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Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria

Nature Chemistry volume 1, pages 377–383 (2009)Cite this article

Abstract

The design of systems with life-like properties from simple chemical components may offer insights into biological processes, with the ultimate goal of creating an artificial chemical cell that would be considered to be alive. Most efforts to create artificial cells have concentrated on systems based on complex natural molecules such as DNA and RNA. Here we have constructed a lipid-bound protometabolism that synthesizes complex carbohydrates from simple feedstocks, which are capable of engaging the natural quorum sensing mechanism of the marine bacterium Vibrio harveyi and stimulating a proportional bioluminescent response. This encapsulated system may represent the first step towards the realization of a cellular ‘mimic’ and a starting point for ‘bottom-up’ designs of other chemical cells, which could perhaps display complex behaviours such as communication with natural cells.

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Figure 1: The chemical cell concept.
Figure 2: Evidence for protometabolic formation of carbohydrates inside a vesicle.
Figure 3: Illustration of the structural analogy between signalling molecule autoinducer-2 (AI-2) and products of the formose reaction.
Figure 4: Induction of bioluminescence in Vibrio harveyi by carbohydrate-borate complexes.

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References

  1. Bean, H. D., Anet, F. A. L., Gould, I. R. & Hud, N. V. Glyoxylate as a backbone linkage for a prebiotic ancestor of RNA. Orig. Life Evol. Biosph. 36, 39–63 (2006).

    Article  CAS  Google Scholar 

  2. Eschenmoser, A. & Krishnamurthy, R. Chemical etiology of nucleic acid structure. Pure Appl. Chem. 72, 343–345 (2000).

    Article  CAS  Google Scholar 

  3. Gilbert, W. The RNA world. Nature 319, 618 (1986).

    Article  Google Scholar 

  4. Laine, R. A. A calculation of all possible oligosaccharide isomers both branched and linear yields 1.05 × 1012 structures for a reducing hexasaccharide: the Isomer Barrier to development of single-method saccharide sequencing or synthesis systems. Glycobiology 4, 759–767 (1994).

    Article  CAS  Google Scholar 

  5. Wittung, P., Nielsen, P. E., Buchardt, O., Egholm, M. & Norden, B. DNA-like double helix formed by peptide nucleic acid. Nature 368, 561–563 (1994).

    Article  CAS  Google Scholar 

  6. Luisi, P. L. The Emergence of Life. From Chemical Origins to Synthetic Biology (Cambridge Univ. Press, 2006).

  7. Bedau, M. A. et al. Open problems in artificial life. Artif. Life 6, 363–376 (2000).

    Article  CAS  Google Scholar 

  8. Deamer, D. A giant step towards artificial life? Trends Biotechnol. 23, 336–338 (2005).

    Article  CAS  Google Scholar 

  9. Rasmussen, S. et al. Evolution: Transitions from nonliving to living matter. Science 303, 963–965 (2004).

    Article  CAS  Google Scholar 

  10. Glass, J. I. et al. Essential genes of a minimal bacterium. Proc. Natl Acad. Sci. USA 103, 425–430 (2006).

    Article  CAS  Google Scholar 

  11. Lartigue, C. et al. Genome transplantation in bacteria: Changing one species to another. Science 317, 632–638 (2007).

    Article  CAS  Google Scholar 

  12. Noireaux, V. & Libchaber, A. A vesicle bioreactor as a step toward an artificial cell assembly. Proc. Natl Acad. Sci. USA 101, 17669–17674 (2004).

    Article  CAS  Google Scholar 

  13. Monnard, P. A., Luptak, A. & Deamer, D. W. Models of primitive cellular life: polymerases and templates in liposomes. Phil. Trans. R. Soc. B 362, 1741–1750 (2007).

    Article  CAS  Google Scholar 

  14. Mansy, S. S. et al. Template-directed synthesis of a genetic polymer in a model protocell. Nature 454, 122–125 (2008).

    Article  CAS  Google Scholar 

  15. Murtas, G., Kuruma, Y., Bianchini, P., Diaspro, A. & Luisi, P. L. Protein synthesis in liposomes with a minimal set of enzymes. Biochem. Biophys. Res. Commun. 363, 12–17 (2007).

    Article  CAS  Google Scholar 

  16. Ganti, T. The Principles of Life (Oxford Univ. Press, 2003).

  17. Breslow, R. Mechanism of the formose reaction. Tetrahedron Lett. 1, 22–26 (1959).

    Article  Google Scholar 

  18. Cronin, L. et al. The imitation game—a computational chemical approach to recognizing life. Nature Biotechnol. 24, 1203–1206 (2006).

    Article  CAS  Google Scholar 

  19. Butlerow, A. Bildung einer zuckerartigen Substanz durch Synthese. Annalen 120, 295–298 (1861).

    Article  Google Scholar 

  20. Pfeil, E. Über den Mechanismus der Cannizzaroschen Reaktion. Chem. Ber. 84, 229–245 (1951).

    Article  CAS  Google Scholar 

  21. Lin, B. Z., Yin, C. C. & Hauser, H. The effect of positive and negative pH-gradients on the stability of small unilamellar vesicles of negatively charged phospholipids. Biochim. Biophys. Acta Biomembranes 1147, 237–244 (1993).

    Article  CAS  Google Scholar 

  22. Takakura, K., Toyota, T. & Sugawara, T. A novel system of self-reproducing giant vesicles. J. Am. Chem. Soc. 125, 8134–8140 (2003).

    Article  CAS  Google Scholar 

  23. Cerc, G. Phospholipids Handbook (Marcel Decker, 1993).

    Google Scholar 

  24. Biegel, C. M. & Gould, J. M. Kinetics of hydrogen ion diffusion across phospholipid vesicle membranes. Biochemistry 20, 3474–3479 (1981).

    Article  CAS  Google Scholar 

  25. Shigemasa, Y., Nagae, O., Sakazawa, C., Nakashima, R. & Matsuura, T. Formose reactions. 5. A selective formose reaction. J. Am. Chem. Soc. 100, 1309–1310 (1978).

    Article  CAS  Google Scholar 

  26. Shigemasa, Y., Ueda, T. & Saimoto, H. Formose reactions. XXVIII. Selective formation of 2, 4-bis(hydroxymethyl)-3-pentulose in N, N-dimethylformamide-water. Bull. Chem Soc. Jpn 63, 389–394 (1990).

    Article  CAS  Google Scholar 

  27. Gao, X., Zhang, Y. & Wang, B. A highly fluorescent water-soluble boronic acid reporter for saccharide sensing that shows ratiometric UV changes and significant fluorescence changes. Tetrahedron 61, 9111–9117 (2005).

    Article  CAS  Google Scholar 

  28. Bassler, B. L., Wright, M., Showalter, R. E. & Silverman, M. R. Intercellular signaling in Vibrio-harveyi—sequence and function of genes regulating expression of luminescence. Mol. Microbiol. 9, 773–786 (1993).

    Article  CAS  Google Scholar 

  29. Waters, C. M. & Bassler, B. L. Quorum sensing: Cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol. 21, 319–346 (2005).

    Article  CAS  Google Scholar 

  30. Chen, X. et al. Structural identification of a bacterial quorum-sensing signal containing boron. Nature 415, 545–549 (2002).

    Article  CAS  Google Scholar 

  31. Xavier, K. B. & Bassler, B. L. LuxS quorum sensing: more than just a numbers game. Curr. Opin. Microbiol. 6, 191–197 (2003).

    Article  CAS  Google Scholar 

  32. Bassler, B. L., Greenberg, E. P. & Stevens, A. M. Cross-species induction of luminescence in the quorum-sensing bacterium Vibrio harveyi. J. Bacteriol. 179, 4043–4045 (1997).

    Article  CAS  Google Scholar 

  33. Lyon, G. J. & Muir, T. W. Chemical signaling among bacteria and its inhibition. Chem. Biol. 10, 1007–1021 (2003).

    Article  CAS  Google Scholar 

  34. Zhang, L.-H. & Dong, Y.-H. Quorum sensing and signal interference: Diverse implications. Mol. Microbiol. 53, 1563–1571 (2004).

    Article  CAS  Google Scholar 

  35. Rasmussen, T. B. & Givskov, M. Quorum sensing inhibitors: A bargain of effects. Microbiology 152, 895–904 (2006).

    Article  CAS  Google Scholar 

  36. Geske, G. D., Wezeman, R. J., Siegel, A. P. & Blackwell, H. E. Small molecule inhibitors of bacterial quorum sensing and biofilm formation. J. Am. Chem. Soc. 127, 12762–12763 (2005).

    Article  CAS  Google Scholar 

  37. Persson, T. et al. Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic. Org. Biomol. Chem. 3, 253–262 (2005).

    Article  CAS  Google Scholar 

  38. Welch, M. et al. Cell-cell communication in Gram-negative bacteria. Mol. Biosyst. 1, 196–202 (2005).

    Article  CAS  Google Scholar 

  39. Semmelhack, M. F., Campagna, S. R., Hwa, C., Federle, M. J. & Bassler, B. L. Boron binding with the quorum sensing signal AI-2 and analogues. Org. Lett. 6, 2635–2637 (2004).

    Article  CAS  Google Scholar 

  40. Schauder, S., Shokat, K., Surette, M. G. & Bassler, B. L. The LuxS family of bacterial autoinducers: biosynthesis of a novel quorum-sensing signal molecule. Mol. Microbiol. 41, 463–476 (2001).

    Article  CAS  Google Scholar 

  41. Xavier, K. B. & Bassler, B. L. Interference with Al-2-mediated bacterial cell-cell communication. Nature 437, 750–753 (2005).

    Article  CAS  Google Scholar 

  42. De Keersmaecker, S. C. J. et al. Chemical synthesis of (S)-4, 5-dihydroxy-2, 3-pentanedione, a bacterial signal molecule precursor, and validation of its activity in Salmonella typhimurium. J. Biol. Chem. 280, 19563–19568 (2005).

    Article  CAS  Google Scholar 

  43. Miller, S. T. et al. Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal Al-2. Mol. Cell 15, 677–687 (2004).

    Article  CAS  Google Scholar 

  44. Surette, M. G., Miller, M. B. & Bassler, B. L. Quorum sensing in Escherichia coli, Salmonella typhimurium, and Vibrio harveyi: A new family of genes responsible for autoinducer production. Proc. Natl Acad. Sci. USA 96, 1639–1644 (1999).

    Article  CAS  Google Scholar 

  45. Song, L. Z. et al. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 274, 1859–1866 (1996).

    Article  CAS  Google Scholar 

  46. Eroglu, A. et al. Intracellular trehalose improves the survival of cryopreserved mammalian cells. Nature Biotechnol. 18, 163–167 (2000).

    Article  CAS  Google Scholar 

  47. Nomura, S. et al. Gene expression within cell-sized lipid vesicles. ChemBioChem 4, 1172–1175 (2003).

    Article  CAS  Google Scholar 

  48. Sacerdote, M. G. & Szostak, J. W. Semipermeable lipid bilayers exhibit diastereoselectivity favoring ribose. Proc. Natl Acad. Sci. USA 102, 6004–6008 (2005).

    Article  CAS  Google Scholar 

  49. Weber, A. L. Sugars as the optimal biosynthetic carbon substrate of aqueous life throughout the Universe. Orig. Life Evol. Biosph. 30, 33–43 (2000).

    Article  CAS  Google Scholar 

  50. Chapelle, S. & Verchere, J. F. A boron-11 and carbon-13 NMR determination of the structures of borate complexes of pentoses and related sugars. Tetrahedron 44, 4469–4482 (1988).

    Article  CAS  Google Scholar 

  51. van den Berg, R., Peters, J. A. & van Bekkum, H. The structure and (local) stability constants of borate esters of mono- and disaccharides as studied by 11B and 13C NMR spectroscopy. Carbohydr. Res. 253, 1–12 (1994).

    Article  CAS  Google Scholar 

  52. Greenberg, E. P., Hastings, J. W. & Ulitzur, S. Induction of luciferase synthesis in Beneckea harveyi by other marine bacteria. Arch. Microbiol. 120, 87–91 (1979).

    Article  CAS  Google Scholar 

  53. Gao, X., Zhang, Y. & Wang, B. Naphthalene-based water-soluble fluorescent boronic acid isomers suitable for ratiometric and off-on sensing of saccharides at physiological pH. New J. Chem. 29, 579–586 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Bassler for the gift of V. harveyi strain MM32 and J. H. Bayley for the gift of alpha-haemolysin. We would like to thank our Chellnet colleagues (www.chellnet.org) for their input and in particular Lee Cronin, Cameron Alexander and Natalio Krasnogor. We also thank James Errey and Conor Barry for useful discussions during the preparation of this manuscript and the EPSRC (EP/D023343/1, EP/D023327/1, EP/E000614/1) for funding.

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Authors and Affiliations

  1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK

    Paul M. Gardner & Benjamin G. Davis

  2. School of Molecular Medical Sciences, Centre for Biomolecular Sciences, University Park, University of Nottingham, Nottingham, NG7 2RD, UK

    Klaus Winzer

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All authors conceived and designed experiments, analysed the data and discussed the results. P.M.G. performed the experiments and P.M.G. and B.G.D. co-wrote the paper.

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Correspondence to Benjamin G. Davis.

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Gardner, P., Winzer, K. & Davis, B. Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria. Nature Chem 1, 377–383 (2009). https://doi.org/10.1038/nchem.296

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