Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer
Abstract
Despite the astonishing diversity of naturally occurring biocatalytic processes, enzymes do not catalyze many of the transformations favored by synthetic chemists. Either nature does not care about the specific products, or if she does, she has adopted a different synthetic strategy. In many cases, the appropriate reagents used by synthetic chemists are not readily accessible to biological systems. Here, we discuss our efforts to expand the catalytic repertoire of enzymes to encompass powerful reactions previously known only in small-molecule catalysis: formation and transfer of reactive carbene and nitrene intermediates leading to a broad range of products, including products with bonds not known in biology. In light of the structural similarity of iron carbene (Fe=C(R1)(R2)) and iron nitrene (Fe=NR) to the iron oxo (Fe=O) intermediate involved in cytochrome P450-catalyzed oxidation, we have used synthetic carbene and nitrene precursors that biological systems have not encountered and repurposed P450s to catalyze reactions that are not known in the natural world. The resulting protein catalysts are fully genetically encoded and function in intact microbial cells or cell-free lysates, where their performance can be improved and optimized by directed evolution. By leveraging the catalytic promiscuity of P450 enzymes, we evolved a range of carbene andmore »
- Authors:
-
[1];
[1]
- Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
- Publication Date:
- Research Org.:
- California Institute of Technology (CalTech), Pasadena, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1762538
- Alternate Identifier(s):
- OSTI ID: 1768387
- Grant/Contract Number:
- SC0021141
- Resource Type:
- Published Article
- Journal Name:
- Accounts of Chemical Research
- Additional Journal Information:
- Journal Name: Accounts of Chemical Research Journal Volume: 54 Journal Issue: 5; Journal ID: ISSN 0001-4842
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Carbene compounds; Bioinorganic chemistry; Peptides and proteins; Cyclopropanation; Organic reactions
Citation Formats
Yang, Yang, and Arnold, Frances H. Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer. United States: N. p., 2021.
Web. doi:10.1021/acs.accounts.0c00591.
Yang, Yang, & Arnold, Frances H. Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer. United States. https://doi.org/10.1021/acs.accounts.0c00591
Yang, Yang, and Arnold, Frances H. Mon .
"Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer". United States. https://doi.org/10.1021/acs.accounts.0c00591.
@article{osti_1762538,
title = {Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer},
author = {Yang, Yang and Arnold, Frances H.},
abstractNote = {Despite the astonishing diversity of naturally occurring biocatalytic processes, enzymes do not catalyze many of the transformations favored by synthetic chemists. Either nature does not care about the specific products, or if she does, she has adopted a different synthetic strategy. In many cases, the appropriate reagents used by synthetic chemists are not readily accessible to biological systems. Here, we discuss our efforts to expand the catalytic repertoire of enzymes to encompass powerful reactions previously known only in small-molecule catalysis: formation and transfer of reactive carbene and nitrene intermediates leading to a broad range of products, including products with bonds not known in biology. In light of the structural similarity of iron carbene (Fe=C(R1)(R2)) and iron nitrene (Fe=NR) to the iron oxo (Fe=O) intermediate involved in cytochrome P450-catalyzed oxidation, we have used synthetic carbene and nitrene precursors that biological systems have not encountered and repurposed P450s to catalyze reactions that are not known in the natural world. The resulting protein catalysts are fully genetically encoded and function in intact microbial cells or cell-free lysates, where their performance can be improved and optimized by directed evolution. By leveraging the catalytic promiscuity of P450 enzymes, we evolved a range of carbene and nitrene transferases exhibiting excellent activity toward these new-to-nature reactions. Since our initial report in 2012, a number of other heme proteins including myoglobins, protoglobins, and cytochromes c have also been found and engineered to promote unnatural carbene and nitrene transfer. Due to the altered active-site environments, these heme proteins often displayed complementary activities and selectivities to P450s.},
doi = {10.1021/acs.accounts.0c00591},
journal = {Accounts of Chemical Research},
number = 5,
volume = 54,
place = {United States},
year = {Mon Jan 25 00:00:00 EST 2021},
month = {Mon Jan 25 00:00:00 EST 2021}
}
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