一种基于机制的激素脱甲基酶LSD1的激素脱甲基酶激活剂
Jeffrey C Culhane1, Lawrence M Szewczuk, Xin Liu
1Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Journal of the American Chemical Society
|April 6, 2006
概括
研究人员开发了一种选择性抑制剂,化合物1,向激素脱甲基酶LSD1 (氨酸特异性脱甲基酶1). 这种基于机制的非激活剂与FAD有共性结合,为研究基因素修饰和染色质重塑提供了一个新的工具.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 基因组脱甲基酶LSD1 (lysine-specific demethylase 1) 是表观遗传调节中的一个关键酶.
- LSD1催化了甲基从组素H3 lysine 4 (H3K4) 中去除甲基,从而影响了基因表达.
- LSD1活动的失调与包括癌症在内的各种疾病有关.
研究的目的:
- 设计和合成针对LSD1.1的新型基抑制剂.
- 描述开发的化合物的抑制和选择性的机制.
- 建立一种化学工具,用于研究LSD1在基因素修饰和染色质重塑中的功能.
主要方法:
- 基于的抑制剂类似物的设计和合成.
- 酶抑制试验用于评估LSD1活性.
- 时间依赖的无活化研究,以确定作用机制.
- 质谱测量用于识别共价 adducts.
- 选择性分析针对相关酶,如单胺氧化酶 B. 选择性分析.
主要成果:
- 合成了两种基于的抑制剂类似物,其中化合物1显示了LSD1.1的强有力的时间依赖性失活.
- 化合物1含有一组propargylamine,并与LSD1.1的FAD辅因子形成共价.
- 化合物1的抑制受到基质以度依赖的方式保护.
- 化合物1显示出高选择性,没有观察到单胺氧化酶B的显著抑制.
- 质谱学证实了化合物1和FAD之间的共价相互作用.
结论:
- 化合物1是一种选择性的,基于机制的,激素脱甲基酶LSD1.1. 的失活剂.
- 甲基胺的功能和共价FAD adduct形成是其抑制活性的关键.
- 化合物1作为一种有价值的化学探针,用于研究LSD1在基因素修饰和染色质重塑中的生物学作用.
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