对循环氧化酶反应的立体化学的结构见解
J R Kiefer1, J L Pawlitz, K T Moreland
1Searle Discovery Research, Monsanto Company, St Louis, Missouri 63198, USA.
Nature
|May 16, 2000
概括
循环氧化原酶-2酶通过两个反应合成前列腺素. 同晶体结构揭示了前列腺素G2的立体特异合成的分子基础,澄清了酶的功能.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 结构生物学 结构生物学
背景情况:
- 循环氧化原酶 (COX) 是eicosanoid合成中的关键酶,催化阿拉基酸的转化.
- 两个异构体,COX-1和COX-2,具有重要的序列和结构相似性.
- 在不同的活性位点内,COX酶执行顺序循环氧化酶和过氧化酶反应.
研究的目的:
- 阐明通过循环氧基因酶-2.2进行前列腺素G2的立体特异合成的分子机制.
- 研究COX-2中基质结合和产物形成的结构基础.
主要方法:
- 对类Apo-cyclooxygenase-2的共同晶体结构的确定.
- 复杂的形成与阿拉基酸和前列腺素中间体.
- 进行X射线晶体学以解决酶-连接体相互作用.
主要成果:
- 报道了环氧化原酶-2与阿拉基酸和前列腺素的共同晶体结构.
- 确定了关键的结构特征,决定了前列腺素G2形成的立体特异性.
- 提供了对结合的环氧化酶和过氧化酶活动的原子级洞察力.
结论:
- 确定的结构为COX-2的立体特异性前列腺素G2合成提供了分子解释.
- 了解这些机制可以为开发向治疗提供信息.
- 结构洞察力突出了复杂的活性位点架构,使序列酶反应成为可能.
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