title: Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization.
abstract: Aromatase (CYP19) catalyzes the terminal step in estrogen biosynthesis, which requires three separate oxidation reactions, culminating in an enigmatic aromatization that converts an androgen to an estrogen. A stable ferric peroxo (Fe(3+)O(2)(2-)) intermediate is seen by electron paramagnetic resonance, but its role in this complex reaction remains controversial. Combining molecular dynamics simulation and hybrid quantum mechanics/molecular mechanics, we show that ferric peroxo addition to the 19-aldehyde initiates the reaction. Stepwise cleavage of the C10-C19 and O-O bonds of the peroxohemiacetal extrudes formate and yields Compound II, which in turn desaturates the steroid through successive abstraction of the 1β-hydrogen atom and deprotonation of the 2β-position. Throughout the transformation, a proton is cyclically relayed between D309 and the substrate to stabilize reaction intermediates. This mechanism invokes novel oxygen intermediates and provides a unifying interpretation of past experimental mechanistic studies.
authors.affiliation: Institute for Structural Biology and Drug Discovery and School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23219, USA.
authors.forename: Kakali
authors.initials: K
authors.lastname: Sen
authors.forename: John C
authors.initials: JC
authors.lastname: Hackett
mesh_terms: D000728:Androgens / Q000737:chemistry* / Q000378:metabolism; D001141:Aromatase / Q000737:chemistry*; D002384:Catalysis; D004579:Electron Transport; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011522:Protons
chemical_list: D000728:Androgens; D011522:Protons; D001141:Aromatase; D010100:Oxygen