Journal
ACS CATALYSIS
Volume 8, Issue 4, Pages 2629-2634Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.7b04423
Keywords
biocatalysis; Cytochrome P450; cyclopropanes; carbene transfer
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Funding
- National Science Foundation, Division of Molecular and Cellular Biosciences [MCB-1513007]
- Defense Advanced Research Projects Agency Biological Robustness in Complex Settings [HR0011-15-C-0093]
- Deutsche Forschungsgemeinschaft (DFG) [BR 5238/1-1]
- Swiss National Science Foundation (SNF) [P300PA-171225]
- Resnick Sustainability Institute
- NSF Graduate Research Fellowship [1745301]
- Caltech's Center for Environmental Microbial Interactions
- Div Of Molecular and Cellular Bioscience [1513007] Funding Source: National Science Foundation
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The repurposing of hemoproteins for non-natural carbene transfer activities has generated enzymes for functions previously accessible only to chemical catalysts. With activities constrained to specific substrate classes, however, the synthetic utility of these new biocatalysts has been limited. To expand the capabilities of non-natural carbene transfer biocatalysis, we engineered variants of Cytochrome P450(Bm3), that catalyze the cyclopropanation of heteroatom-bearing alkenes, providing valuable nitrogen-, oxygen-, and sulfur-substituted cyclopropanes. Four or five active-site mutations converted a single parent enzyme into selective catalysts for the synthesis of both cis and trans heteroatom-substituted cyclopropanes, with high diastereoselectivities and enantioselectivities and up to 40 000 total turnovers. This work highlights the ease of tuning hemoproteins by directed evolution for efficient cyclopropanation of new substrate classes and expands the catalytic functions of iron heme proteins.
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