., & Feist, A. M. (2013). Basic and applied uses of genome-scale metabolic network reconstructions of Escherichia coli. Molecular System Biology, 9, 661.  https://doi.org/10.1038/msb.2013.18.CrossRefGoogle Scholar
  68. Mitsuhashi, S. (2014). Current topics in the biotechnological production of essential amino acids, functional amino acids, and dipeptides. Current Opinion in Biotechnology, 26, 38–44.PubMedCrossRefGoogle Scholar
  69. Mo, M. L., Palsson, B., & Herrgård, M. J. (2009). Connecting extracellular metabolomic measurements to intracellular flux states in yeast. BMC System Biology.  https://doi.org/10.1186/1752-0509-3-37.Google Scholar
  70. Molenaar, D., Van Berlo, R., De Ridder, D., & Teusink, B. (2009). Shifts in growth strategies reflect tradeoffs in cellular economics. Molecular System Biology, 5, 323.  https://doi.org/10.1038/msb.2009.82.CrossRefGoogle Scholar
  71. Moreno-Sanchez, R., Saavedra, E., Rodriguez-Enriquez, S., & Olin-Sandoval, V. (2008). Metabolic control analysis: A tool for designing strategies to manipulate metabolic pathways. Journal of Biomedicine and Biotechnology, 2008: 597913.Google Scholar
  72. Nakamura, J., Hirano, S., Ito, H., & Wachi, M. (2007). Mutations of the Corynebacterium glutamicum ncgl1221 gene, encoding a mechanosensitive channel homolog, induce l-glutamic acid production. Applied and Environmental Microbiology, 73, 4491–4498.  https://doi.org/10.1128/AEM.02446-06.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Nehls, U., Mikolajewski, S., Magel, E., & Hampp, R. (2001). Carbohydrate metabolism in ectomycorrhizas: Gene expression, monosaccharide transport and metabolic control. New Phytologist, 150, 533–541.  https://doi.org/10.1046/j.1469-8137.2001.00141.x.CrossRefGoogle Scholar
  74. Neijssel, O. M., & Tempest, D. W. (1975). Production of gluconic acid and 2 ketogluconic acid by Klebsiella aerogenes NCTC 418. Archives in Microbiology, 105, 183–185.CrossRefGoogle Scholar
  75. Neijssel, O. M., & Tempest, D. W. (1976). Role of energy-spilling reactions in growth of klebsiella-aerogenes NCTC-418 in aerobic chemostat culture. Archives of Microbiology, 110, 305–311.PubMedCrossRefGoogle Scholar
  76. Netik, A., Torres, N. V., Riol, J. M., & Kubicek, C. P. (1997). Uptake and export of citric acid by Aspergillus niger is reciprocally regulated by manganese ions. BBA-Biomembranes, 1326, 287–294.  https://doi.org/10.1016/S0005-2736(97)00032-1.PubMedCrossRefGoogle Scholar
  77. Nikaido, H. (1993). Transport across the bacterial outer-membrane. Journal of Bioenergetics and Biomembranes, 25, 581–589.PubMedGoogle Scholar
  78. Notebaart, R. A., Szappanos, B., Kintses, B., Pál, F., Györkei, Á, & Bogos, B., et al. (2014). Network-level architecture and the evolutionary potential of underground metabolism. Proceedings of National Academy of Science of the United States of America 111, 11762–11767.  https://doi.org/10.1073/pnas.1406102111.CrossRefGoogle Scholar
  79. Orth, J. D., Conrad, T. M., Na, J., Lerman, J. A., Nam, H., Feist, A. M., et al. (2011). A comprehensive genome-scale reconstruction of Escherichia coli metabolism-2011. Molecular System Biology, 7, 535.  https://doi.org/10.1038/msb.2011.65.CrossRefGoogle Scholar
  80. Orth, J. D., Thiele, I., & Palsson, B. O. (2010). What is flux balance analysis? Nature Biotechnology, 28, 245–248.  https://doi.org/10.1038/nbt.1614.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Paczia, N., Nilgen, A., Lehmann, T., Gätgens, J., Wiechert, W., & Noack, S. (2012). Extensive exometabolome analysis reveals extended overflow metabolism in various microorganisms. Microbial Cell Factories, 11, 122.  https://doi.org/10.1186/1475-2859-11-122.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Perez-Garcia, O., Villas-Boas, S. G., & Singhal, N. (2014). A method to calibrate metabolic network models with experimental datasets. 8th International Conference on Practical Applications of Computational Biology and Bioinformatics, PACCB 2014, 294, 183–190.  https://doi.org/10.1007/978-3-319-07581-5_22.
  83. Pinu, F. R., & Villas-Boas, S. G. (2017). Extracellular microbial metabolomics: The state of the art. Metabolites, 7, 3.CrossRefGoogle Scholar
  84. Ponomarova, O., & Patil, K. R. (2015). Metabolic interactions in microbial communities: Untangling the Gordian knot. Current Opinion in Microbiology, 27, 37–44.PubMedCrossRefGoogle Scholar
  85. Poole, K. (2004). Efflux-mediated multiresistance in gram-negative bacteria. Clinical Microbiology and Infection, 10, 12–26.  https://doi.org/10.1111/j.1469-0691.2004.00763.x.PubMedCrossRefGoogle Scholar
  86. Pronk, J. T., Steensma, H. Y., & Van Dijken, J. P. (1996). Pyruvate metabolism in Saccharomyces cerevisiae. Yeast, 12, 1607–1633.  https://doi.org/10.1002/(SICI)1097-0061(199612)12:16<1607::AID-YEA70>3.0.CO;2-4
  87. Rancourt, D. E., Stephenson, J. T., & Vickell, G. A. (1984). Proline excretion by Escherichia coli K12. Biotechnology and Bioengineering, 26, 74–80.  https://doi.org/10.1002/bit.260260114.PubMedCrossRefGoogle Scholar
  88. Reaves, M. L., Young, B. D., Hosios, A. M., Xu, Y. F., & Rabinowitz, J. D. (2013). Pyrimidine homeostasis is accomplished by directed overflow metabolism. Nature, 500, 237–241.  https://doi.org/10.1038/nature12445.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Roberts, S. B., Gowen, C. M., Brooks, J. P., & Fong, S. S. (2010). Genome-scale metabolic analysis of Clostridium thermocellum for bioethanol production. BMC System Biology, 4, 31.  https://doi.org/10.1186/1752-0509-4-31.CrossRefGoogle Scholar
  90. Saier, M. H., Jr. (2000). A functional-phylogenetic classification system for transmembrane solute transporters. Microbiology and Molecular Biology Reviews, 64, 354–411.  https://doi.org/10.1128/MMBR.64.2.354-411.2000.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Saier, M. H., Jr., Tran, C. V., & Barabote, R. D. (2006). TCDB: The transporter classification database for membrane transport protein analyses and information. Nucleic Acids Research, 34, D181–D186.  https://doi.org/10.1093/nar/gkj001.PubMedCrossRefGoogle Scholar
  92. Schink, B. (2002). Synergistic interactions in the microbial world. Antonie Van Leeuwenhoek International Journal of General and Molecular Microbiology, 81, 257–261.CrossRefGoogle Scholar
  93. Schweikhard, E. S., & Ziegler, C. M. (2012). Amino acid secondary transporters: Toward a common transport mechanism. Current Topics in Membranes, 70, 1–28.  https://doi.org/10.1016/B978-0-12-394316-3.00001-6.PubMedCrossRefGoogle Scholar
  94. Segrè, D., Vitkup, D., & Church, G. M. (2002). Analysis of optimality in natural and perturbed metabolic networks. Proceedings of National Academy of Science of the United States of America, 99, 15112–15117.  https://doi.org/10.1073/pnas.232349399.CrossRefGoogle Scholar
  95. Segura, A., Molina, L., Fillet, S., Krell, T., Bernal, P., Muñoz-Rojas, J., et al. (2012). Solvent tolerance in gram-negative bacteria. Current Opinion in Biotechnology, 23, 415–421.  https://doi.org/10.1016/j.copbio.2011.11.015.PubMedCrossRefGoogle Scholar
  96. Shankaranand, V. S., & Lonsane, B. K. (1994). Ability of Aspergillus niger to tolerate metal ions and minerals in a solid-state fermentation system for the production of citric acid. Process Biochemistry, 29, 29–37.  https://doi.org/10.1016/0032-9592(94)80056-1.CrossRefGoogle Scholar
  97. Shinfuku, Y., Sorpitiporn, N., Sono, M., Furusawa, C. T. H., & Shimizu, H. (2009). Development and experimental verification of a genome-scale metabolic model for Corynebacterium glutamicum. Microbial Cell Factories, 8, 43.  https://doi.org/10.1186/1475-2859-8-43.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Shlykov, M. A., Zheng, W. H., Wang, E., Nguyen, J. D., & Saier, M. H., Jr. (2013). Transmembrane molecular transporters facilitating export of molecules from cells and organelles. In E. W. Yu, Q. Zhang & M. H. Brown (Eds.), Microbial efflux pumps: Current research. Norfolk: Caister Academic Press.Google Scholar
  99. Simic, P., Sahm, H., & Eggeling, L. (2001). L-threonine export: Use of peptides to identify a new translocator from Corynebactedum glutamicum. Journal of Bacteriology, 183, 5317–5324.  https://doi.org/10.1128/JB.183.18.5317-5324.2001.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Smith, D., Artursson, P., Avdeef, A., Di, L., Ecker, G.F., Faller, B., et al. (2014). Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition. Molecular Pharmaceutics, 11, 1727–1738.PubMedCrossRefGoogle Scholar
  101. Soccol, C. R., Vandenberghe, L. P. S., Rodrigues, C., & Pandey, A. (2006). New perspectives for citric acid production and application. Food Technology and Biotechnology, 44, 141–149.Google Scholar
  102. Sonenshein, A. L. (2007). Control of key metabolic intersections in Bacillus subtilis. Nature Reviews Microbiology, 5, 917–927.  https://doi.org/10.1038/nrmicro1772.PubMedCrossRefGoogle Scholar
  103. Stäbler, N., Oikawa, T., Bott, M., & Eggeling, L. (2011). Corynebacterium glutamicum as a host for synthesis and export of d-amino acids. Journal of Bacteriology, 193,, 1702–1709.  https://doi.org/10.1128/JB.01295-10.CrossRefGoogle Scholar
  104. Tempest, D. W., & Neijssel, O. M. (1979). Overflow metabolism in aerobic micro-organisms. Biochemical Society Transactions, 7, 82–85.PubMedCrossRefGoogle Scholar
  105. Trötschel, C., Deutenberg, D., Bathe, B., Burkovski, A., & Krämer, R. (2005). Characterization of methionine export in Corynebacterium glutamicum. Journal of Bacteriology, 187, 3786–3794.  https://doi.org/10.1128/JB.187.11.3786-3794.2005.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Valgepea, K., Adamberg, K., Nahku, R., Lahtvee, P., 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 System Biology.  https://doi.org/10.1186/1752-0509-4-166.Google Scholar
  107. van Berlo, R. J. P., de Ridder, D., Daran, J. M., Daran-Lapujade, P. A. S., Teusink, B., & Reinders, M. J. T. (2011). Predicting metabolic fluxes using gene expression differences as constraints. IEEE-ACM Transactions on Computational Biology and Bioinformatics, 8, 206–216.PubMedCrossRefGoogle Scholar
  108. Van Dyk, T. K. (2008). Bacterial efflux transport in biotechnology. Advanced Applied Microbiology, 63, 231–247.  https://doi.org/10.1016/S0065-2164(07)00006-8.CrossRefGoogle Scholar
  109. Van Dyk, T. K., Templeton, L. J., Cantera, K. A., Sharpe, P. L., & Sariaslani, F. S. (2004). Characterization of the Escherichia coli AAEAB efflux pump: A metabolic relief valve? Journal of Bacteriology, 186, 7196–7204.  https://doi.org/10.1128/JB.186.21.7196-7204.2004.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Van Hoek, M. J. A., & Merks, R. M. H. (2012). Redox balance is key to explaining full vs. Partial switching to low-yield metabolism. BMC System Biology, 6, 22.  https://doi.org/10.1186/1752-0509-6-22.CrossRefGoogle Scholar
  111. Velasco, I., Tenreiro, S., Calderon, I. L., & André, B. (2004). Saccharomyces cerevisiae Aqr1 is an internal-membrane transporter involved in excretion of amino acids. Eukaryotic Cell, 3, 1492–1503.  https://doi.org/10.1128/EC.3.6.1492-1503.2004.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Vemuri, G. N., Altman, E., Sangurdekar, D. P., Khodursky, A. B., & Eiteman, M. A. (2006a). Overflow metabolism in Escherichia coli during steady-state growth: Transcriptional regulation and effect of the redox ratio. Applied and Environmental Microbiology, 72, 3653–3661.  https://doi.org/10.1128/AEM.72.5.3653-3661.2006.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Vemuri, G. N., Eiteman, M. A., & Altman, E. (2006b). Increased recombinant protein production in Escherichia coli strains with overexpressed water-forming NADH oxidase and a deleted ARCA regulatory protein. Biotechnology and Bioengineering, 94, 538–542.  https://doi.org/10.1002/bit.20853.PubMedCrossRefGoogle Scholar
  114. Verkhovskaya, M. L., Barquera, B., & Wikström, M. (2001). Deletion of one of two Escherichia coli genes encoding putative Na/H exchangers (ycgO) perturbs cytoplasmic alkali cation balance at low osmolarity. Microbiology, 147, 3005–3013.  https://doi.org/10.1099/00221287-147-11-3005.PubMedCrossRefGoogle Scholar
  115. Villas-Bôas, S. G., Moon, C. D., Noel, S., Hussein, H., Kelly, W. J., et al. (2008). Phenotypic characterization of transposon-inserted mutants of Clostridium proteoclasticum B316T using extracellular metabolomics. Journal of Bacteriology, 134, 55–63.  https://doi.org/10.1016/j.jbiotec.2008.01.010.Google Scholar
  116. Villas-Bôas, S. G., Noel, S., Lane, G. A., Attwood, G., & Cookson, A. (2006). Extracellular metabolomics: A metabolic footprinting approach to assess fiber degradation in complex media. Analytical Biochemistry, 349, 297–305.  https://doi.org/10.1016/j.ab.2005.11.019.PubMedCrossRefGoogle Scholar
  117. Vrljic, M., Sahm, H., & Eggeling, L. (1996). A new type of transporter with a new type of cellular function: L-lysine export from Corynebacterium glutamicum. Molecular Microbiology, 22, 815–826.  https://doi.org/10.1046/j.1365-2958.1996.01527.x.PubMedCrossRefGoogle Scholar
  118. Wachi, M. (2013). Amino acid exporters in Corynebacterium glutamicum. In H. Yukawa & M. Inui (Eds.), Corynebacterium glutamicum. Berlin: Springer.Google Scholar
  119. Walter, A., & Gutknecht, J. (1984). Monocarboxylic acid permeation through lipid bilayer membranes. Journal of Membrane Biology, 77, 255–264.  https://doi.org/10.1007/BF01870573.PubMedCrossRefGoogle Scholar
  120. Wendisch, V. F., Bott, M., & Eikmanns, B. J. (2006). Metabolic engineering of Escherichia coli and Corynebacterium glutamicum for biotechnological production of organic acids and amino acids. Current Opinion in Microbiology, 9, 268–274.  https://doi.org/10.1016/j.mib.2006.03.001.PubMedCrossRefGoogle Scholar
  121. West, I. C. (1997). Ligand conduction and the gated-pore mechanism of transmembrane transport. BBA-Review Biomembranes, 1331, 213–234.  https://doi.org/10.1016/S0304-4157(97)00007-5.Google Scholar
  122. Wiebe, M. G., Rintala, E., Tamminen, A., Simolin, H., Salusjärvi, L., & Toivari, M., et al. (2008). Central carbon metabolism of Saccharomyces cerevisiae in anaerobic, oxygen-limited and fully aerobic steady-state conditions and following a shift to anaerobic conditions. FEMS Yeast Research, 8, 140–154.  https://doi.org/10.1111/j.1567-1364.2007.00234.x.PubMedCrossRefGoogle Scholar
  123. Willemsen, A. M., Hendrickx, D. M., Hoefsloot, H. C. J., Hendriks, M. M. W. B., Wahl, S. A., Teusink, B., et al. (2015). METDFBA: Incorporating time-resolved metabolomics measurements into dynamic flux balance analysis. Molecular Biosystems, 11, 137–145.  https://doi.org/10.1039/c4mb00510d.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Farhana R. Pinu
    • 1
  • Ninna Granucci
    • 2
  • James Daniell
    • 2
    • 3
  • Ting-Li Han
    • 2
  • Sonia Carneiro
    • 4
  • Isabel Rocha
    • 4
  • Jens Nielsen
    • 5
    • 6
  • Silas G. Villas-Boas
    • 2
  1. 1.The New Zealand Institute for Plant and Food Research LimitedAucklandNew Zealand
  2. 2.School of Biological SciencesUniversity of AucklandAucklandNew Zealand
  3. 3.LanzaTechSkokieUSA
  4. 4.Center of Biological EngineeringUniversity of MinhoBragaPortugal
  5. 5.Department of Biology and Biological EngineeringChalmers University of TechnologyGothenburgSweden
  6. 6.Novo Nordisk Foundation Center for BiosustainabilityTechnical University of DenmarkHørsholmDenmark

Personalised recommendations