Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization.
Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization.
复制标题
CYP19 催化雄激素芳构化最后一步中的耦合电子转移和质子跳跃。
DOI：
10.1021/bi300017p
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发表时间：
2012
期刊：
影响因子：
2.9
通讯作者：
Hackett,JohnC
中科院分区：
文献类型：
--
作者：
Sen,Kakali;Hackett,JohnC
芳香化酶（CYP19）催化雌激素生物合成的最后一步，这需要三个单独的氧化反应，最终在一个神秘的芳香化过程中将雄激素转化为雌激素。一个稳定的过氧铁（Fe3+O22 -）中间体被电子顺磁共振观察到，但它在这个复杂反应中的作用仍然存在争议。结合分子动力学模拟和混合量子力学/分子力学，我们证明了过氧化铁加入19-醛引发了反应。过氧半缩醛的C10-C19键和O-O键的逐步裂解得到甲酸酯，生成化合物II，化合物II通过连续提取1β-氢原子和2β-位置的去质子化而使甾体去饱和。在整个转化过程中，一个质子在D309和底物之间循环传递，以稳定反应中间体。这一机制引发了新的氧中间体，并为过去的实验机制研究提供了统一的解释。
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 (Fe3+O22–) 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.