Estrogen Formation via H-Abstraction from the O–H Bond of gem-Diol by Compound I in the Reaction of CYP19A1: Mechanistic Scenario Derived from Multiscale QM/MM Calculations

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Recent experiments suggested that, contrary to traditional belief, the third step of aromatase-catalyzed estrogen formation should be effected by compound I (Cpd I), rather than by ferric peroxide. We performed QM/MM calculations to address the question of how Cpd I drives the aromatization process. Surprisingly, the calculations show that the reaction begins with hydrogen abstraction from the O–H bond of a gem-diol substrate, which is followed by barrierless homolytic C–C bond cleavage and then 1β-H-abstraction. Proton-coupled electron transfer enables the cleavage of the strong O–H bond. Another product, carboxylic acid, can be formed from either the gem-diol or aldehyde.