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Efficient reductive desymmetrization of bulky 1,3-cyclodiketones enabled by structure-guided directed evolution of a carbonyl reductase

Nature Catalysis volume 2, pages 931–941 (2019)Cite this article

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Abstract

Reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to 2,2-disubstituted-3-hydroxycycloketones is a highly desired transformation for the construction of complex molecules with multiple chiral centres, but the generation of a single stereoisomer is difficult and an extremely challenging task in organic chemistry. In this study, by using ethyl secodione as the model substrate and an engineered carbonyl reductase from Ralstonia sp. as the biocatalyst, we realized the efficient reductive desymmetrization of 2,2-disubstituted cyclodiketones to give essentially one single stereoisomer. The mutant enzyme F12 (I91V/I187S/I188L/Q191N/F205A) showed an 183-fold enhancement of enzyme activity and outstanding stereoselectivity towards most of the tested prochiral 1,3-cyclodiketones. Crystal structural analysis and molecular dynamics studies reveal the molecular basis for activity improvement and the stereoselectivity control mechanism. Our results show that by altering the active site conformation populations (particularly the position of an α-helix) to properly accommodate the larger substrate and co-factor for catalysis, this challenging synthetic problem can ultimately be addressed.

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Fig. 1: Reductive desymmetrization of 2,2-disubstituted-1,3-cyclodiones.
Fig. 2: Docking of 1a into the substrate binding site of RasADH.
Fig. 3: Crystal structures of wild-type and mutant F12.
Fig. 4: Conformational population analyses.
Fig. 5: Comparison of molecular dynamics data and the crystal structure.

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Data availability

Crystallographic data of this study has been deposited in the PDB under accession codes 6IHI and 6IHH. The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We would like to thank L. Pu of the Department of Chemistry, University of Virginia for the helpful discussions about the chirality of the products. This work was financially supported by the National Key R&D Program of China (no. 2018YFA0901600), National Natural Science Foundation of China (no. 21602246) and Tianjin Municipal Science and Technology Commission (nos 15PTGCCX00060 and 15PTCYSY00020). M.A.M.S. is grateful to the Spanish MINECO for a PhD fellowship (BES-2015-074964). S.O. thanks the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-2015-StG-679001) and the Spanish MINECO for I+D project PGC2018-102192-B-I00. M.A.M.S. and S.O. thank the Generalitat de Catalunya for the group-emergent CompBioLab (2017 SGR-1707).

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Author notes

  1. These authors contributed equally: Xi Chen and Hongliu Zhang.

Authors and Affiliations

  1. National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China

    Xi Chen, Hongliu Zhang, Weidong Liu, Juan Li, Jinhui Feng, Xiangtao Liu, Rey-Ting Guo, Qiaqing Wu, Dunming Zhu & Yanhe Ma

  2. CompBioLab group, Institut de Química Computacional i Catàlisi, Department of Chemistry, University of Girona, Girona, Spain

    Miguel A. Maria-Solano & Sílvia Osuna

  3. University of the Chinese Academy of Sciences, Beijing, China

    Juan Li & Dunming Zhu

  4. ICREA, Barcelona, Spain

    Sílvia Osuna

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Contributions

X.C., H.Z., Q.W., Y.M. and D.Z. conceived and designed the project. X.C. synthesized the compounds, purified the products and analysed the chirality of all of the products. H.Z. designed and performed the mutation, screening and growing crystal experiments. M.A.M.-S. performed the molecular dynamics simulations. J.L. performed the HPLC analyses. W.L. and R.-T.G. collected crystallographic data and solved all of the structures. J.F. carried the docking experiments. X.L. optimized the fermentation conditions. X.C., H.Z., M.A.M.-S., S.O., Q.W. and D.Z. wrote the manuscript. S.O., Q.W., Y.M and D.Z. directed the project.

Corresponding authors

Correspondence to Sílvia Osuna, Qiaqing Wu or Dunming Zhu.

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Supplementary information

Supplementary Information

Supplementary Methods, Tables 1–4, Figs. 1–28 and References

Reporting Summary

Supplementary Data 1

Initial_structure_MD_F12-C_1a-13R17S

Supplementary Data 2

Initial_structure_MD_F12-C_3k-2R3S

Supplementary Data 3

Initial_structure_MD_F12-C_3k-2S3R

Supplementary Data 4

Initial_structure_MD_F12-D_1a-13R17R

Supplementary Data 5

Initial_structure_MD_WT

Supplementary Data 6

Initial_structure_MD_WT-E_1a-13R17R

Supplementary Data 7

Initial_structure_MD_WT-E_1a-13R17S

Supplementary Data 8

Initial_structure_MD_WT-E_1a-13S17R

Supplementary Data 9

Initial_structure_MD_WT-E_1a-13S17S

Supplementary Data 10

Initial_structute_MD_F12

Supplementary Data 11

Substrate_1a_QM

Supplementary Data 12

Substrate_3k_QM

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Chen, X., Zhang, H., Maria-Solano, M.A. et al. Efficient reductive desymmetrization of bulky 1,3-cyclodiketones enabled by structure-guided directed evolution of a carbonyl reductase. Nat Catal 2, 931–941 (2019). https://doi.org/10.1038/s41929-019-0347-y

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