Enzymatic hydroxylation of an unactivated methylene C-H bond guided by molecular dynamics simulations

  1. Narayan, A.R.H. 2
  2. Jiménez-Osés, G. 1
  3. Liu, P. 1
  4. Negretti, S. 2
  5. Zhao, W. 2
  6. Gilbert, M.M. 2
  7. Ramabhadran, R.O. 1
  8. Yang, Y.-F. 1
  9. Furan, L.R. 1
  10. Li, Z. 1
  11. Podust, L.M. 3
  12. Montgomery, J. 2
  13. Houk, K.N. 1
  14. Sherman, D.H. 2
  1. 1 University of California Los Angeles
    info

    University of California Los Angeles

    Los Ángeles, Estados Unidos

    ROR https://ror.org/046rm7j60

  2. 2 University of Michigan–Ann Arbor
    info

    University of Michigan–Ann Arbor

    Ann Arbor, Estados Unidos

    ROR https://ror.org/00jmfr291

  3. 3 University of California, San Diego
    info

    University of California, San Diego

    San Diego, Estados Unidos

    ROR https://ror.org/0168r3w48

Mostrar afiliaciones +
Revista:
Nature chemistry

ISSN: 1755-4330

Año de publicación: 2015

Volumen: 7

Número: 8

Páginas: 653-660

Tipo: Artículo

DOI: 10.1038/NCHEM.2285 SCOPUS: 2-s2.0-84937899531 GOOGLE SCHOLAR

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.