The Identification of a Novel Natural Activator of p300 Histone Acetyltranferase Provides New Insights into the Modulation Mechanism of this Enzyme
The Identification of a Novel Natural Activator of p300 Histone Acetyltranferase Provides New Insights into the Modulation Mechanism of this Enzyme
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DOI：
10.1002/cbic.200900721
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发表时间：
2010-04-12
期刊：
影响因子：
3.2
通讯作者：
De Tommasi, Nunziatina
中科院分区：
文献类型：
--
作者：
Dal Piaz, Fabrizio;Tosco, Alessandra;De Tommasi, Nunziatina
许多严重的人类病理改变与组蛋白乙酰化和去乙酰化之间的精细平衡的改变有关；因为并不是所有这些疾病都涉及低乙酰化，但也包括高乙酰化，能够增强或抑制组蛋白乙酰转移酶(HATS)活性的化合物可能是有前途的治疗药物。我们在体外和细胞内评估了11种天然多异戊二烯基二苯甲酮衍生物调节p300/CBP HAT活性的能力，p300/CBP是一种在各种细胞过程中发挥关键作用的酶。一些被测试的化合物有效地结合到p300/CBP蛋白上：特别是古蒂菲尔酮A、古蒂菲尔酮E和马钱子酮抑制其HAT活性，而尼莫司酮则显示出惊人的激活该酶的能力。尼莫司酮具有穿透细胞膜和调节组蛋白乙酰化进入细胞的能力，以及它对p300/CBP酶的高亲和力，使该化合物成为设计优化抗癌药物的合适先导。此外，在细胞和分子水平上对抑制剂和激活剂进行的研究为小分子对p300/CBP的调控机制提供了新的见解。
Many severe human pathologies are related to alterations of the fine balance between histone acetylation and deacetylation; because not all such diseases involve hypoacetylation, but also hyperacetylation, compounds able to enhance or repress the activities of histone acetyltransferases (HATs) could be promising therapeutic agents. We evaluated in vitro and in cell the ability of eleven natural polyisoprenylated benzophenone derivatives to modulate the HAT activity of p300/CBP, an enzyme that plays a pivotal role in a variety of cellular processes. Some of the tested compounds bound efficiently to the p300/CBP protein: in particular, guttiferone A, guttiferone E and clusianone inhibit its HAT activity, whereas nemorosone showed a surprising ability to activate the enzyme. The ability of nemorosone to penetrate cell membranes and modulate histone acetylation into the cell together with its high affinity for the p300/CBP enzyme made this compound a suitable lead for the design of optimized anticancer drugs. Besides, the studies performed at a cellular and molecular level on both the inhibitors and the activator provided new insights into the modulation mechanism of p300/CBP by small molecules.