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Opportunities and challenges for combining chemo- and biocatalysis

An Author Correction to this article was published on 07 March 2018

This article has been updated


The past decade has seen a substantial increase in successful examples of the combination of chemo- and biocatalysis for multistep syntheses. This is driven by obvious advantages such as higher yields, decreased costs, environmental benefits and high selectivity. On the downside, efforts must be undertaken to combine the divergent reaction conditions, reagent tolerance and solvent systems of these ‘different worlds of catalysis’. Owing to progress in enzyme discovery and engineering, as well as in the development of milder and more compatible conditions for operating with various chemocatalysts, many historical limitations can already be overcome. This Review highlights the opportunities available in the chemical space of combined syntheses using prominent examples, but also discusses the current challenges and emerging solutions, keeping in mind the fast progress in transition metal-, organo-, photo-, electro-, hetero- and biocatalysis.

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Fig. 1: Definition of different terms for one-pot cascade reactions used in this Review.
Fig. 2: Selected examples of combinations of transition metal- and enzyme-catalysed reactions.
Fig. 3: Selected examples of combinations of organo- and biocatalytic reactions.
Fig. 4: Selected example for the combination of a photo-/electrochemical and biocatalytic reaction.
Fig. 5: Reaction engineering strategies to cope with catalyst incompatibilities.

Change history

  • 07 March 2018

    In this Review Article originally published, the ORCID number for the author Radka Snajdrova was incorrect; it should have been 0000-0002-4809-1066. This has now been corrected in all versions of the Review Article.


  1. 1.

    Muschiol, J. et al. Cascade catalysis — strategies and challenges en route to preparative synthetic biology. Chem. Commun. 51, 5798–5811 (2015).

    CAS  Article  Google Scholar 

  2. 2.

    France, S. P., Hepworth, L. J., Turner, N. J. & Flitsch, S. L. Constructing biocatalytic cascades: in vitro and in vivo approaches to de novo multi-enzyme pathways. ACS Catal. 7, 710–724 (2017).

    CAS  Article  Google Scholar 

  3. 3.

    Gröger, H. & Hummel, W. Combining the ‘two worlds’ of chemocatalysis and biocatalysis towards multi-step one-pot processes in aqueous media. Curr. Opin. Chem. Biol. 19, 171–179 (2014).

    Article  CAS  Google Scholar 

  4. 4.

    Denard, C. A., Hartwig, J. 0F. & Zhao, H. M. Multistep one-pot reactions combining biocatalysts and chemical catalysts for asymmetric synthesis. ACS Catal. 3, 2856–2864 (2013).

    CAS  Article  Google Scholar 

  5. 5.

    Ricca, E., Brucher, B. & Schrittwieser, J. H. Multi-enzymatic cascade reactions: overview and perspectives. Adv. Synth. Catal. 353, 2239–2262 (2011).

    CAS  Article  Google Scholar 

  6. 6.

    Oroz-Guinea, I. & Garcia-Junceda, E. Enzyme catalysed tandem reactions. Curr. Opin. Chem. Biol. 17, 236–249 (2013).

    CAS  Article  Google Scholar 

  7. 7.

    Bruggink, A., Schoevaart, R. & Kieboom, T. Concepts of nature in organic synthesis: cascade catalysis and multistep conversions in concert. Org. Proc. Res. Dev. 7, 622–640 (2003).

    CAS  Article  Google Scholar 

  8. 8.

    Kourist, R., Schmidt, S. & Castiglione, K. Overcoming the incompatibility challenge in chemo-enzymatic and multi-catalytic cascade reactions. Chem. Eur. J. 23, 1–15 (2017).

  9. 9.

    Makkee, M., Kieboom, A. P. G. & van Bekkum, H. Combined action of enzyme and metal catalyst, applied to the preparation of d-mannitol. J. Chem. Soc. Chem. Commun. 930–931 (1980).

  10. 10.

    Allen, J. V. & Williams, J. M. J. Dynamic kinetic resolution with enzyme and palladium combinations. Tetrahedron Lett. 37, 1859–1862 (1996).

    CAS  Article  Google Scholar 

  11. 11.

    Dinh, P. M., Howarth, J. A., Hudnott, A. R., Williams, J. M. J. & Harris, W. Catalytic racemisation of alcohols: applications to enzymatic resolution reactions. Tetrahedron Lett. 37, 7623–7626 (1996).

    CAS  Article  Google Scholar 

  12. 12.

    Kim, M. J., Ahn, Y. & Park, J. Dynamic kinetic resolutions and asymmetric transformations by enzymes coupled with metalcatalysis. Curr. Opin. Biotechnol. 13, 578–587 (2002).

    CAS  Article  Google Scholar 

  13. 13.

    Larsson, A. L. E., Persson, B. A. & Bäckvall, J.-E. Enzymic resolution of alcohols coupled with ruthenium-catalyzed racemization of the substrate alcohol. Angew. Chem. Int. Ed. 36, 1211–1212 (1997).

    CAS  Article  Google Scholar 

  14. 14.

    Reetz, M. T. & Schimossek, K. Lipase-catalyzed dynamic kinetic resolution of chiral amines: use of palladium as the racemization catalyst. Chimia 50, 668–669 (1996).

    CAS  Google Scholar 

  15. 15.

    Carr, R. et al. Directed evolution of an amine oxidase for the preparative deracemisation of cyclic secondary amines. ChemBioChem 6, 637–639 (2005).

    CAS  Article  Google Scholar 

  16. 16.

    de Souza, R., Miranda, L. S. M. & Bornscheuer, U. T. A retrosynthesis approach for biocatalysis in organic synthesis. Chem. Eur. J. 23, 12040–12063 (2017). An in-depth review providing many examples for planning retrosynthesis reactions with enzymes.

    Article  CAS  Google Scholar 

  17. 17.

    Hönig, M., Sondermann, P., Turner, N. J. & Carreira, E. M. Enantioselective chemo- and biocatalysis: partners in retrosynthesis. Angew. Chem. Int. Ed. 56, 8942–8973 (2017). An in-depth review providing many examples for planning retrosynthesis reactions with enzymes.

    Article  CAS  Google Scholar 

  18. 18.

    Turner, N. J. & O’Reilly, E. Biocatalytic retrosynthesis. Nat. Chem. Biol. 9, 285–288 (2013).

    CAS  Article  Google Scholar 

  19. 19.

    Pamies, O. & Bäckvall, J. E. Combination of enzymes and metal catalysts. A powerful approach in asymmetric catalysis. Chem. Rev. 103, 3247–3262 (2003).

    CAS  Article  Google Scholar 

  20. 20.

    Persson, B. A., Larsson, A. L. E., Le Ray, M. & Bäckvall, J. E. Ruthenium- and enzyme-catalyzed dynamic kinetic resolution of secondary alcohols. J. Am. Chem. Soc. 121, 1645–1650 (1999).

    CAS  Article  Google Scholar 

  21. 21.

    Choi, J. H. et al. Aminocyclopentadienyl ruthenium chloride: catalytic racemization and dynamic kinetic resolution of alcohols at ambient temperature. Angew. Chem. Int. Ed. 41, 2373–2376 (2002).

    CAS  Article  Google Scholar 

  22. 22.

    Berkessel, A., Sebastian-Ibarz, M. L. & Müller, T. N. Lipase/aluminum-catalyzed dynamic kinetic resolution of secondary alcohols. Angew. Chem. Int. Ed. 45, 6567–6570 (2006).

    CAS  Article  Google Scholar 

  23. 23.

    Egi, M. et al. A mesoporous-silica-immobilized oxovanadium cocatalyst for the lipase-catalyzed dynamic kinetic resolution of racemic alcohols. Angew. Chem. Int. Ed. 52, 3654–3658 (2013).

    CAS  Article  Google Scholar 

  24. 24.

    Simons, C., Hanefeld, U., Arends, I. W. C. E., Maschmeyer, T. & Sheldon, R. A. Towards catalytic cascade reactions: asymmetric synthesis using combined chemo-enzymatic catalysts. Top. Catal. 40, 35–44 (2006).

    CAS  Article  Google Scholar 

  25. 25.

    Burda, E., Hummel, W. & Gröger, H. Modular chemoenzymatic one-pot syntheses in aqueous media: combination of a palladium-catalyzed cross-coupling with an asymmetric biotransformation. Angew. Chem. Int. Ed. 47, 9551–9554 (2008).

    CAS  Article  Google Scholar 

  26. 26.

    Rios-Lombardia, N. et al. From a sequential to a concurrent reaction in aqueous medium: ruthenium-catalyzed allylic alcohol isomerization and asymmetric bioreduction. Angew. Chem. Int. Ed. 55, 8691–8695 (2016). The presented study is one of the rare cases where a concurrent cascade was developed for the synthesis of chiral alcohols without applying any special engineering techniques.

    CAS  Article  Google Scholar 

  27. 27.

    Gröger, H. Metals and Metal Complexes in Cooperative Catalysis with Enzymes Within Organic-Synthetic One-Pot Processes, in Cooperative Catalysis: Designing Efficient Catalysts for Synthesis (Wiley-VCH, Weinheim, Germany, 2015).

  28. 28.

    Huo, Y., Zeng, H. & Zhang, Y. Integrating metabolic engineering and heterogeneous chemocatalysis: new opportunities for biomass to chemicals. ChemSusChem 9, 1078–1080 (2016).

    CAS  Article  Google Scholar 

  29. 29.

    Yuryev, R., Strompen, S. & Liese, A. Coupled chemo(enzymatic) reactions in continuous flow. Beilstein J. Org. Chem. 7, 1449–1467 (2011).

    CAS  Article  Google Scholar 

  30. 30.

    Fink, M. J., Schön, M., Rudroff, F., Schnürch, M. & Mihovilovic, M. D. Single operation stereoselective synthesis of aerangis lactones: combining continuous flow hydrogenation and biocatalysts in a chemoenzymatic sequence. ChemCatChem 5, 724–727 (2013).

    CAS  Article  Google Scholar 

  31. 31.

    Vennestrøm, P. N. R. et al. Chemoenzymatic combination of glucose oxidase with titanium silicalite-1. ChemCatChem 2, 943–945 (2010).

    Article  CAS  Google Scholar 

  32. 32.

    Sirasani, G., Tong, L. & Balskus, E. P. A biocompatible alkene hydrogenation merges organic synthesis with microbial metabolism. Angew. Chem. Int. Ed. 53, 7785–7788 (2014).

    CAS  Article  Google Scholar 

  33. 33.

    Suastegui, M. et al. Combining metabolic engineering and electrocatalysis: application to the production of polyamides from sugar. Angew. Chem. Int. Ed. 55, 2368–2373 (2016).

    CAS  Article  Google Scholar 

  34. 34.

    Baer, K. et al. Sequential and modular synthesis of chiral 1,3-diols with two stereogenic centers: access to all four stereoisomers by combination of organo- and biocatalysis. Angew. Chem. Int. Ed. 48, 9355–9358 (2009).

    CAS  Article  Google Scholar 

  35. 35.

    Rulli, G. et al. Direction of kinetically versus thermodynamically controlled organocatalysis and its application in chemoenzymatic synthesis. Angew. Chem. Int. Ed. 50, 7944–7947 (2011).

    CAS  Article  Google Scholar 

  36. 36.

    Rulli, G., Duangdee, N., Hummel, W., Berkessel, A. & Gröger, H. First tandem-type one-pot process combining asymmetric organo- and biocatalytic reactions in aqueous media exemplified for the enantioselective and diastereoselective synthesis of 1,3-diols. Eur. J. Org. Chem. 2017, 812–817 (2017).

    CAS  Article  Google Scholar 

  37. 37.

    Simon, R. C. et al. Stereoselective synthesis of gamma-hydroxynorvaline through combination of organo- and biocatalysis. Chem. Commun. 50, 15669–15672 (2014).

    CAS  Article  Google Scholar 

  38. 38.

    Suljic, S., Pietruszka, J. & Worgull, D. Asymmetric bio- and organocatalytic cascade reaction — laccase and secondary amine-catalyzed alpha-arylation of aldehydes. Adv. Synth. Catal. 357, 1822–1830 (2015).

    CAS  Article  Google Scholar 

  39. 39.

    Chen, S. T., Huang, W. H. & Wang, K. T. Resolution of amino-acids in a mixture of 2-methyl-2-propanol water (19/1) catalyzed by alcalase via in-situ racemization of one antipode mediated by pyridoxal 5-phosphate. J. Org. Chem. 59, 7580–7581 (1994).

    CAS  Article  Google Scholar 

  40. 40.

    Zimmermann, V., Beller, M. & Kragl, U. Modelling the reaction course of a dynamic kinetic resolution of amino acid derivatives: identifying and overcoming bottlenecks. Org. Proc. Res. Dev. 10, 622–627 (2006).

    CAS  Article  Google Scholar 

  41. 41.

    Berkessel, A., Jurkiewicz, I. & Mohan, R. Enzymatic dynamic kinetic resolution of oxazinones: a new approach to enantiopure beta(2)-amino acids. ChemCatChem 3, 319–330 (2011).

    CAS  Article  Google Scholar 

  42. 42.

    Hoyos, P., Pace, V. & Alcantara, A. R. Dynamic kinetic resolution via hydrolase-metal combo catalysis in stereoselective synthesis of bioactive compounds. Adv. Synth. Catal. 354, 2585–2611 (2012).

    CAS  Article  Google Scholar 

  43. 43.

    Lee, S. H., Kim, J. H. & Park, C. B. Coupling photocatalysis and redox biocatalysis toward biocatalyzed artificial photosynthesis. Chem. Eur. J. 19, 4392–4406 (2013).

    CAS  Article  Google Scholar 

  44. 44.

    Ji, X., Su, Z., Wang, P., Ma, G. & Zhang, S. Integration of artificial photosynthesis system for enhanced electronic energy-transfer efficacy: a case study for solar-energy driven bioconversion of carbon dioxide to methanol. Small 12, 4753–4762 (2016).

    CAS  Article  Google Scholar 

  45. 45.

    Butti, S. K. et al. Microbial electrochemical technologies with the perspective of harnessing bioenergy: maneuvering towards upscaling. Renew. Sust. Energy Rev. 53, 462–476 (2016).

    CAS  Article  Google Scholar 

  46. 46.

    Kochius, S., Magnusson, A. O., Hollmann, F., Schrader, J. & Holtmann, D. Immobilized redox mediators for electrochemical NAD(P)+ regeneration. App. Microbiol. Biotechnol. 93, 2251–2264 (2012).

    CAS  Article  Google Scholar 

  47. 47.

    Hollmann, F. & Schmid, A. Electrochemical regeneration of oxidoreductases for cell-free biocatalytic redox reactions. Biocat. Biotrans. 22, 63–88 (2004).

    CAS  Article  Google Scholar 

  48. 48.

    Fisher, K. et al. Electro-enzymatic viologen-mediated substrate reduction using pentaerythritol tetranitrate reductase and a parallel, segmented fluid flow system. Catal. Sci. Technol. 3, 1505–1511 (2013).

    CAS  Article  Google Scholar 

  49. 49.

    Nerimetla, R., Walgama, C., Singh, V., Hartson, S. D. & Krishnan, S. Mechanistic insights into voltage-driven biocatalysis of a cytochrome P450 bactosomal film on a self-assembled monolayer. ACS Catal. 7, 3446–3453 (2017).

    CAS  Article  Google Scholar 

  50. 50.

    Gunther, H., Walter, K., Köhler, P. & Simon, H. On a new artificial mediator accepting NADP(H) oxidoreductase from Clostridium thermoaceticum. J. Biotechnol. 83, 253–267 (2000).

    CAS  Article  Google Scholar 

  51. 51.

    Suye, S.-i, Aramoto, Y., Nakamura, M., Tabata, I. & Sakakibara, M. Electrochemical reduction of immobilized NADP+ on a polymer modified electrode with a co-polymerized mediator. Enzyme Microb. Technol. 30, 139–144 (2002).

    CAS  Article  Google Scholar 

  52. 52.

    Venkata Mohan, S., Velvizhi, G., Vamshi Krishna, K. & Lenin Babu, M. Microbial catalyzed electrochemical systems: a bio-factory with multi-facet applications. Bioresour. Technol. 165, 355–364 (2014).

    CAS  Article  Google Scholar 

  53. 53.

    Kuk, S. K. et al. Photoelectrochemical reduction of carbon dioxide to methanol through a highly efficient enzyme cascade. Angew. Chem. Int. Ed. 56, 3827–3832 (2017). An excellent example for the combination of three enzymes.

    CAS  Article  Google Scholar 

  54. 54.

    Sorigue, D. et al. An algal photoenzyme converts fatty acids to hydrocarbons. Science 357, 903–907 (2017).

    CAS  Article  Google Scholar 

  55. 55.

    Tomasek, J. & Schatz, J. Olefin metathesis in aqueous media. Green Chem. 15, 2317–2338 (2013).

    CAS  Article  Google Scholar 

  56. 56.

    Denard, C. A. et al. Cooperative tandem catalysis by an organometallic complex and a metalloenzyme. Angew. Chem. Int. Ed. 53, 465–469 (2014).

    CAS  Article  Google Scholar 

  57. 57.

    Heidlindemann, M., Rulli, G., Berkessel, A., Hummel, W. & Gröger, H. Combination of asymmetric organo- and biocatalytic reactions in organic media using immobilized catalysts in different compartments. ACS Catal. 4, 1099–1103 (2014).

    CAS  Article  Google Scholar 

  58. 58.

    Wang, Y. & Zhao, H. Tandem reactions combining biocatalysts and chemical catalysts for asymmetric synthesis. Catalysts 6, 194 (2016).

    Article  CAS  Google Scholar 

  59. 59.

    Huang, H. et al. Tandem catalytic conversion of glucose to 5-hydroxymethylfurfural with an immobilized enzyme and a solid acid. ACS Catal. 4, 2165–2168 (2014).

    CAS  Article  Google Scholar 

  60. 60.

    Lee, Y. C., Dutta, S. & Wu, K. C. Integrated, cascading enzyme-/chemocatalytic cellulose conversion using catalysts based on mesoporous silica nanoparticles. ChemSusChem 7, 3241–3246 (2014).

    CAS  Article  Google Scholar 

  61. 61.

    Ganai, A. K., Shinde, P., Dhar, B. B., Sen Gupta, S. & Prasad, B. L. V. Development of a multifunctional catalyst for a “relay” reaction. RSC Adv. 3, 2186–2191 (2013).

    CAS  Article  Google Scholar 

  62. 62.

    Gómez Baraibar, A. et al. A one-pot cascade reaction combining an encapsulated decarboxylase with a metathesis catalyst for the synthesis of bio-based antioxidants. Angew. Chem. Int. Ed. 55, 14823–14827 (2016).

    Article  CAS  Google Scholar 

  63. 63.

    Wang, Z. J., Clary, K. N., Bergman, R. G., Raymond, K. N. & Toste, F. D. A supramolecular approach to combining enzymatic and transition metalcatalysis. Nat. Chem. 5, 100–103 (2013). This paper describes a very elegant way of spatially separating various catalysts on the microscale by applying a supramolecular approach.

    CAS  Article  Google Scholar 

  64. 64.

    Brahma, A. et al. An orthogonal biocatalytic approach for the safe generation and use of HCN in a multistep continuous preparation of chiral O-acetylcyanohydrins. Synlett 27, 262–266 (2016).

    CAS  Google Scholar 

  65. 65.

    Köhler, V. et al. Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes. Nat. Chem. 5, 93–99 (2013). This is the first combination of an artifical metallo-enzyme with various enzymes in a concurrent-type cascade.

    Article  CAS  Google Scholar 

  66. 66.

    Okamoto, Y., Köhler, V. & Ward, T. R. An NAD(P)H-dependent artificial transfer hydrogenase for multienzymatic cascades. J. Am. Chem. Soc. 138, 5781–5784 (2016).

    CAS  Article  Google Scholar 

  67. 67.

    Okamoto, Y., Köhler, V., Paul, C. E., Hollmann, F. & Ward, T. R. Efficient in situ regeneration of NADH mimics by an artificial metalloenzyme. ACS Catal. 6, 3553–3557 (2016).

    CAS  Article  Google Scholar 

  68. 68.

    Sato, H., Hummel, W. & Gröger, H. Cooperative catalysis of noncompatible catalysts through compartmentalization: Wacker oxidation and enzymatic reduction in a one-pot process in aqueous media. Angew. Chem. Int. Ed. 54, 4488–4492 (2015).

    CAS  Article  Google Scholar 

  69. 69.

    Wallace, S. & Balskus, E. P. Interfacing microbial styrene production with a biocompatible cyclopropanation reaction. Angew. Chem. Int. Ed. 54, 7106–7109 (2015).

    CAS  Article  Google Scholar 

  70. 70.

    Lee, Y., Umeano, A. & Balskus, E. P. Rescuing auxotrophic microorganisms with nonenzymatic chemistry. Angew. Chem. Int. Ed. 52, 11800–11803 (2013).

    CAS  Article  Google Scholar 

  71. 71.

    Huang, P. S., Boyken, S. E. & Baker, D. The coming of age of de novo protein design. Nature 537, 320–327 (2016).

    CAS  Article  Google Scholar 

  72. 72.

    Obexer, R., Pott, M., Zeymer, C., Griffiths, A. D. & Hilvert, D. Efficient laboratory evolution of computationally designed enzymes with low starting activities using fluorescence-activated droplet sorting. Prot. Eng. Des. Sel. 29, 355–366 (2016).

    CAS  Article  Google Scholar 

  73. 73.

    Garrabou, X., Verez, R. & Hilvert, D. Enantiocomplementary synthesis of gamma-nitroketones using designed and evolved carboligases. J. Am. Chem. Soc. 139, 103–106 (2017).

    CAS  Article  Google Scholar 

  74. 74.

    Brandenberg, O. F., Fasan, R. & Arnold, F. Exploiting and engineering hemoproteins for abiological carben and nitrne transfer reactions. Curr. Opin. Biotechnol. 47, 102–111 (2017).

    CAS  Article  Google Scholar 

  75. 75.

    Prier, C. K. & Arnold, F. H. Chemomimetic biocatalysis: exploiting the synthetic potential of cofactor-dependent enzymes to create new catalysts. J. Am. Chem. Soc. 137, 13992–14006 (2015).

    CAS  Article  Google Scholar 

  76. 76.

    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  Article  Google Scholar 

  77. 77.

    Dydio, P. et al. An artificial metalloenzyme with the kinetics of native enzymes. Science 354, 102–106 (2016). This study demonstrates the beauty of designing and optimizing unnatural metallo-enzymes, which opens access to novel chemistries.

    CAS  Article  Google Scholar 

  78. 78.

    Dydio, P., Key, H. M., Hayashi, H., Clark, D. S. & Hartwig, J. F. Chemoselective, enzymatic C–H bond amination catalyzed by a cytochrome P450 containing an Ir(Me)-PIX cofactor. J. Am. Chem. Soc. 139, 1750–1753 (2017).

    CAS  Article  Google Scholar 

  79. 79.

    Bordeaux, M., Tyagi, V. & Fasan, R. Highly diastereoselective and enantioselective olefin cyclopropanation using engineered myoglobin-based catalysts. Angew. Chem. Int. Ed. 54, 1744–1748 (2015).

    CAS  Article  Google Scholar 

  80. 80.

    Sauer, D. F. et al. A highly active biohybrid catalyst for olefin metathesis in water: impact of a hydrophobic cavity in a beta-barrel protein. ACS Catal. 5, 7519–7522 (2015).

    CAS  Article  Google Scholar 

  81. 81.

    Srivastava, P., Yang, H., Ellis-Guardiola, K. & Lewis, J. C. Engineering a dirhodium artificial metalloenzyme for selective olefin cyclopropanation. Nat. Commun. 6, 7789 (2015).

    CAS  Article  Google Scholar 

  82. 82.

    Heinisch, T. & Ward, T. R. Artificial metalloenzymes based on the biotin–streptavidin technology: challenges and opportunities. Acc. Chem. Res. 49, 1711–1721 (2016).

    CAS  Article  Google Scholar 

  83. 83.

    Schwizer, F. et al. Artificial metalloenzymes: reaction scope and optimization strategies. Chem. Rev. (2017).

  84. 84.

    Jeschek, M. et al. Directed evolution of artificial metalloenzymes for in vivo metathesis. Nature 537, 661–665 (2016). The first example achieving a metathesis reaction in vivo using the streptavidin concept with a Ru catalyst.

    CAS  Article  Google Scholar 

  85. 85.

    Emmanuel, M. A., Greenberg, N. R., Oblinsky, D. G. & Hyster, T. K. Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light. Nature 540, 414–417 (2016). Novel chemistry was achieved by enantioselective light-driven dehalogenation of racemic halolactones.

    CAS  Article  Google Scholar 

  86. 86.

    Sandoval, B. A., Meichan, A. J. & Hyster, T. K. Enantioselective hydrogen atom transfer: discovery of catalytic promiscuity in flavin-dependent ‘ene’-reductases. J. Am. Chem. Soc. 139, 11313–11316 (2017).

    CAS  Article  Google Scholar 

  87. 87.

    Hummel, W., Schütte, H., Schmidt, E., Wandrey, C. & Kula, M.-R. Isolation of l-phenylalanine dehydrogenase from Rhodococcus sp. M4 and its application for the production of l-phenylalanine. App. Microbiol. Biotechnol. 26, 409–416 (1987).

    CAS  Article  Google Scholar 

  88. 88.

    Bloh, J. Z. & Marschall, R. Heterogeneous photoredox catalysis: reactions, materials, and reaction engineering. Eur. J. Org. Chem. 2017, 2085–2094 (2017).

    CAS  Article  Google Scholar 

  89. 89.

    Brown, K. A. et al. Photocatalytic regeneration of nicotinamide cofactors by quantum dot-enzyme biohybrid complexes. ACS Catal. 6, 2201–2204 (2016).

    CAS  Article  Google Scholar 

  90. 90.

    Choudhury, S., Baeg, J. O., Park, N. J. & Yadav, R. K. A solar light-driven, eco-friendly protocol for highly enantioselective synthesis of chiral alcohols via photocatalytic/biocatalytic cascades. Green Chem. 16, 4389–4400 (2014).

    CAS  Article  Google Scholar 

  91. 91.

    Lam, Q., Kato, M. & Cheruzel, L. Ru(II)-diimine functionalized metalloproteins: from electron transfer studies to light-driven biocatalysis. Biochim. Biophys. Acta Bioenerg. 1857, 589–597 (2016).

    CAS  Article  Google Scholar 

  92. 92.

    Churakova, E. et al. Specific photobiocatalytic oxyfunctionalization reactions. Angew. Chem. Int. Ed. 50, 10716–10719 (2011).

    CAS  Article  Google Scholar 

  93. 93.

    Girhard, M., Kunigk, E., Tihovsky, S., Shumyantseva, V. V. & Urlacher, V. B. Light-driven biocatalysis with cytochrome P450 peroxygenases. Biotechnol. Appl. Biochem. 60, 111–118 (2013).

    CAS  Article  Google Scholar 

  94. 94.

    Tran, N. H. et al. An efficient light-driven P450 BM3 biocatalyst. J. Am. Chem. Soc. 135, 14484–14487 (2013).

    CAS  Article  Google Scholar 

  95. 95.

    Park, J. H. et al. Cofactor-free light-driven whole-cell cytochrome P450 catalysis. Angew. Chem. Int. Ed. 54, 969–973 (2015).

    CAS  Article  Google Scholar 

  96. 96.

    Lee, S. H. et al. Cofactor-free, direct photoactivation of enoate reductases for the asymmetric reduction of C=C bonds. Angew. Chem. Int. Ed. 56, 8681–8685 (2017).

    CAS  Article  Google Scholar 

  97. 97.

    Cannella, D. et al. Light-driven oxidation of polysaccharides by photosynthetic pigments and a metalloenzyme. Nat. Commun. 7, 11134 (2016).

    CAS  Article  Google Scholar 

  98. 98.

    Thomas, B. et al. Application of biocatalysis to on-DNA carbohydrate library synthesis. ChemBioChem 18, 858–863 (2017).

    CAS  Article  Google Scholar 

  99. 99.

    Milczek, E. M. Commercial applications for enzyme-mediated protein conjugation: new developments in enzymatic processes to deliver functionalized proteins on the commercial scale. Chem. Rev (2017).

  100. 100.

    Bornscheuer, U. T. et al. Engineering the third wave of biocatalysis. Nature 485, 185–194 (2012).

    CAS  Article  Google Scholar 

  101. 101.

    Kazlauskas, R. J. & Bornscheuer, U. T. Finding better protein engineering strategies. Nat. Chem. Biol. 5, 526–529 (2009).

    CAS  Article  Google Scholar 

  102. 102.

    Anastas, P. T. & Warner, J. C. Green Chemistry: Theory and Practice (Oxford Univ. Press, Oxford, 1998).

  103. 103.

    Börner, A. & Franke, R. E. Hydroformylation (Wiley-VCH, 2016).

  104. 104.

    Gabriel, C. M. et al. Effects of co-solvents on reactions run under micellar catalysis conditions. Org. Lett. 19, 194–197 (2017).

    CAS  Article  Google Scholar 

  105. 105.

    Armenise, N., Malferrari, D., Ricciardulli, S., Galletti, P. & Tagliavini, E. Multicomponent cascade synthesis of biaryl-based chalcones in pure water and in an aqueous micellar environment. Eur. J. Org. Chem. 2016, 3177–3185 (2016).

    CAS  Article  Google Scholar 

  106. 106.

    Gallou, F., Isley, N. A., Ganic, A., Onken, U. & Parmentier, M. Surfactant technology applied toward an active pharmaceutical ingredient: more than a simple green chemistry advance. Green Chem. 18, 14–19 (2016).

    Article  Google Scholar 

  107. 107.

    Choluj, A., Zielinski, A., Grela, K. & Chmielewski, M. J. Metathesis@MOF: simple and robust immobilization of olefin metathesis catalysts inside (Al)MIL-101-NH2. ACS Catal. 6, 6343–6349 (2016).

    CAS  Article  Google Scholar 

  108. 108.

    Yang, H., Fu, L., Wei, L., Liang, J. & Binks, B. P. Compartmentalization of incompatible reagents within Pickering emulsion droplets for one-pot cascade reactions. J. Am. Chem. Soc. 137, 1362–1371 (2015).

    CAS  Article  Google Scholar 

  109. 109.

    Palivan, C. G. et al. Bioinspired polymer vesicles and membranes for biological and medical applications. Chem. Soc. Rev. 45, 377–411 (2016).

    CAS  Article  Google Scholar 

  110. 110.

    Worsdorfer, B., Woycechowsky, K. J. & Hilvert, D. Directed evolution of a protein container. Science 331, 589–592 (2011).

    Article  CAS  Google Scholar 

  111. 111.

    Wells, A. S., Finch, G. L., Michels, P. C. & Wong, J. W. Use of enzymes in the manufacture of active pharmaceutical ingredients — a science and safety-based approach to ensure patient safety and drug quality. Org. Proc. Res. Dev. 16, 1986–1993 (2012).

    CAS  Article  Google Scholar 

  112. 112.

    Wells, A. S. et al. Case studies illustrating a science and risk-based approach to ensuring drug quality when using enzymes in the manufacture of active pharmaceuticals ingredients for oral dosage form. Org. Proc. Res. Dev. 20, 594–601 (2016).

    CAS  Article  Google Scholar 

  113. 113.

    Lohr, T. L. & Marks, T. J. Orthogonal tandem catalysis. Nat. Chem. 7, 477–482 (2015).

    CAS  Article  Google Scholar 

  114. 114.

    Filice, M. & Palomo, J. M. Cascade reactions catalyzed by bionanostructures. ACS Catal. 4, 1588–1598 (2014).

    CAS  Article  Google Scholar 

  115. 115.

    Kroutil, W. & Rueping, M. Introduction to ACS Catalysis virtual special issue on cascade catalysis. ACS Catal. 4, 2086–2087 (2014).

    CAS  Article  Google Scholar 

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We are grateful to R. J. Carroll and M. Höhne for critical reading of the manuscript.

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Correspondence to Uwe T. Bornscheuer.

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R.S. is an employee of Novartis Pharma AG and H.I. is an employee of F. Hoffmann-La Roche Ltd.

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Rudroff, F., Mihovilovic, M.D., Gröger, H. et al. Opportunities and challenges for combining chemo- and biocatalysis. Nat Catal 1, 12–22 (2018).

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