On the Histone Lysine Methyltransferase Activity of Fungal Metabolite Chaetocin
On the Histone Lysine Methyltransferase Activity of Fungal Metabolite Chaetocin
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DOI：
10.1021/jm401063r
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发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Fuchter, Matthew J.
中科院分区：
文献类型：
--
作者：
Cherblanc, Fanny L.;Chapman, Kathryn L.;Fuchter, Matthew J.
组蛋白赖氨酸甲基转移酶(HKMT)是一类重要的表观遗传治疗靶点。1(毛壳素)是一种表硫二酮基哌嗪(ETP)的天然产物，据报道是一种特异性的SU(VAR)3-9类HKMT的抑制剂。我们研究了1和功能相关类似物对HKMT G9a的抑制作用。我们的结果表明，只有结构上唯一的ETP核心才需要抑制，并且这种抑制是时间依赖的和不可逆的(在没有DTT的情况下)，最终导致蛋白质变性。质谱学数据为这种效应提供了分子基础，证明了1与蛋白质之间形成共价加合物。这为在体外观察到的选择性抑制多种HKMT提供了一个潜在的理论基础，并对ETP针对这些重要的表观遗传靶点的活性有一定的影响。
Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets.