Enzymatic hydroxylation of an unactivated methylene C-H bond guided by molecular dynamics simulations
- Narayan, A.R.H. 2
- Jiménez-Osés, G. 1
- Liu, P. 1
- Negretti, S. 2
- Zhao, W. 2
- Gilbert, M.M. 2
- Ramabhadran, R.O. 1
- Yang, Y.-F. 1
- Furan, L.R. 1
- Li, Z. 1
- Podust, L.M. 3
- Montgomery, J. 2
- Houk, K.N. 1
- Sherman, D.H. 2
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1
University of California Los Angeles
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2
University of Michigan–Ann Arbor
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3
University of California, San Diego
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ISSN: 1755-4330
Año de publicación: 2015
Volumen: 7
Número: 8
Páginas: 653-660
Tipo: Artículo
Otras publicaciones en: Nature chemistry
Resumen
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.