title: Type II ligands as chemical auxiliaries to favor enzymatic transformations by P450 2E1.
abstract: The remarkable ability of P450 enzymes to oxidize inactivated C-H bonds and the high substrate promiscuity of many P450 isoforms have inspired us and others to investigate their use as biocatalysts. Our lab has pioneered a chemical-auxiliary approach to control the promiscuity of P450 3A4 and provide product predictability. The recent realization that type II ligands are sometimes also P450 substrates has prompted the design of a new generation of chemical auxiliaries with type II binding properties. This approach takes advantage of the high affinity of type II ligands for the active site of these enzymes. Although type II ligands typically block P450 activity, we report here that type II ligation can be harnessed to achieve just the opposite, that is, to favor biocatalysis and afford predictable oxidation of small hydrocarbon substrates with P450 2E1. Moreover, the observed predictability was rationalized by molecular docking. We hope that this approach might find future use with other P450 isoforms and yield complimentary products.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal, Quebec, H3A 0B8, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Ménard
authors.forename: Camilo
authors.initials: C
authors.lastname: Fabra
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
mesh_terms: D055162:Biocatalysis; D001711:Biotransformation; D020134:Catalytic Domain; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006838:Hydrocarbons / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D009525:Niacin / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D006838:Hydrocarbons; D008024:Ligands; D009525:Niacin; D019392:Cytochrome P-450 CYP2E1