Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase
Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase
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DOI：
10.1210/me.2006-0281
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发表时间：
2007-02-01
影响因子：
--
通讯作者：
Chen, Shiuan
中科院分区：
文献类型：
--
作者：
Hong, Yanyan;Yu, Bin;Chen, Shiuan
芳香酶将雄激素转化为芳香雌激素。芳香酶抑制剂已被用作治疗激素依赖型乳腺癌的一线药物。由于芳香酶的三维结构未知，其芳构化反应和药物识别的结构基础尚不清楚。在本研究中，我们从大肠杆菌中表达并纯化了重组人芳香化酶。用此纯化的活性制剂，蛋白质组学分析揭示了芳香酶的三维折叠。结合定点突变，对依西美坦参与酶催化和自杀抑制的几个关键残基进行了评价。基于我们的结果，提出了底物/依西美坦与活性中心结合的一种新的钳制机制。这些芳香酶的结构和功能研究将为设计更有效的芳香酶抑制剂预防和治疗激素依赖型乳腺癌提供有用的信息。
Aromatase converts androgens to aromatic estrogens. Aromatase inhibitors have been used as first-line drugs in the treatment of hormone-dependent breast cancer. Structural basis of the aromatization reaction and drug recognition by aromatase has remained elusive because of its unknown three-dimensional structure. In this study, recombinant human aromatase was expressed and purified from Escherichia coli. Using this purified and active preparation, the three-dimensional folding of aromatase was revealed by proteomic analysis. Combined with site-directed mutagenesis, several critical residues involved in enzyme catalysis and suicide inhibition by exemestane were evaluated. Based on our results, a new clamping mechanism of substrate/ exemestane binding to the active site is proposed. These structure-function studies of aromatase would provide useful information to design more effective aromatase inhibitors for the prevention and the treatment of hormone-dependent breast cancer.