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J Am Chem Soc. 2014 Oct 22;136(42):15016-25. doi: 10.1021/ja508185d. Epub 2014 Oct 10.

Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19A1 steroid aromatase.

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.

Abstract

Aromatase is the cytochrome P450 enzyme that cleaves the C10-C19 carbon-carbon bond of androgens to form estrogens, in a three-step process. Compound I (FeO(3+)) and ferric peroxide (FeO2(-)) have both been proposed in the literature as the active iron species in the third step, yielding an estrogen and formic acid. Incubation of purified aromatase with its 19-deutero-19-oxo androgen substrate was performed in the presence of (18)O2, and the products were derivatized using a novel diazo reagent. Analysis of the products by high-resolution mass spectrometry showed a lack of (18)O incorporation in the product formic acid, supporting only the Compound I pathway. Furthermore, a new androgen 19-carboxylic acid product was identified. The rates of nonenzymatic hydration of the 19-oxo androgen and dehydration of the 19,19-gem-diol were shown to be catalytically competent. Thus, the evidence supports Compound I and not ferric peroxide as the active iron species in the third step of the steroid aromatase reaction.

PMID:
25252141
PMCID:
PMC4210144
DOI:
10.1021/ja508185d
[Indexed for MEDLINE]
Free PMC Article

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