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Squalene hopene cyclases are protonases for stereoselective Brønsted acid catalysis

Nature Chemical Biology volume 11, pages 121–126 (2015)Cite this article

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Abstract

For many important reactions catalyzed in chemical laboratories, the corresponding enzymes are missing, representing a restriction in biocatalysis. Although nature provides highly developed machineries appropriate to catalyze such reactions, their potential is often ignored. This also applies to Brønsted acid catalysis, a powerful method to promote a myriad of chemical transformations. Here, we report on the unique protonation machinery of a squalene hopene cyclase (SHC). Active site engineering of this highly evolvable enzyme yielded a platform for enzymatic Brønsted acid catalysis in water. This is illustrated by activation of different functional groups (alkenes, epoxides and carbonyls), enabling the highly stereoselective syntheses of various cyclohexanoids while uncoupling SHC from polycyclization chemistry. This work highlights the potential of systematic investigation on nature's catalytic machineries to generate unique catalysts.

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Figure 1: Natural activity, protonation machinery and active site of AacSHC.
Figure 2: Cyclization of geraniol (4) and (S)-6,7-epoxygeraniol (7).
Figure 3: Prins reaction of citronellal (9).

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Acknowledgements

We gratefully acknowledge funding by the European Union's Seventh Framework Programme FP7/2007–2013 under grant agreement no. 289646 as well as a Kekulé scholarship by the Fonds der Chemischen Industrie (to SCH, grant number K 187/01). We thank P.-O. Syrén (KTH Royal Institute of Technology, Stockholm) for stimulating discussions, M. Breuer (BASF SE, Ludwigshafen) for the AacSHC gene, C. Geinitz (University of Stuttgart) for providing the mutants at position F365 and E. Kervio (University of Stuttgart) for help with measuring specific rotations of the products.

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  1. Institute of Technical Biochemistry, University of Stuttgart, Stuttgart, Germany

    Stephan C Hammer, Antonija Marjanovic, Jörg M Dominicus, Bettina M Nestl & Bernhard Hauer

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  1. Stephan C Hammer
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Contributions

S.C.H., B.M.N. and B.H. designed the research. S.C.H. and A.M. designed and performed the experiments. J.M.D. synthesized the racemic standards. All authors contributed to the interpretation of the results and the preparation of the manuscript.

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Correspondence to Bernhard Hauer.

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The authors declare no competing financial interests.

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Supplementary Notes, Supplementary Results, Supplementary Figures 1–24 and Supplementary Table 1. (PDF 5011 kb)

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Hammer, S., Marjanovic, A., Dominicus, J. et al. Squalene hopene cyclases are protonases for stereoselective Brønsted acid catalysis. Nat Chem Biol 11, 121–126 (2015). https://doi.org/10.1038/nchembio.1719

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