Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19A1 steroid aromatase.
Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19A1 steroid aromatase.
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DOI：
10.1021/ja508185d
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发表时间：
2014-10-22
影响因子：
15
通讯作者：
Guengerich, F. Peter
中科院分区：
文献类型：
--
作者：
Yoshimoto, Francis K.;Guengerich, F. Peter
芳香化酶是一种细胞色素P450酶，它通过三步分解雄激素的C10-C19碳-碳键形成雌激素。化合物I （FeO3+）和过氧化铁（FeO2 -）都被文献提出作为第三步的活性铁种，产生雌激素和甲酸。纯化的芳香化酶与其19-deutero-19-oxo雄激素底物在18O2存在下孵育，并用一种新型重氮试剂衍生化产物。高分辨率质谱分析表明，产物甲酸中缺乏18O掺入，仅支持化合物I途径。此外，还鉴定了一个新的雄激素19-羧酸产物。19-氧雄激素的非酶化水化速率和19,19-宝石二醇的脱水速率被证明具有催化能力。因此，证据支持化合物I而不是过氧化铁作为类固醇芳香化酶反应第三步的活性铁。
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 (FeO3+) 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 18O2, and the products were derivatized using a novel diazo reagent. Analysis of the products by high-resolution mass spectrometry showed a lack of 18O 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.
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