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Abiotic reduction of ketones with silanes catalysed by carbonic anhydrase through an enzymatic zinc hydride


Enzymatic reactions through mononuclear metal hydrides are unknown in nature, despite the prevalence of such intermediates in the reactions of synthetic transition-metal catalysts. If metalloenzymes could react through abiotic intermediates like these, then the scope of enzyme-catalysed reactions would expand. Here we show that zinc-containing carbonic anhydrase enzymes catalyse hydride transfers from silanes to ketones with high enantioselectivity. We report mechanistic data providing strong evidence that the process involves a mononuclear zinc hydride. This work shows that abiotic silanes can act as reducing equivalents in an enzyme-catalysed process and that monomeric hydrides of electropositive metals, which are typically unstable in protic environments, can be catalytic intermediates in enzymatic processes. Overall, this work bridges a gap between the types of transformation in molecular catalysis and biocatalysis.

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Fig. 1: Structure and catalytic mechanism of human carbonic anhydrase.
Fig. 2: Catalytic reduction of ketones with hCAII in whole cells.
Fig. 3: Mechanistic study of the reduction of ketone catalysed by carbonic anhydrase.
Fig. 4: Computational study of hydride generation and transfer.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information.


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The work on enantioselective reductions was supported by the NIH (grant no. R37 GM130387) and the studies pertaining to the intermediacy of the metal hydride were supported by the Director, Office of Science, of the US Department of Energy under Contract No. DEAC02-05CH11231. We thank the Berkeley DNA Sequencing Facility for plasmid sequencing. We thank the College of Chemistry’s Molecular Graphics and Computing Facility for resources provided and K. Durkin for her assistance. The COC-MGCF is supported in part by the NIH (grant no. S10OD023532). P.J. acknowledges support from the Miller Institute for Basic Research in Science at the University of California Berkeley for a postdoctoral fellowship.

Author information




P.J. and J.F.H. conceived and designed the project. P.J. performed initial discovery and optimization of reaction conditions, mechanistic studies and all computational experiments. P.J. and J.-Y.P. performed the study of substrate scope. Y.G. and P.J. screened the activity of different mutants. P.J., D.S.C. and J.F.H analysed the data. P.J. and J.F.H. wrote the manuscript with input from all other authors.

Corresponding author

Correspondence to John F. Hartwig.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks the, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary information includes methods for protein expression and purification, DNA and protein sequences, protocols for catalytic reactions (including those with purified protein and with the whole cells), procedure for mechanistic experiments, preparation of racemic standards, computational study, products and characterizations and NMR spectra, Supplementary Figs. 1–33 and Table 1.

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Ji, P., Park, J., Gu, Y. et al. Abiotic reduction of ketones with silanes catalysed by carbonic anhydrase through an enzymatic zinc hydride. Nat. Chem. 13, 312–318 (2021).

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