Zn(II)-dependent histone deacetylase inhibitors: Suberoylanilide hydroxamic acid and trichostatin A
Zn(II)-dependent histone deacetylase inhibitors: Suberoylanilide hydroxamic acid and trichostatin A
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DOI：
10.1016/j.biocel.2008.05.026
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发表时间：
2009-04-01
影响因子：
4
通讯作者：
Pakchung, Amalie A. H.
中科院分区：
文献类型：
--
作者：
Codd, Rachel;Braich, Najwa;Pakchung, Amalie A. H.
辛二酰苯胺异羟肟酸（SAHA，伏立诺他，Zolinza（R））和甲氨蝶呤A（TSA）是Zn（II）依赖性I类和II类组蛋白脱乙酰酶（HDAC）的抑制剂，所述HDAC是与组蛋白乙酰转移酶（HAT）协同作用以调节染色质中核小体组蛋白的赖氨酸残基的ε-氨基的乙酰化状态的酶。由Zn（II）依赖性HDAC的SAHA或TSA抑制引起的组蛋白乙酰化水平增加松弛染色质结构并上调转录。20世纪90年代，HDAC活性的抑制与肿瘤生长的抑制之间的联系使HDAC抑制剂（HDACi）的设计成为肿瘤学研究的前沿。SAHA对血液和实体肿瘤具有抗癌活性，并已被FDA批准用于治疗皮肤T细胞淋巴瘤。从X射线晶体学对I类和IIa类HDAC的分子水平理解的增加突出了活性位点远端残基和空腔大小的差异，这对HDACi底物特异性和酶机制具有影响。HDAC聚焦的基于活性的蛋白质谱分析实验的结果可能导致设计类特异性HDACi的分子。(C)2008爱思唯尔有限公司版权所有。
Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza(R)) and trichostatin A (TSA) are inhibitors of the Zn(II)-dependent class I and class II histone deacetylases (HDACs), which are enzymes that operate in concert with histone acetyltransferases (HATs) to regulate the acetylation status of the epsilon-amino group of lysine residues of nucleosomal histones in chromatin. An increased level of histone acetylation resulting from the SAHA or TSA inhibition of Zn(II)-dependent HDACs relaxes the chromatin structure and upregulates transcription. The links made in the 1990s between the inhibition of HDAC activity and the suppression of tumor growth have brought the design of HDAC inhibitors (HDACi) to the forefront of oncology research. SAHA has anticancer activity against hematologic and solid tumors and has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The increased molecular-level understanding of class I and class IIa HDACs from X-ray crystallography highlights differences in the residues distal to the active site and in the cavity size, which has implications for HDACi substrate specificity and enzyme mechanism. Results from HDAC-focussed activity-based protein profiling experiments may lead to the design of molecules that are class-specific HDACi. (C) 2008 Elsevier Ltd. All rights reserved.