在细胞染色体P450 3A4的活性部位的pyrene.pyrene复合物:证据表明多个基质结合部位
Michael J Dabrowski1, Michael L Schrag, Larry C Wienkers
1Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, WA 98195-7610, USA.
Journal of the American Chemical Society
|October 3, 2002
概括
细胞染色体P450单氧化酶 (CYP) 显示合作动力学. 这项研究提供了第一个光谱证据,即基质复合物,而不是单个分子,在人体CYP3A4的流体活性部位内结合,影响药物代谢.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 细胞染色体P450单氧化酶 (CYP) 对药物和毒素代谢至关重要.
- CYPs表现出全动力学,但潜在的机制仍然不清楚.
- 了解CYP全精度对于预测药物相互作用和疗效至关重要.
研究的目的:
- 为了阐明人体细胞染色体P450 3A4 (CYP3A4) 的合作动力学的机制.
- 为了研究CYP3A4活性部位内的多种基质的结合.
- 为在流体活性部位中提供第一个基质复合物形成的光谱证据.
主要方法:
- 利用pyrene的光特性来区分单体基质和复杂基质.
- 在二烯结合后监测CYP3A4血旋转状态的变化.
- 在存在或缺少CYP3A4和丸激素时分析了pyrene excimer/monomer比率和激发光谱.
主要成果:
- 二烯结合诱导了CYP3A4血红组的低旋转到高旋转转换.
- CYP3A4降低了二烯排放剂/单体比率,这表明基质复合物形成.
- 光谱学变化表明基质复合体占据了一个单一的,流体活性位点.
- 丸激素逆转了这些观察到的光谱变化.
结论:
- 已证明的烯-烯复合体占据了CYP3A4的活性部位.
- 提供了第一个在单个流体活性位点内的基质复合物的光谱证据.
- 提出基质复合体,而不是单个基质,决定反应动力学和选择性.
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