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Enantioselective Intramolecular C[BOND]H Amination Catalyzed by Engineered Cytochrome P450 Enzymes In Vitro and In Vivo

Authors

  • Dr. John A. McIntosh,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
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    • These authors contributed equally to this work.

  • Dr. Pedro S. Coelho,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
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    • These authors contributed equally to this work.

  • Christopher C. Farwell,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
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  • Dr. Z. Jane Wang,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
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  • Prof. Dr. Jared C. Lewis,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
    2. Current address: Department of Chemistry, University of Chicago, Chicago, IL 60637 (USA)
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  • Tristan R. Brown,

    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
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  • Prof. Dr. Frances H. Arnold

    Corresponding author
    1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)
    • Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC 210-41, Pasadena, CA 91125 (USA)

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  • We thank S. Virgil and the 3CS catalysis center at Caltech for assistance with HPLC and LC–MS analyses, and D. Montgomery, Y. Liu, N. Peck, K. Rabe, R. Lauchli, and D. VanderVelde for helpful discussions. This work was supported by the Department of the Navy, Office of Naval Research (grant N00014-11-1-0205), and by the Jacobs Institute for Molecular Engineering for Medicine at Caltech. J.A.M. and Z.J.W. are supported by Ruth L. Kirschstein National Research Service Awards (F32GM101792) and (F32EB015846). C.C.F. is supported by an NSF Graduate Research Fellowship.

Abstract

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Nitrogen activation: Though P450 enzymes are masters of oxygen activation and insertion into C[BOND]H bonds, their ability to use nitrogen for the same purpose has so far not been explored. Engineered variants of cytochrome P450BM3 have now been found to catalyze intramolecular C[BOND]H aminations in azide substrates. Mutations to two highly conserved residues significantly increased this activity.

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