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The nature of chemical innovation: new enzymes by evolution

Arnold, Frances H. (2015) The nature of chemical innovation: new enzymes by evolution. Quarterly Reviews of Biophysics, 48 (4). pp. 404-410. ISSN 0033-5835. doi:10.1017/S003358351500013X.

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I describe how we direct the evolution of non-natural enzyme activities, using chemical intuition and information on structure and mechanism to guide us to the most promising reaction/enzyme systems. With synthetic reagents to generate new reactive intermediates and just a few amino acid substitutions to tune the active site, a cytochrome P450 can catalyze a variety of carbene and nitrene transfer reactions. The cyclopropanation, N–H insertion, C–H amination, sulfimidation, and aziridination reactions now demonstrated are all well known in chemical catalysis but have no counterparts in nature. The new enzymes are fully genetically encoded, assemble and function inside of cells, and can be optimized for different substrates, activities, and selectivities. We are learning how to use nature's innovation mechanisms to marry some of the synthetic chemists’ favorite transformations with the exquisite selectivity and tunability of enzymes.

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Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2015 Cambridge University Press. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Published online: 16 July 2015. Our research is supported by the Jacobs Institute for Molecular Engineering for Medicine at Caltech, the Gordon and Betty Moore Foundation through grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative, and the National Science Foundation, Office of Chemical, Bioengineering, Environmental and Transport Systems SusChEM Initiative (grant CBET-1403077). I would like to thank Hans Renata, Chris Prier, and Todd Hyster for preparing the figures and Eric Brustad, Pedro Coelho, Jane Wang, Jared Lewis, John McIntosh, Andrew Buller, Christopher Prier, Todd Hyster, Sheel Dodani, Chris Farwell, Hans Renata, and Ruije Zhang for valuable discussions and scientific contributions.
Funding AgencyGrant Number
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Gordon and Betty Moore FoundationGBMF2809
Subject Keywords:biocatalysis, non-natural enzymes, cytochrome P450, directed evolution
Issue or Number:4
Record Number:CaltechAUTHORS:20151109-085022815
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Official Citation: Frances H. Arnold (2015). The nature of chemical innovation: new enzymes by evolution. Quarterly Reviews of Biophysics, 48, pp 404-410. doi:10.1017/S003358351500013X
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:61974
Deposited By: Tony Diaz
Deposited On:09 Nov 2015 17:59
Last Modified:10 Nov 2021 22:56

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