Journal
ACS CATALYSIS
Volume 12, Issue 2, Pages 935-942Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.1c04748
Keywords
B-12; cobalamin; C-H functionalization; biocatalysis; non-native enzyme catalysis
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Funding
- U.S. Army Research Laboratory [W911NF-19-1-0074]
- U.S. Army Research Office [W911NF-19-1-0074]
- NIH [R01 GM115665]
- NSF [MRI CHE-1920026, CHE-1808133, CHE1726633]
- Graduate Training Program in Quantitative and Chemical Biology at Indiana University [T32 GM131994]
- Indiana Clinical and Translational Sciences Institute
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In this study, a variant of the transcription factor CarH, named CarH*, was engineered to catalyze styrene C-H alkylation with improved yields and selectivity compared to cobalamin. Mechanistic studies suggest that the selectivity of CarH* results from its ability to impart a cage effect on radical intermediates, laying the groundwork for the development of B-12-dependent enzymes as catalysts for non-native transformations.
Vitamin B-12 derivatives catalyze a wide range of organic transformations, but B-12-dependent enzymes are underutilized in biocatalysis relative to other metalloenzymes. In this study, we engineered a variant of the transcription factor CarH, called CarH*, that catalyzes styrene C-H alkylation with improved yields (2 6.5 fold) and selectivity relative to cobalamin. While the native function of CarH involves transcription regulation via adenosylcobalamin (AdoCbl) Co(III)-carbon bond cleavage and beta-hydride elimination to generate 4',5'-didehydroadenosine, CarH*-catalyzed styrene alkylation proceeds via non-native oxidative addition and olefin addition coupled with a native-like beta-hydride elimination. Mechanistic studies on this reaction echo findings from earlier studies on AdoCbl homolysis to suggest that CarH* selectivity results from its ability to impart a cage effect on radical intermediates. These findings lay the groundwork for the development of B-12-dependent enzymes as catalysts for non-native transformations.
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