基质解构和酶识别的非添加性
Sarah Barelier1, Jennifer A Cummings, Alissa M Rauwerdink
1Department of Pharmaceutical Chemistry, University of California - San Francisco , 1700 Fourth Street, Byers Hall, San Francisco, California 94158, United States.
Journal of the American Chemical Society
|May 6, 2014
概括
酶基质的发现是具有挑战性的. 研究了用较小的分子碎片,而不是完整的基质探测酶,但发现对识别酶功能的有效性不大. 对于酶研究,建议使用完整代谢物库.
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:
- 识别酶基质对于理解生物通路和功能至关重要.
- 目前用于基质发现的方法受到可测试化学结构的复杂性所限制.
- 基于碎片的方法,在抑制剂发现中取得了成功,被假定可以加速基质识别.
研究的目的:
- 研究使用小分子碎片来发现酶基质的可行性.
- 为了确定基于碎片的探测是否可以帮助将功能分配给具有未知作用的酶.
- 了解在颗粒级别上对酶基质识别的结构基础.
主要方法:
- 已知酶基质的分解成41个重叠的碎片.
- 测试来自三个超级家族的六种酶的碎片活性和结合亲和力.
- 用X射线晶体学来确定β-乳酸酶基质的碎片酶复合物的结构.
主要成果:
- 碎片,即使是那些含有活性组的碎片,也显示出最小的活性或结合.
- 酶需要大多数基质特征才能识别;去除单个原子大大减少了结合 (高达6个日志序列).
- 结构分析揭示了基质识别所必需的复杂相互作用.
结论:
- 酶基质的发现并不容易接受基于片段的方法.
- 酶识别需要大量的基质,这限制了小碎片的实用性.
- 开发完整代谢物库是一个更务实的策略,用于酶功能发现.
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