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Non‐natural Olefin Cyclopropanation Catalyzed by Diverse Cytochrome P450s and Other Hemoproteins
Author(s) -
Heel Thomas,
McIntosh John A.,
Dodani Sheel C.,
Meyerowitz Joseph T.,
Arnold Frances H.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402286
Subject(s) - cyclopropanation , carbene , chemistry , stereochemistry , olefin fiber , cytochrome p450 , catalysis , combinatorial chemistry , enzyme , organic chemistry
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.