期刊
NATURE CHEMISTRY
卷 7, 期 8, 页码 653-660出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2285
关键词
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资金
- National Science Foundation under CCI Center for Selective C-H Functionalization [CHE-1205646]
- National Institutes of Health (NIH) [GM078553, GM075962]
- NSF [OCI-1053575]
- UCLA Institute of Digital Research and Education (IDRE)
- Life Sciences Research Foundation
- University of Michigan Chemistry-Biology Interface (CBI) training programme [GM008597]
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES012236] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008597, R01GM075962, R01GM078553] Funding Source: NIH RePORTER
The hallmark of enzymes from secondary metabolic pathways is the pairing of powerful reactivity with exquisite site selectivity. The application of these biocatalytic tools in organic synthesis, however, remains under-utilized due to limitations in substrate scope and scalability. Here, we report how the reactivity of a monooxygenase (PikC) from the pikromycin pathway is modified through computationally guided protein and substrate engineering, and applied to the oxidation of unactivated methylene C-H bonds. Molecular dynamics and quantum mechanical calculations were used to develop a predictive model for substrate scope, site selectivity and stereoselectivity of PikC-mediated C-H oxidation. A suite of menthol derivatives was screened computationally and evaluated through in vitro reactions, where each substrate adhered to the predicted models for selectivity and conversion to product. This platform was also expanded beyond menthol-based substrates to the selective hydroxylation of a variety of substrate cores ranging from cyclic to fused bicyclic and bridged bicyclic compounds.
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