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Non-natural Olefin Cyclopropanation Catalyzed by Diverse Cytochrome P450s and Other Hemoproteins

Heel, Thomas and McIntosh, John A. and Dodani, Sheel C. and Meyerowitz, Joseph T. and Arnold, Frances H. (2014) Non-natural Olefin Cyclopropanation Catalyzed by Diverse Cytochrome P450s and Other Hemoproteins. ChemBioChem, 15 (17). pp. 2556-2562. ISSN 1439-4227. PMCID PMC4287214. doi:10.1002/cbic.201402286. https://resolver.caltech.edu/CaltechAUTHORS:20141015-151531581

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Abstract

Recent work has shown that engineered variants of cytochrome P450_(BM3) (CYP102A1) efficiently catalyze non-natural reactions, including carbene and nitrene transfer reactions. Given the broad substrate range of natural P450 enzymes, we set out to explore if this diversity could be leveraged to generate a broad panel of new catalysts for olefin cyclopropanation (i.e., carbene transfer). Here, we took a step towards this goal by characterizing the carbene transfer activities of four new wild-type P450s that have different native substrates. All four were active and exhibited a range of product selectivities in the model reaction: cyclopropanation of styrene by using ethyl diazoacetate (EDA). Previous work on P450_(BM3) demonstrated that mutation of the axial coordinating cysteine, universally conserved among P450 enzymes, to a serine residue, increased activity for this non-natural reaction. The equivalent mutation in the selected P450s was found to activate carbene transfer chemistry both in vitro and in vivo. Furthermore, serum albumins complexed with hemin were also found to be efficient in vitro cyclopropanation catalysts.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://onlinelibrary.wiley.com/doi/10.1002/cbic.201402286/abstractPublisherArticle
http://dx.doi.org/10.1002/cbic.201402286DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/cbic.201402286/suppinfoPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287214PubMed CentralArticle
ORCID:
AuthorORCID
McIntosh, John A.0000-0002-9487-490X
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2014 Wiley-VCH Verlag GmbH & Co. Received: June 5, 2014; Published online on October 7, 2014. The authors thank Kersten Rabe, Nicole E. Peck, and Z. Jane Wang for helpful discussions and Yapeng Su for help with experiments. We also thank the Gordon and Betty Moore Foundation for grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative. T.H. is supported by a FWF Schroedinger fellowship (J3327-B21). S.C.D. and J.A.M. are supported by Ruth L. Kirschstein NRSA postdoctoral fellowships from the National Institutes of Health (5F32M106618 and F32M101792, respectively). J.T.M. is supported by the Department of Defense through the National Defense Science & Engineering Graduate Fellowship Program and by the National Science Foundation through the Graduate Research Fellowship Program. The content of this paper is solely the responsibility of the authors and does not represent the official views of any of the funding agencies.
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF2809
FWF Der WissenschaftsfondsJ3327-B21
NIH Postdoctoral Fellowship5F32M106618
NIH Postdoctoral FellowshipF32M101792
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:cyclopropanation; cytochromes; enzyme catalysis; metalloenzyme
Issue or Number:17
PubMed Central ID:PMC4287214
DOI:10.1002/cbic.201402286
Record Number:CaltechAUTHORS:20141015-151531581
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141015-151531581
Official Citation:Heel, T., McIntosh, J. A., Dodani, S. C., Meyerowitz, J. T. and Arnold, F. H. (2014), Non-natural Olefin Cyclopropanation Catalyzed by Diverse Cytochrome P450s and Other Hemoproteins. ChemBioChem, 15: 2556–2562. doi: 10.1002/cbic.201402286
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50425
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:15 Oct 2014 22:45
Last Modified:10 Nov 2021 18:55

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