title: The directive of the protein: how does cytochrome P450 select the mechanism of dopamine formation?
abstract: Dopamine can be generated from tyramine via arene hydroxylation catalyzed by a cytochrome P450 enzyme (CYP2D6). Our quantum mechanical/molecular mechanical (QM/MM) results reveal the decisive impact of the protein in selecting the 'best' reaction mechanism. Instead of the traditional Meisenheimer-complex mechanism, the study reveals a mechanism involving an initial hydrogen atom transfer from the phenolic hydroxyl group of the tyramine to the iron-oxo of the compound I (Cpd I), followed by a ring-π radical rebound that eventually leads to dopamine by keto-enol rearrangement. This mechanism is not viable in the gas phase since the O-H bond activation by Cpd I is endothermic and the process does not form a stable intermediate. By contrast, the in-protein reaction has a low barrier and is exothermic. It is shown that the local electric field of the protein environment serves as a template that stabilizes the intermediate of the H-abstraction step and thereby mediates the catalysis of dopamine formation at a lower energy cost. Furthermore, it is shown that external electric fields can either catalyze or inhibit the process depending on their directionality.
authors.affiliation: Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Patric
authors.initials: P
authors.lastname: Schyman
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Lai
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism*; D011789:Quantum Theory
chemical_list: D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D004298:Dopamine