基因氨酸3-单氧基酶抑制的结构基础
Marta Amaral1, Colin Levy, Derren J Heyes
1Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Nature
|April 12, 2013
概括
抑制 kynurenine 3-monooxygenase (KMO) 显示了神经退行性疾病的治疗潜力. KMO的第一个晶体结构揭示了抑制剂如何结合,使得基于结构的药物设计能够用于阿尔茨海默氏症和帕金森症等疾病.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 神经科学是一个神经科学.
背景情况:
- kynurenine 3-monooxygenase (KMO) 是 kynurenine 途径中的一个关键酶,与亨廷顿病和阿尔茨海默病等神经退行性疾病有关.
- kynurenine 途径代谢物的失调与各种脑部疾病,癌症和炎症状况有关.
- 现有化合物抑制KMO的分子机制以前是未知的,阻碍了药物开发.
研究的目的:
- 确定Saccharomyces cerevisiae KMO的第一个晶体结构,其自由形式和复合与抑制剂UPF 648.
- 通过UPF 648.8阐明KMO抑制的分子基础.
- 验证酵母KMO结构作为设计人类KMO抑制剂用于神经退行性疾病的模板.
主要方法:
- 使用X射线晶体学来确定酵母KMO的结构,其复杂性为UPF 648.
- 使用功能测定和向突变发生法来研究酶的活性部位和抑制剂结合.
- 酵母KMO结构和抑制剂与人类KMO结合的比较.
主要成果:
- 晶体结构显示UPF 648在FAD辅因子附近结合,改变活性位点并防止基质结合.
- 在酵母和人类KMO之间保留了活性站点架构和抑制剂结合模式.
- 酵母KMO-UPF 648复杂结构作为基于结构的药物设计的验证模板.
结论:
- 确定的KMO结构为UPF 648.8的抑制机制提供了关键的见解.
- 这些结构信息有助于设计针对神经退行性疾病的新型KMO抑制剂.
- 未来开发穿透血脑屏障的KMO抑制剂可能会导致对亨廷顿病,阿尔茨海默病和帕金森病的有效治疗方法.
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