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Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network

Nature Chemistry volume 14, pages 623–631 (2022)Cite this article

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Abstract

The evolution of life from the prebiotic environment required a gradual process of chemical evolution towards greater molecular complexity. Elaborate prebiotically relevant synthetic routes to the building blocks of life have been established. However, it is still unclear how functional chemical systems evolved with direction using only the interaction between inherent molecular chemical reactivity and the abiotic environment. Here we demonstrate how complex systems of chemical reactions exhibit well-defined self-organization in response to varying environmental conditions. This self-organization allows the compositional complexity of the reaction products to be controlled as a function of factors such as feedstock and catalyst availability. We observe how Breslow’s cycle contributes to the reaction composition by feeding C2 building blocks into the network, alongside reaction pathways dominated by formaldehyde-driven chain growth. The emergence of organized systems of chemical reactions in response to changes in the environment offers a potential mechanism for a chemical evolution process that bridges the gap between prebiotic chemical building blocks and the origin of life.

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Fig. 1: Background to this work.
Fig. 2: Description of the reaction composition dataset collected in this work.
Fig. 3: Elucidation of how the formose reaction network reorganizes in response to varying conditions.
Fig. 4: A summary of key reaction pathways governing the behaviour of the formose reaction.

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Data availability

All data supporting the findings of this study are available within the paper and Supplementary Data and Supplementary Information. Source data are provided with this paper.

Code availability

All programs used to analyse and plot the data are available on GitHub (https://github.com/huckgroup/formose-2021.git).

References

  1. Surman, A. J. et al. Environmental control programs the emergence of distinct functional ensembles from unconstrained chemical reactions. Proc. Natl Acad. Sci. USA 116, 5387–5392 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Powner, M. W., Gerland, B. & Sutherland, J. D. Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature 459, 239–242 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Foden, C. S. et al. Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water. Science 370, 865–869 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Springsteen, G., Yerabolu, J. R., Nelson, J., Rhea, C. J. & Krishnamurthy, R. Linked cycles of oxidative decarboxylation of glyoxylate as protometabolic analogs of the citric acid cycle. Nat. Commun. 9, 91 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Becker, S. et al. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science 366, 76–82 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Ritson, D. J., Mojzsis, S. J. & Sutherland, J. D. Supply of phosphate to early Earth by photogeochemistry after meteoritic weathering. Nat. Geosci. 13, 344–348 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wołos, A. et al. Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry. Science 369, eaaw1955 (2020).

    Article  PubMed  Google Scholar 

  8. Muchowska, K. B., Varma, S. J. & Moran, J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 569, 104–107 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stubbs, R. T., Yadav, M., Krishnamurthy, R. & Springsteen, G. A plausible metal-free ancestral analogue of the Krebs cycle composed entirely of α-ketoacids. Nat. Chem. 12, 1016–1022 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu, L.-F. & Sutherland, J. D. Provisioning the origin and early evolution of life. Emerging Top. Life Sci. 3, 459–468 (2019).

    Article  CAS  Google Scholar 

  11. Pascal, R., Pross, A. & Sutherland, J. D. Towards an evolutionary theory of the origin of life based on kinetics and thermodynamics. Open Biol. 3, 130156 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Semenov, S. N. et al. Autocatalytic, bistable, oscillatory networks of biologically relevant organic reactions. Nature 537, 656–660 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Semenov, S. N. et al. Rational design of functional and tunable oscillating enzymatic networks. Nat. Chem. 7, 160–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Jinich, A. et al. A thermodynamic atlas of carbon redox chemical space. Proc. Natl Acad. Sci. USA 117, 32910–32918 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Orgel, L. E. Self-organizing biochemical cycles. Proc. Natl Acad. Sci. USA 97, 12503–12507 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shapiro, R. Prebiotic ribose synthesis: a critical analysis. Orig. Life. Evol. Biosph. 18, 71–85 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Sasselov, D. D., Grotzinger, J. P. & Sutherland, J. D. The origin of life as a planetary phenomenon. Sci. Adv. 6, eaax3419 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Samoilov, M., Arkin, A. & Ross, J. Signal processing by simple chemical systems. J. Phys. Chem. A 106, 10205–10221 (2002).

    Article  CAS  Google Scholar 

  19. Roszak, R., Bajczyk, M. D., Gajewska, E. P., Hołyst, R. & Grzybowski, B. A. Propagation of oscillating chemical signals through reaction networks. Angew. Chem. Int. Ed. 58, 4520–4525 (2019).

    Article  CAS  Google Scholar 

  20. Urmès, C. et al. Periodic reactor operation for parameter estimation in catalytic heterogeneous kinetics. Case study for ethylene adsorption on Ni/Al2O3. Chem. Eng. Sci. 214, 114544 (2020).

    Article  Google Scholar 

  21. Mettetal, J. T., Muzzey, D., Gomez-Uribe, C. & van Oudenaarden, A. The frequency dependence of osmo-adaptation in Saccharomyces cerevisiae. Science 319, 482–484 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, H.-J. et al. Synthesis of carbohydrates in mineral-guided prebiotic cycles. J. Am. Chem. Soc. 133, 9457–9468 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Delidovich, I. V., Simonov, A. N., Taran, O. P. & Parmon, V. N. Catalytic formation of monosaccharides: from the formose reaction towards selective synthesis. ChemSusChem 7, 1833–1846 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Simonov, A. N. et al. Selective synthesis of erythrulose and 3-pentulose from formaldehyde and dihydroxyacetone catalyzed by phosphates in a neutral aqueous medium. Kinet. Catal. 48, 550–555 (2007).

    Article  CAS  Google Scholar 

  25. Iqbal, Z. & Novalin, S. The formose reaction: a tool to produce synthetic carbohydrates within a regenerative life support system. Curr. Org. Chem. 16, 769–788 (2012).

    Article  CAS  Google Scholar 

  26. Lambert, J. B., Gurusamy-Thangavelu, S. A. & Ma, K. The silicate-mediated formose reaction: bottom-up synthesis of sugar silicates. Science 327, 984–986 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Ricardo, A., Carrigan, M., Olcott, A. & Benner, S. Borate minerals stabilize ribose. Science 303, 196–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Colón‐Santos, S., Cooper, G. J. T. & Cronin, L. Taming the combinatorial explosion of the formose reaction via recursion within mineral environments. ChemSystemsChem 1, e1900014 (2019).

    Article  Google Scholar 

  29. Huskey, W. P. & Epstein, I. R. Autocatalysis and apparent bistability in the formose reaction. J. Am. Chem. Soc. 111, 3157–3163 (1989).

    Article  CAS  Google Scholar 

  30. Weiss, A. H., LaPierre, R. B. & Shapira, J. Homogeneously catalyzed formaldehyde condensation to carbohydrates. J. Catal. 16, 332–347 (1970).

    Article  CAS  Google Scholar 

  31. Weiss, A. H., Socha, R. F., Likholobov, V. A. & Sakharov, M. M. Formose sugars from formaldehyde. Appl. Catal. 1, 237–246 (1981).

    Article  CAS  Google Scholar 

  32. Kopetzki, D. & Antonietti, M. Hydrothermal formose reaction. New J. Chem. 35, 1787 (2011).

    Article  CAS  Google Scholar 

  33. Haas, M., Lamour, S. & Trapp, O. Development of an advanced derivatization protocol for the unambiguous identification of monosaccharides in complex mixtures by gas and liquid chromatography. J. Chromatogr. A 1568, 160–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Becker, M., Liebner, F., Rosenau, T. & Potthast, A. Ethoximation–silylation approach for mono- and disaccharide analysis and characterization of their identification parameters by GC/MS. Talanta 115, 642–651 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Becker, M. et al. Evaluation of different derivatisation approaches for gas chromatographic–mass spectrometric analysis of carbohydrates in complex matrices of biological and synthetic origin. J. Chromatogr. A 1281, 115–126 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Ziemecki, S., LaPierre, R. B., Weiss, A. H. & Sakharov, M. Homogeneously catalyzed condensation of formaldehyde to carbohydrates VI. Preparation and spectroscopic investigation of complexes active in formaldehyde condensation. J. Catal. 50, 455–463 (1977).

    Article  CAS  Google Scholar 

  37. Weber, A. L. Prebiotic sugar synthesis: hexose and hydroxy acid synthesis from glyceraldehyde catalyzed by iron(III) hydroxide oxide. J. Mol. Evol. 35, 1–6 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Khomenko, T. Homogeneously catalyzed formaldehyde condensation to carbohydrates IV. Alkaline earth hydroxide catalysts used with glycolaldehyde co-catalyst. J. Catal. 45, 356–366 (1976).

    Article  CAS  Google Scholar 

  39. Kooyman, C., Vellenga, K. & De Wilt, H. G. J. The isomerization of d-glucose into d-fructose in aqueous alkaline solutions. Carbohydr. Res. 54, 33–44 (1977).

    Article  CAS  Google Scholar 

  40. Gutsche, C. David et al. Base-catalyzed triose condensations. J. Am. Chem. Soc. 89, 1235–1245 (1967).

    Article  CAS  PubMed  Google Scholar 

  41. Nagorski, R. W. & Richard, J. P. Mechanistic imperatives for aldose−ketose isomerization in water: specific, general base- and metal ion-catalyzed isomerization of glyceraldehyde with proton and hydride transfer. J. Am. Chem. Soc. 123, 794–802 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Andersen, J. L., Flamm, C., Merkle, D. & Stadler, P. F. Inferring chemical reaction patterns using rule composition in graph grammars. J. Syst. Chem. 4, 4 (2013).

    Article  CAS  Google Scholar 

  43. Andersen, J. L., Flamm, C., Merkle, D. & Stadler, P. F. Rule composition in graph transformation models of chemical reactions. MATCH Commun. Math. Comput. Chem. 80, 661–704 (2018).

    Google Scholar 

  44. Simm, G. N. & Reiher, M. Context-driven exploration of complex chemical reaction networks. J. Chem. Theory Comput. 13, 6108–6119 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Bajczyk, M. D., Dittwald, P., Wołos, A., Szymkuć, S. & Grzybowski, B. A. Discovery and enumeration of organic-chemical and biomimetic reaction cycles within the network of chemistry. Angew. Chem. Int. Ed. 57, 2367–2371 (2018).

    Article  CAS  Google Scholar 

  46. Kowalik, M. et al. Parallel optimization of synthetic pathways within the network of organic chemistry. Angew. Chem. Int. Ed. 51, 7928–7932 (2012).

    Article  CAS  Google Scholar 

  47. Harsch, G., Bauer, H. & Voelter, W. Kinetik, Katalyse und Mechanismus der Sekundärreaktion in der Schlußphase der Formose-Reaktion. Liebigs Ann. Chem. 1984, 623–635 (1984).

    Article  Google Scholar 

  48. Berl, W. G. & Feazel, C. E. The kinetics of hexose formation from trioses in alkaline solution. J. Am. Chem. Soc. 73, 2054–2057 (1951).

    Article  CAS  Google Scholar 

  49. Simonov, A. N., Pestunova, O. P., Matvienko, L. G. & Parmon, V. N. The nature of autocatalysis in the Butlerov reaction. Kinet. Catal. 48, 245–254 (2007).

    Article  CAS  Google Scholar 

  50. Delidovich, I. V., Simonov, A. N., Pestunova, O. P. & Parmon, V. N. Catalytic condensation of glycolaldehyde and glyceraldehyde with formaldehyde in neutral and weakly alkaline aqueous media: kinetics and mechanism. Kinet. Catal. 50, 297–303 (2009).

    Article  CAS  Google Scholar 

  51. Breslow, R. On the mechanism of the formose reaction. Tetrahedron Lett. 1, 22–26 (1959).

    Article  Google Scholar 

  52. Pross, A. & Pascal, R. How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution. Beilstein J. Org. Chem. 13, 665–674 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Horowitz, J. M. & England, J. L. Spontaneous fine-tuning to environment in many-species chemical reaction networks. Proc. Natl Acad. Sci. USA 114, 7565–7570 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Patel, B. H., Percivalle, C., Ritson, D. J., Duffy, C. D. & Sutherland, J. D. Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nat. Chem. 7, 301–307 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Harris, C. R. et al. Array programming with NumPy. Nature 585, 357–362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. SciPy 1.0 Contributors. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020).

    Article  Google Scholar 

  57. Laine, R. A. & Sweeley, C. C. Analysis of trimethylsilyl O-methyloximes of carbohydrates by combined gas-liquid chromatography–mass spectrometry. Anal. Biochem. 43, 533–538 (1971).

    Article  CAS  PubMed  Google Scholar 

  58. Meyer, D., Friedland, J., Kohn, T. & Güttel, R. Transfer functions for periodic reactor operation: fundamental methodology for simple reaction networks. Chem. Eng. Technol. 40, 2096–2103 (2017).

    Article  CAS  Google Scholar 

  59. Hagberg, A. A., Schult, D. A. & Swart, P. J. Exploring network structure, dynamics, and function using NetworkX. in Proc. 7th Python in Science Conference (SciPy 2008) (eds Varoquaux, G., Vaught, T., & Millman, J.) 11–15 (2008).

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Acknowledgements

This work was supported by funding from the Simons Collaboration on the Origins of Life (SCOL; award 477123, W.T.S.H., W.E.R.) and the Dutch Ministry of Education, Culture and Science (Functional Molecular Systems Gravity programme 024.001.035, W.T.S.H., W.E.R., E.D., P.D.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank P van Galen, R de Graaf and J del Pozo Mellado for support with GC–MS analysis.

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Authors and Affiliations

  1. Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, Netherlands

    William E. Robinson, Elena Daines, Peer van Duppen, Thijs de Jong & Wilhelm T. S. Huck

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Contributions

W.E.R. and W.T.S.H. conceived the research and acquired funding. W.E.R. and E.D. developed the experimental methodology. W.T.S.H. administered the project and resources. All authors contributed to the design of experiments. W.E.R., E.D., P.v.D. and T.d.J. performed the experiments. W.E.R. curated and analysed the data. W.E.R. wrote the data analysis software and developed data visualizations. W.T.S.H. supervised the investigation. W.E.R. and W.T.S.H. wrote the original draft and all authors discussed the results and commented on the manuscript.

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Correspondence to Wilhelm T. S. Huck.

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Nature Chemistry thanks Subhabrata Maiti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Reaction types of the formose reaction.

Detailed reaction types which describe the transformations shown in Fig. 1a (main text).

Extended Data Fig. 2 A detailed schematic of the continuous stirred-tank reactor used in this work.

a Side schematic of the reactor depicting how inputs and the outlet were connected to the reactor and how the temperature was controlled. b Bottom view of the reactor showing the geometry of the inlet holes into the reactor.

Extended Data Fig. 3

The structures of compounds assigned in this work and their corresponding numbering scheme.

Extended Data Fig. 4 Mappings of key conditionals variations across data sets to the leaves of the dendrogram.

a Formaldehyde, b dihydroxyacetone, c CaCl2, d NaOH, e the ratio of CaCl2:NaOH, f The location of glycolaldehyde (2), erythrulose (9) and ribose (19) initiated reactions. The colour bars below each dendrogram indicate mapping of the colour to the value of each condition.

Extended Data Fig. 5 Variation of the composition of the formose reaction with temperature.

Conditions: formaldehyde (200 mM), dihydroxyacetone (25 mM amplitude, 50 mM offset, period 6 min.), CaCl2 (15 mM), NaOH (30 mM).

Extended Data Fig. 6 Variation of the formose reaction’s composition with residence time.

The data were determined from flow reactions at 21 °C, with inputs of dihydroxyacetone (25 mM amplitude, 50 mM offset, period three times the residence time), formaldehyde (200 mM), CaCl2 (15 mM), and NaOH (30 mM). Input concentrations are quoted as the initial concentration of compounds upon entering the continuous stirred-tank reactor.

Extended Data Fig. 7 A proposed mechanism for the selectivity between 14 and 20.

a The C2-C3 reaction to create 14 via a six-membered ring transition state in which α-hydroxymethyl groups adopt lower energy equatorial positions. b A similar reaction and transition state as show in panel a from which compound 20 is formed. Dashed bonds indicate those formed and broken over the course of the reaction.

Extended Data Fig. 8 A proposed mechanism for the selectivity between 12 and 13.

a The open-chain structure of 12. b The open-chain structure of 13. The likely conformation of the six-membered ring formed via coordination of Ca2+ to 12 (c) and 13 (d). Charges (Ca2+, O–) are omitted for clarity.

Supplementary information

Supplementary Information

Supplementary Figs. 1–11.

Source data

Source Data Fig. 2

Data used to create the bar charts in Fig. 2a. Data used to create the traces in Fig. 2c. Data used to create the traces in Fig. 2e.

Source Data Fig. 3

Data used to create the traces in Fig. 3a. Data used to create the heatmap in Fig. 3d.

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Robinson, W.E., Daines, E., van Duppen, P. et al. Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network. Nat. Chem. 14, 623–631 (2022). https://doi.org/10.1038/s41557-022-00956-7

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