期刊
NATURE CHEMISTRY
卷 13, 期 12, 页码 1166-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41557-021-00794-z
关键词
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资金
- National Science Foundation Division of Molecular and Cellular Biosciences [2016137]
- US Army Research Office Institute for Collaborative Biotechnologies [W911NF-19-2-0026]
- Spanish Ministry of Science and Innovation MICINN [PID2019-111300GA-I00]
- Generalitat de Catalunya AGAUR Beatriu de Pinos H2020 MSCA-Cofund [2018-BP-00204]
- Resnick Sustainability Institute at Caltech
- Barcelona Supercomputing Center BSC-RES [RES-QSB-2020-2-0016]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [2016137] Funding Source: National Science Foundation
A haem protein has been reported as a dual-function catalyst for inserting a carbene into an N-H bond to form alpha-amino lactones. The engineered cytochrome P450 enzymes demonstrate high activity and enantioselectivity in this enzymatic reaction. Computational studies provide insight into the detailed mechanism and stereocontrol of this new-to-nature reaction.
A haem protein that serves as a dual-function catalyst capable of inserting a carbene into a N-H bond to form alpha-amino lactones has been reported. The enzyme catalyses both carbene transfer and the subsequent proton transfer in a single active site. This transformation can proceed at the gram scale with high efficiency and enantioselective control. Chiral amines can be made by insertion of a carbene into an N-H bond using two-catalyst systems that combine a transition metal-based carbene-transfer catalyst and a chiral proton-transfer catalyst to enforce stereocontrol. Haem proteins can effect carbene N-H insertion, but asymmetric protonation in an active site replete with proton sources is challenging. Here we describe engineered cytochrome P450 enzymes that catalyse carbene N-H insertion to prepare biologically relevant alpha-amino lactones with high activity and enantioselectivity (up to 32,100 total turnovers, >99% yield and 98% e.e.). These enzymes serve as dual-function catalysts, inducing carbene transfer and promoting the subsequent proton transfer with excellent stereoselectivity in a single active site. Computational studies uncover the detailed mechanism of this new-to-nature enzymatic reaction and explain how active-site residues accelerate this transformation and provide stereocontrol.
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