X-ray structure of human aromatase reveals an androgen-specific active site
X-ray structure of human aromatase reveals an androgen-specific active site
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DOI：
10.1016/j.jsbmb.2009.09.012
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发表时间：
2010-02-28
影响因子：
4.1
通讯作者：
Pangborn, Walter
中科院分区：
文献类型：
--
作者：
Ghosh, Debashis;Griswold, Jennifer;Pangborn, Walter
芳香化酶是一种独特的细胞色素P450，催化雄激素的19-甲基基团的去除和A-环的芳构化以合成雌激素。所有人类雌激素都是通过这种酶促芳构化途径合成的。芳香化酶抑制剂因此构成了雌激素依赖性乳腺癌的一线治疗。尽管几十年的深入研究，这种酶的内质网膜已回避所有的结构确定的努力。我们已经确定了从人胎盘中纯化的高活性芳香酶的晶体结构，与其天然底物雄烯二酮复合。该结构显示了雄烯二酮在酶的催化活性氧化高自旋铁状态下的结合模式。氢键形成相互作用和紧密堆积的疏水侧链，补充了类固醇骨架的褶皱，为芳香酶的独特雄激素特异性提供了分子基础。催化剂残留物和水分子的位置揭示了芳构化步骤的机理。该结构还表明，膜整合模型指示类固醇通过脂质双层。(C)2009爱思唯尔有限公司保留所有权利。
Aromatase is a unique cytochrome P450 that catalyzes the removal of the 19-methyl group and aromatization of the A-ring of androgens for the synthesis of estrogens. All human estrogens are synthesized via this enzymatic aromatization pathway. Aromatase inhibitors thus constitute a frontline therapy for estrogen-dependent breast cancer. Despite decades of intense investigation, this enzyme of the endoplasmic reticulum membrane has eluded all structure determination efforts. We have determined the crystal structure of the highly active aromatase purified from human placenta, in complex with its natural substrate androstenedione. The structure shows the binding mode of androstenedione in the catalytically active oxidized high-spin ferric state of the enzyme. Hydrogen bond-forming interactions and tight packing hydrophobic side chains that complement the puckering of the steroid backbone provide the molecular basis for the exclusive androgenic specificity of aromatase. Locations of catalytic residues and water molecules shed new light on the mechanism of the aromatization step. The structure also suggests a membrane integration model indicative of the passage of steroids through the lipid bilayer. (C) 2009 Elsevier Ltd. All rights reserved.