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Biochemistry. 2012 Apr 10;51(14):3039-49. doi: 10.1021/bi300017p. Epub 2012 Mar 27.

Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization.

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1
Institute for Structural Biology and Drug Discovery and School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23219, USA.

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.

PMID:
22439696
PMCID:
PMC3326664
DOI:
10.1021/bi300017p
[Indexed for MEDLINE]
Free PMC Article
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