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  • Perspective
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A roadmap towards integrated catalytic systems of the future

Nature Catalysis volume 3, pages 186–192 (2020)Cite this article

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Abstract

Modern-day chemical synthesis is still mainly a linear process that focuses on the design and optimization of single catalysts and reactions. By contrast, (bio)synthesis in nature is carried out by metabolic networks that are highly integrated, self-optimizing, multi-catalyst systems operating out of thermodynamic equilibrium. This allows the continuous, self-improving, multi-step synthesis of compounds from sustainable starting materials under mild and environmentally friendly conditions. While our capabilities to build catalytic systems of similar performance have been limited so far, current developments in chemistry, material sciences and synthetic biology open new paths technologically and conceptually. In this Perspective, we develop the idea that the future of catalysis is bio-inspired integrated catalytic systems that show life-like properties and provide a roadmap towards achieving this goal along five key steps: the design of biocatalysts, their combination into complex catalytic networks, the coupling of these reaction networks to energy modules, their compartmentalization and finally, their endowment with Darwinian properties.

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Fig. 1: The five key steps on the road to integrated catalytic systems.
Fig. 2: The design, build, test and learn cycle to develop new-to-nature enzyme reactions for complex reaction networks.

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References

  1. Armor, J. N. A history of industrial catalysis. Catal. Today 163, 3–9 (2011).

    CAS  Google Scholar 

  2. Seeman, J. I. The Nozoe Autograph Books: Stories behind the Stories. Chem. Rec. 13, 483–514 (2013).

    CAS  Google Scholar 

  3. Eschenmoser, A. & Wintner, C. E. Natural product synthesis and vitamin B12. Science 196, 1410–1420 (1977).

    CAS  PubMed  Google Scholar 

  4. Li, K. T. et al. An effective and simplified pH-stat control strategy for the industrial fermentation of vitamin B(12) by Pseudomonas denitrificans. Bioprocess. Biosyst. Eng. 31, 605–610 (2008).

    CAS  PubMed  Google Scholar 

  5. Beneyton, T. et al. Out-of-equilibrium microcompartments for the bottom-up integration of metabolic functions. Nat. Commun. 9, 2391 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Weiss, M. et al. Sequential bottom-up assembly of mechanically stabilized synthetic cells by microfluidics. Nat. Mater. 17, 89–96 (2018).

    CAS  PubMed  Google Scholar 

  7. Deshpande, S. et al. Spatiotemporal control of coacervate formation within liposomes. Nat. Commun. 10, 1800 (2019).

    PubMed  PubMed Central  Google Scholar 

  8. Hasatani, K. et al. High-throughput and long-term observation of compartmentalized biochemical oscillators. ChemComm 49, 8090–8092 (2013).

    CAS  Google Scholar 

  9. Dupin, A. & Simmel, F. C. Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits. Nat. Chem. 11, 32–39 (2019).

    CAS  PubMed  Google Scholar 

  10. Booth, M. J., Restrepo Schild, V., Box, S. J. & Bayley, H. Light-patterning of synthetic tissues with single droplet resolution. Sci. Rep. 7, 9315 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Schwille, P. et al. MaxSynBio: avenues towards creating cells from the bottom up. Angew. Chem. Int. Ed. 57, 13382–13392 (2018).

    CAS  Google Scholar 

  12. UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 47, D506–D515 (2018).

    Google Scholar 

  13. Jeske, L., Placzek, S., Schomburg, I., Chang, A. & Schomburg, D. BRENDA in 2019: a European ELIXIR core data resource. Nucleic Acids Res. 47, D542–D549 (2018).

    PubMed Central  Google Scholar 

  14. Yahya, A. R. M., Anderson, W. A. & Moo-Young, M. Ester synthesis in lipase-catalyzed reactions. Enzyme Microb. Technol. 23, 438–450 (1998).

    CAS  Google Scholar 

  15. Bornscheuer, U. T. & Kazlauskas, R. J. Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways. Angew. Chem. Int. Ed. 43, 6032–6040 (2004).

    CAS  Google Scholar 

  16. Glueck, S. M., Gumus, S., Fabian, W. M. F. & Faber, K. Biocatalytic carboxylation. Chem. Soc. Rev. 39, 313–328 (2010).

    CAS  PubMed  Google Scholar 

  17. Martin, J., Eisoldt, L. & Skerra, A. Fixation of gaseous CO2 by reversing a decarboxylase for the biocatalytic synthesis of the essential amino acid l-methionine. Nat. Catal. 1, 555–561 (2018).

    CAS  Google Scholar 

  18. Bernhardsgrutter, I. et al. Awakening the sleeping carboxylase function of enzymes: engineering the natural CO2-binding potential of reductases. J. Am. Chem. Soc. 141, 9778–9782 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. Schwander, T., Schada von Borzyskowski, L., Burgener, S., Cortina, N. S. & Erb, T. J. A synthetic pathway for the fixation of carbon dioxide in vitro. Science 354, 900–904 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Burgener, S., Schwander, T., Romero, E., Fraaije, M. W. & Erb, T. J. Molecular basis for converting (2S)-methylsuccinyl-CoA dehydrogenase into an oxidase. Molecules 23, 68 (2017).

    PubMed Central  Google Scholar 

  21. Hammer, S. C., Knight, A. M. & Arnold, F. H. Design and evolution of enzymes for non-natural chemistry. Curr. Opin. Green Sust. 7, 23–30 (2017).

    Google Scholar 

  22. Jeschek, M., Panke, S. & Ward, T. R. Artificial metalloenzymes on the verge of new-to-nature metabolism. Trends Biotechnol. 36, 60–72 (2018).

    CAS  PubMed  Google Scholar 

  23. Coelho, P. S., Brustad, E. M., Kannan, A. & Arnold, F. H. Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes. Science 339, 307–310 (2013).

    CAS  PubMed  Google Scholar 

  24. Kan, S. B., Lewis, R. D., Chen, K. & Arnold, F. H. Directed evolution of cytochrome c for carbon-silicon bond formation: Bringing silicon to life. Science 354, 1048–1051 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hammer, S. C. et al. Anti-Markovnikov alkene oxidation by metal-oxo-mediated enzyme catalysis. Science 358, 215–218 (2017).

    CAS  PubMed  Google Scholar 

  26. Hammer, S. C., Marjanovic, A., Dominicus, J. M., Nestl, B. M. & Hauer, B. Squalene hopene cyclases are protonases for stereoselective Bronsted acid catalysis. Nat. Chem. Biol. 11, 121–126 (2015).

    CAS  PubMed  Google Scholar 

  27. Gally, C., Nestl, B. M. & Hauer, B. Engineering Rieske non-heme iron oxygenases for the asymmetric dihydroxylation of alkenes. Angew. Chem. Int. Ed. 54, 12952–12956 (2015).

    CAS  Google Scholar 

  28. Alonso-de Castro, S., Cortajarena, A. L., López-Gallego, F. & Salassa, L. Bioorthogonal catalytic activation of platinum and ruthenium anticancer complexes by FAD and flavoproteins. Angew. Chem. Int. Ed. 57, 3143–3147 (2018).

    CAS  Google Scholar 

  29. Obexer, R. et al. Emergence of a catalytic tetrad during evolution of a highly active artificial aldolase. Nat. Chem. 9, 50–56 (2017).

    CAS  PubMed  Google Scholar 

  30. Jeschek, M. et al. Directed evolution of artificial metalloenzymes for in vivo metathesis. Nature 537, 661–665 (2016).

    CAS  PubMed  Google Scholar 

  31. Key, H. M., Dydio, P., Clark, D. S. & Hartwig, J. F. Abiological catalysis by artificial haem proteins containing noble metals in place of iron. Nature 534, 534–537 (2016).

    CAS  PubMed  Google Scholar 

  32. Jewett, M. C., Calhoun, K. A., Voloshin, A., Wuu, J. J. & Swartz, J. R. An integrated cell-free metabolic platform for protein production and synthetic biology. Mol. Syst. Biol. 4, 220 (2008).

    PubMed  PubMed Central  Google Scholar 

  33. Hold, C., Billerbeck, S. & Panke, S. Forward design of a complex enzyme cascade reaction. Nat. Commun. 7, 12971 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Opgenorth, P. H., Korman, T. P. & Bowie, J. U. A synthetic biochemistry module for production of bio-based chemicals from glucose. Nat. Chem. Biol. 12, 393–395 (2016).

    CAS  PubMed  Google Scholar 

  35. Valliere, M. A. et al. A cell-free platform for the prenylation of natural products and application to cannabinoid production. Nat. Commun. 10, 565 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Carbonell, P., Parutto, P., Baudier, C., Junot, C. & Faulon, J. L. Retropath: automated pipeline for embedded metabolic circuits. ACS Synth. Biol. 3, 565–577 (2014).

    CAS  PubMed  Google Scholar 

  37. Erb, T. J., Jones, P. R. & Bar-Even, A. Synthetic metabolism: metabolic engineering meets enzyme design. Curr. Opin. Chem. Biol. 37, 56–62 (2017).

    CAS  PubMed  Google Scholar 

  38. Siegel, J. B. et al. Computational protein design enables a novel one-carbon assimilation pathway. Proc. Natl Acad. Sci. USA 112, 3704–3709 (2015).

    CAS  PubMed  Google Scholar 

  39. Bogorad, I. W., Lin, T. S. & Liao, J. C. Synthetic non-oxidative glycolysis enables complete carbon conservation. Nature 502, 693–697 (2013).

    CAS  PubMed  Google Scholar 

  40. Sun, J., Jeffryes, J. G., Henry, C. S., Bruner, S. D. & Hanson, A. D. Metabolite damage and repair in metabolic engineering design. Metab. Eng. 44, 150–159 (2017).

    CAS  PubMed  Google Scholar 

  41. Opgenorth, P. H., Korman, T. P. & Bowie, J. U. A synthetic biochemistry molecular purge valve module that maintains redox balance. Nat. Commun. 5, 4113 (2014).

    CAS  PubMed  Google Scholar 

  42. Opgenorth, P. H., Korman, T. P., Iancu, L. & Bowie, J. U. A molecular rheostat maintains ATP levels to drive a synthetic biochemistry system. Nat. Chem. Biol. 13, 938–942 (2017).

    CAS  PubMed  Google Scholar 

  43. Andexer, J. N. & Richter, M. Emerging enzymes for ATP regeneration in biocatalytic processes. ChemBioChem 16, 380–386 (2015).

    CAS  PubMed  Google Scholar 

  44. Mordhorst, S. et al. Several polyphosphate kinase 2 enzymes catalyse the production of adenosine 5’-polyphosphates. ChemBioChem 20, 1019–1022 (2019).

    CAS  PubMed  Google Scholar 

  45. Mordhorst, S., Siegrist, J., Müller, M., Richter, M. & Andexer, J. N. Catalytic alkylation using a cyclic S-adenosylmethionine regeneration system. Angew. Chem. Int. Ed. 56, 4037–4041 (2017).

    CAS  Google Scholar 

  46. Masada, S. et al. An efficient chemoenzymatic production of small molecule glucosides with in situ UDP-glucose recycling. FEBS Lett. 581, 2562–2566 (2007).

    CAS  PubMed  Google Scholar 

  47. Spaans, S. K., Weusthuis, R. A., van der Oost, J. & Kengen, S. W. NADPH-generating systems in bacteria and archaea. Front. Microbiol. 6, 742 (2015).

    PubMed  PubMed Central  Google Scholar 

  48. Huang, R., Chen, H., Zhong, C., Kim, J. E. & Zhang, Y. H. High-throughput screening of coenzyme preference change of thermophilic 6-phosphogluconate dehydrogenase from NADP+ to NAD+. Sci. Rep. 6, 32644 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Megarity, C. F. et al. Electrocatalytic volleyball: rapid nanoconfined nicotinamide cycling for organic synthesis in electrode pores. Angew. Chem. Int. Ed. 58, 4948–4952 (2019).

    CAS  Google Scholar 

  50. Otrin, L. et al. Toward artificial mitochondrion: mimicking oxidative phosphorylation in polymer and hybrid membranes. Nano Lett. 17, 6816–6821 (2017).

    CAS  PubMed  Google Scholar 

  51. Lee, K. Y. et al. Photosynthetic artificial organelles sustain and control ATP-dependent reactions in a protocellular system. Nat. Biotechnol. 36, 530–535 (2018).

    CAS  PubMed  Google Scholar 

  52. Schmid-Dannert, C. & López-Gallego, F. Advances and opportunities for the design of self-sufficient and spatially organized cell-free biocatalytic systems. Curr. Opin. Chem. Biol. 49, 97–104 (2019).

    CAS  PubMed  Google Scholar 

  53. Koga, S., Williams, D. S., Perriman, A. W. & Mann, S. Peptide–nucleotide microdroplets as a step towards a membrane-free protocell model. Nat. Chem. 3, 720–724 (2011).

    CAS  PubMed  Google Scholar 

  54. Stadler, B. et al. A microreactor with thousands of subcompartments: enzyme-loaded liposomes within polymer capsules. Angew. Chem. Int. Ed. 48, 4359–4362 (2009).

    CAS  Google Scholar 

  55. Weiss, M. et al. Sequential bottom-up assembly of mechanically stabilized synthetic cells by microfluidics. Nat. Mater. 17, 89–96 (2018).

    CAS  PubMed  Google Scholar 

  56. Jo, S.-M., Wurm, F. R. & Landfester, K. Biomimetic cascade network between interactive multicompartments organized by enzyme-loaded silica nanoreactors. ACS Appl. Mater. Interfaces 10, 34230–34237 (2018).

    CAS  PubMed  Google Scholar 

  57. Ferlez, B., Sutter, M. & Kerfeld, C. A. A designed bacterial microcompartment shell with tunable composition and precision cargo loading. Metab. Eng. 54, 286–291 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Karim, A. S. & Jewett, M. C. A cell-free framework for rapid biosynthetic pathway prototyping and enzyme discovery. Metab. Eng. 36, 116–126 (2016).

    CAS  PubMed  Google Scholar 

  60. Atsumi, S., Hanai, T. & Liao, J. C. Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels. Nature 451, 86–89 (2008).

    CAS  PubMed  Google Scholar 

  61. Dellomonaco, C., Clomburg, J. M., Miller, E. N. & Gonzalez, R. Engineered reversal of the beta-oxidation cycle for the synthesis of fuels and chemicals. Nature 476, 355–359 (2011).

    CAS  PubMed  Google Scholar 

  62. Yim, H. et al. Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. Nat. Chem. Biol. 7, 445–452 (2011).

    CAS  PubMed  Google Scholar 

  63. Clomburg, J. M., Qian, S., Tan, Z., Cheong, S. & Gonzalez, R. The isoprenoid alcohol pathway, a synthetic route for isoprenoid biosynthesis. Proc. Natl Acad. Sci. USA 116, 12810–12815 (2019).

    CAS  PubMed  Google Scholar 

  64. Antonovsky, N. et al. Sugar synthesis from CO2 in Escherichia coli. Cell 166, 115–125 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schada von Borzyskowski, L. et al. An engineered Calvin–Benson–Bassham cycle for carbon dioxide fixation in Methylobacterium extorquens AM1. Metab. Eng. 47, 423–433 (2018).

    CAS  PubMed  Google Scholar 

  66. Lin, P. P. et al. Construction and evolution of an Escherichia coli strain relying on nonoxidative glycolysis for sugar catabolism. Proc. Natl Acad. Sci. USA 115, 3538–3546 (2018).

    CAS  PubMed  Google Scholar 

  67. Bernhardsgrutter, I. et al. The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite. Nat. Chem. Biol. 14, 1127–1132 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Hyde, C. C., Ahmed, S. A., Padlan, E. A., Miles, E. W. & Davies, D. R. Three-dimensional structure of the tryptophan synthase alpha 2 beta 2 multienzyme complex from Salmonella typhimurium. J. Biol. Chem. 263, 17857–17871 (1988).

    CAS  PubMed  Google Scholar 

  69. Ferreira, R. D. G., Azzoni, A. R. & Freitas, S. Techno-economic analysis of the industrial production of a low-cost enzyme using E. coli: the case of recombinant beta-glucosidase. Biotechnol. Biofuels 11, 81 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Korman, T. P., Opgenorth, P. H. & Bowie, J. U. A synthetic biochemistry platform for cell free production of monoterpenes from glucose. Nat. Commun. 8, 15526 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Taylor, H. S. Catalysis in chemical industry. Nature 104, 94–95 (1919).

    Google Scholar 

  72. Tamura, J. et al. Electrochemical reduction of CO2 to ethylene glycol on imidazolium ion-terminated self-assembly monolayer-modified Au electrodes in an aqueous solution. Phys. Chem. Chem. Phys. 17, 26072–26078 (2015).

    CAS  PubMed  Google Scholar 

  73. Kalberer, P. P., Buchanan, B. B. & Arnon, D. I. Rates of photosynthesis by isolated chloroplasts. Proc. Natl Acad. Sci. USA 57, 1542–1549 (1967).

    CAS  PubMed  Google Scholar 

  74. Nickel, H. Gewicht und Zusammensetzung der Chloroplasten von Antirrhinum majus. Flora Abt. A 159, 233–252 (1968).

    Google Scholar 

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Acknowledgements

This work was supported by the MaxSynBio network, jointly funded by the Federal Ministry of Education and Research (BMBF) and the Max Planck Society, the European Research Council (Grant No. 637675 SYBORG), The European Coordination and Support Action on biological standardization BIOROBOOST and the International Max Planck Research School for Environmental, Molecular and Cellular Microbiology.

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  1. Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany

    Simon Burgener, Shanshan Luo, Richard McLean, Tarryn E. Miller & Tobias J. Erb

  2. SYNMIKRO Center of Synthetic Microbiology, Marburg, Germany

    Tobias J. Erb

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  1. Simon Burgener
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  2. Shanshan Luo
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  3. Richard McLean
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Contributions

The manuscript was written with contributions of all authors, in particular S.B. (enzyme design), R.M. and T.E.M. (complex networks and cofactor regeneration), S.L. (Darwinian systems) and T.J.E. (all paragraphs, including introduction and conclusion).

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Correspondence to Tobias J. Erb.

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Burgener, S., Luo, S., McLean, R. et al. A roadmap towards integrated catalytic systems of the future. Nat Catal 3, 186–192 (2020). https://doi.org/10.1038/s41929-020-0429-x

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