Natural inspirations for metal–ligand cooperative catalysis


In conventional homogeneous catalysis, supporting ligands act as spectators that do not interact directly with substrates. However, in metal–ligand cooperative catalysis, ligands are involved in facilitating reaction pathways that would be less favourable were they to occur solely at the metal centre. This catalysis paradigm has been known for some time, in part because it is at play in enzyme catalysis. For example, studies of hydrogenative and dehydrogenative enzymes have revealed striking details of metal–ligand cooperative catalysis that involve functional groups proximal to metal active sites. In addition to the more well-known [FeFe]-hydrogenase and [NiFe]-hydrogenase enzymes, [Fe]-hydrogenase, lactate racemase and alcohol dehydrogenase each makes use of cooperative catalysis. This Perspective highlights these enzymatic examples of metal–ligand cooperative catalysis and describes functional bioinspired molecular catalysts that also make use of these motifs. Although progress has been made in developing molecular catalysts, considerable challenges will need to be addressed before we have synthetic catalysts of practical value.

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Figure 1: Cooperative catalysis in [FeFe]- and [NiFe]-hydrogenases enables the heterolysis of H2.
Figure 2: [Fe]-hydrogenase and its model compounds.
Figure 3: Some features of the lactate racemase and alcohol dehydrogenase active sites have been replicated in synthetic mimics.
Figure 4: [NiFe]-carbon monoxide dehydrogenase, [Ni(cyclam)Cl]+ and an Fe porphyrinate each catalyse CO2 electroreduction to CO.


  1. 1

    Khusnutdinova, J. R. & Milstein, D. Metal–ligand cooperation. Angew. Chem. Int. Ed. 54, 12236–12273 (2015).

    CAS  Article  Google Scholar 

  2. 2

    van der Vlugt, J. I. Cooperative catalysis with first-row late transition metals. Eur. J. Inorg. Chem. 2012, 363–375 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Collman, J. P. Synthetic models for the oxygen-binding hemoproteins. Acc. Chem. Res. 10, 265–272 (1977).

    CAS  Article  Google Scholar 

  4. 4

    Collman, J. P. & Fu, L. Synthetic models for hemoglobin and myoglobin. Acc. Chem. Res. 32, 455–463 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Vignais, P. M., Billoud, B. & Meyer, J. Classification and phylogeny of hydrogenases. FEMS Microbiol. Rev. 25, 455–501 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Lubitz, W., Ogata, H., Rüdiger, O. & Reijerse, E. Hydrogenases. Chem. Rev. 114, 4081–4148 (2014).

    CAS  Article  Google Scholar 

  7. 7

    Zampella, G., Greco, C., Fantucci, P. & De Gioia, L. Proton reduction and dihydrogen oxidation on models of the [2Fe]H cluster of [Fe] hydrogenases. A density functional theory investigation. Inorg. Chem. 45, 4109–4118 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Rauchfuss, T. B. Diiron azadithiolates as models for the [FeFe]-hydrogenase active site and paradigm for the role of the second coordination sphere. Acc. Chem. Res. 48, 2107–2116 (2015).

    CAS  Article  Google Scholar 

  9. 9

    Schilter, D., Camara, J. M., Huynh, M. T., Hammes-Schiffer, S. & Rauchfuss, T. B. Hydrogenase enzymes and their synthetic models: the role of metal hydrides. Chem. Rev. 116, 8693–8749 (2016).

    CAS  Article  Google Scholar 

  10. 10

    Evans, R. M. et al. Mechanism of hydrogen activation by [NiFe] hydrogenases. Nat. Chem. Biol. 12, 46–50 (2016).

    CAS  Article  Google Scholar 

  11. 11

    Berggren, G. et al. Biomimetic assembly and activation of [FeFe]-hydrogenases. Nature 499, 66–69 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Esselborn, J. et al. Spontaneous activation of [FeFe]-hydrogenases by an inorganic [2Fe] active site mimic. Nat. Chem. Biol. 9, 607–609 (2013).

    CAS  Article  Google Scholar 

  13. 13

    Schilter, D. & Rauchfuss, T. B. And the winner is ... azadithiolate: an amine proton relay in the [FeFe] hydrogenases. Angew. Chem. Int. Ed. 52, 13518–13520 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Esselborn, J. et al. A structural view of synthetic cofactor integration into [FeFe]-hydrogenases. Chem. Sci. 7, 959–968 (2016).

    CAS  Article  Google Scholar 

  15. 15

    Siebel, J. F. et al. Hybrid [FeFe]-hydrogenases with modified active sites show remarkable residual enzymatic activity. Biochemistry 54, 1474–1483 (2015).

    CAS  Article  Google Scholar 

  16. 16

    Shima, S. & Thauer, R. K. A third type of hydrogenase catalyzing H2 activation. Chem. Rec. 7, 37–46 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Shima, S. & Ermler, U. Structure and function of [Fe]-hydrogenase and its iron–guanylylpyridinol (FeGP) cofactor. Eur. J. Inorg. Chem. 2011, 963–972 (2011).

    Article  Google Scholar 

  18. 18

    Shima, S. et al. The crystal structure of [Fe]-hydrogenase reveals the geometry of the active site. Science 321, 572–575 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Tamura, H. et al. Crystal structures of [Fe]-hydrogenase in complex with inhibitory isocyanides: implications for the H2-activation site. Angew. Chem. Int. Ed. 52, 9656–9659 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Yang, X. & Hall, M. B. Monoiron hydrogenase catalysis: hydrogen activation with the formation of a dihydrogen, Fe–Hδ−···Hδ+–O, bond and methenyl-H4MPT+ triggered hydride transfer. J. Am. Chem. Soc. 131, 10901–10908 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Finkelmann, A. R., Stiebritz, M. T. & Reiher, M. Kinetic modeling of hydrogen conversion at [Fe] hydrogenase active-site models. J. Phys. Chem. B 117, 4806–4817 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Finkelmann, A. R., Senn, H. M. & Reiher, M. Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling. Chem. Sci. 5, 4474–4482 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Shima, S. et al. Reconstitution of [Fe]-hydrogenase using model complexes. Nat. Chem. 7, 995–1002 (2015).

    CAS  Article  Google Scholar 

  24. 24

    Schultz, K. M., Chen, D. & Hu, X. [Fe]-hydrogenase and models that contain iron–acyl ligation. Chem. Asian J. 8, 1068–1075 (2013).

    CAS  Article  Google Scholar 

  25. 25

    Murray, K. A., Wodrich, M. D., Hu, X. & Corminboeuf, C. Toward functional type III [Fe]-hydrogenase biomimics for H2 activation: insights from computation. Chemistry 21, 3987–3996 (2015).

    CAS  Article  Google Scholar 

  26. 26

    Xu, T. et al. A functional model of [Fe]-hydrogenase. J. Am. Chem. Soc. 138, 3270–3273 (2016).

    CAS  Article  Google Scholar 

  27. 27

    Moore, C. M., Dahl, E. W. & Szymczak, N. K. Beyond H2: exploiting 2-hydroxypyridine as a design element from [Fe]-hydrogenase for energy-relevant catalysis. Curr. Opin. Chem. Biol. 25, 9–17 (2015).

    CAS  Article  Google Scholar 

  28. 28

    Desguin, B. et al. A tethered niacin-derived pincer complex with a nickel–carbon bond in lactate racemase. Science 349, 66–69 (2015).

    CAS  Article  Google Scholar 

  29. 29

    Xu, T., Bauer, G. & Hu, X. A novel nickel pincer complex in the active site of lactate racemase. Chembiochem 17, 31–32 (2016).

    CAS  Article  Google Scholar 

  30. 30

    Desguin, B., Soumillion, P., Hols, P., Hu, J. & Hausinger, R. P. in The Biological Chemistry of Nickel (eds Zamble, D., Rowinska-Zyrek, M. & Kozlowski, H. ) 220–236 (Royal Society of Chemistry, 2017).

    Google Scholar 

  31. 31

    Cantwell, A. & Dennis, D. Lactate racemase. Direct evidence for an α-carbonyl intermediate. Biochemistry 13, 287–291 (1974).

    CAS  Article  Google Scholar 

  32. 32

    Zhang, X. & Chung, L. W. Alternative mechanistic strategy for enzyme catalysis in a Ni-dependent lactate racemase (LarA): intermediate destabilization by the cofactor. Chemistry 23, 3623–3630 (2017).

    CAS  Article  Google Scholar 

  33. 33

    Yu, M.-J. & Chen, S.-L. From NAD+ to nickel pincer complex: a significant cofactorevolution presented by lactate racemase. Chemistry 23, 7545–7557 (2017).

    CAS  Article  Google Scholar 

  34. 34

    Eklund, H., Plapp, B. V., Samama, J.-P. & Brädén, C.-I. Binding of substrate in a ternary complex of horse liver alcohol dehydrogenase. J. Biol. Chem. 257, 14349–14358 (1982).

    CAS  PubMed  Google Scholar 

  35. 35

    Cook, P. F. & Cleland, W. W. pH Variation of isotope effects in enzyme-catalyzed reactions. 2. Isotope-dependent step not pH dependent. Kinetic mechanism of alcohol dehydrogenase. Biochemistry 20, 1805–1816 (1981).

    CAS  Article  Google Scholar 

  36. 36

    Eklund, H. et al. Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 Å resolution. J. Mol. Biol. 102, 27–59 (1976).

    CAS  Article  Google Scholar 

  37. 37

    Ramaswamy, S., Eklund, H. & Plapp, B. V. Structures of horse liver alcohol dehydrogenase complexed with NAD+ and substituted benzyl alcohols. Biochemistry 33, 5230–5237 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Inoue, J., Tomioka, N., Itai, A. & Harayama, S. Proton transfer in benzyl alcohol dehydrogenase during catalysis: alternate proton-relay routes. Biochemistry 37, 3305–3311 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Xu, T., Wodrich, M. D., Scopelliti, R., Corminboeuf, C. & Hu, X. Nickel pincer model of the active site of lactate racemase involves ligand participation in hydride transfer. Proc. Natl Acad. Sci. USA 114, 1242–1245 (2017).

    CAS  Article  Google Scholar 

  40. 40

    Dauth, A., Gellrich, U., Diskin-Posner, Y., Ben-David, Y. & Milstein, D. The ferraquinone–ferrahydroquinone couple: combining quinonic and metal-based reactivity. J. Am. Chem. Soc. 139, 2799–2807 (2017).

    CAS  Article  Google Scholar 

  41. 41

    McSkimming, A., Chan, B., Bhadbhade, M. M., Ball, G. E. & Colbran, S. B. Bio-inspired transition metal–organic hydride conjugates for catalysis of transfer hydrogenation: experiment and theory. Chemistry 21, 2821–2834 (2015).

    CAS  Article  Google Scholar 

  42. 42

    Can, M., Armstrong, F. A. & Ragsdale, S. W. Structure, function, and mechanism of the nickel metalloenzymes, CO dehydrogenase, and acetyl-CoA synthase. Chem. Rev. 114, 4149–4174 (2014).

    CAS  Article  Google Scholar 

  43. 43

    Dobbek, H., Svetlitchnyi, V., Gremer, L., Huber, R. & Meyer, O. Crystal structure of a carbon monoxide dehydrogenase reveals a [Ni-4Fe-5S] cluster. Science 293, 1281–1285 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Jeoung, J.-H. & Dobbek, H. Carbon dioxide activation at the Ni, Fe-cluster of anaerobic carbon monoxide dehydrogenase. Science 318, 1461–1464 (2007).

    CAS  Article  Google Scholar 

  45. 45

    Lindahl, P. A. The Ni-containing carbon monoxide dehydrogenase family: light at the end of the tunnel? Biochemistry 41, 2097–2105 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Feng, J. & Lindahl, P. A. Carbon monoxide dehydrogenase from Rhodospirillum rubrum: effect of redox potential on catalysis. Biochemistry 43, 1552–1559 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Fesseler, J., Jeoung, J.-H. & Dobbek, H. How the [NiFe4S4] cluster of CO dehydrogenase activates CO2 and NCO. Angew. Chem. Int. Ed. 54, 8560–8564 (2015).

    CAS  Article  Google Scholar 

  48. 48

    Kim, E. J., Feng, J., Bramlett, M. R. & Lindahl, P. A. Evidence for a proton transfer network and a required persulfide-bond-forming cysteine residue in Ni-containing carbon monoxide dehydrogenases. Biochemistry 43, 5728–5734 (2004).

    CAS  Article  Google Scholar 

  49. 49

    Rao, P. V. & Holm, R. H. Synthetic analogues of the active sites of iron–sulfur proteins. Chem. Rev. 104, 527–560 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Beley, M., Collin, J.-P., Ruppert, R. & Sauvage, J.-P. Electrocatalytic reduction of CO2 by Ni cyclam2+ in water: study of the factors affecting the efficiency and the selectivity of the process. J. Am. Chem. Soc. 108, 7461–7467 (1986).

    CAS  Article  Google Scholar 

  51. 51

    Costentin, C., Drouet, S., Robert, M. & Savéant, J.-M. A local proton source enhances CO2 electroreduction to CO by a molecular Fe catalyst. Science 338, 90–94 (2012).

    CAS  Article  Google Scholar 

  52. 52

    Rakowski DuBois, M. & DuBois, D. L. The roles of the first and second coordination spheres in the design of molecular catalysts for H2 production and oxidation. Chem. Soc. Rev. 38, 62–72 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Wilson, A. D. et al. Nature of hydrogen interactions with Ni(II) complexes containing cyclic phosphine ligands with pendant nitrogen bases. Proc. Natl Acad. Sci. USA 104, 6951–6956 (2007).

    CAS  Article  Google Scholar 

  54. 54

    Brazzolotto, D. et al. Nickel-centred proton reduction catalysis in a model of [NiFe] hydrogenase. Nat. Chem. 8, 1054–1060 (2016).

    CAS  Article  Google Scholar 

  55. 55

    Crabtree, R. H. Dihydrogen complexation. Chem. Rev. 116, 8750–8769 (2016).

    CAS  Article  Google Scholar 

  56. 56

    DuBois, D. L. & Bullock, R. M. Molecular electrocatalysts for the oxidation of hydrogen and the production of hydrogen — the role of pendant amines as proton relays. Eur. J. Inorg. Chem. 2011, 1017–1027 (2011).

    Article  Google Scholar 

  57. 57

    Xu, T., Chen, D. & Hu, X. Hydrogen-activating models of hydrogenases. Coord. Chem. Rev. 303, 32–41 (2015).

    CAS  Article  Google Scholar 

  58. 58

    Ginovska-Pangovska, B., Dutta, A., Reback, M. L., Linehan, J. C. & Shaw, W. J. Beyond the active site: the impact of the outer coordination sphere on electrocatalysts for hydrogen production and oxidation. Acc. Chem. Res. 47, 2621–2630 (2014).

    CAS  Article  Google Scholar 

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The authors thank the Swiss National Science Foundation for financial support (200020_172486/1). M.D.W. acknowledges C. Corminboeuf (École Polytechnique Fédérale de Lausanne, Switzerland) for financial support. G. Gryn’ova is acknowledged for artistic contributions.

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Both authors contributed equally to the preparation of this manuscript.

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Correspondence to Xile Hu.

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Wodrich, M., Hu, X. Natural inspirations for metal–ligand cooperative catalysis. Nat Rev Chem 2, 0099 (2018).

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