Selvi Ruthrotha B, Kundu Tapas K
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, India.
Biotechnol J. 2009 Mar;4(3):375-90. doi: 10.1002/biot.200900032.
The eukaryotic genome is a highly dynamic nucleoprotein complex that is comprised of DNA, histones, nonhistone proteins and RNA, and is termed as chromatin. The dynamic of the chromatin is responsible for the regulation of all the DNA-templated phenomena in the cell. Several factors, including the nonhistone chromatin components, ATP-dependent remodeling factors and the chromatin-modifying enzymes, mediate the combinatorial post-translational modifications that control the chromatin fluidity and, thereby, the cellular functions. Among these modifications, reversible acetylation plays a central role in the highly orchestrated network. The enzymes responsible for the reversible acetylation, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), not only act on histone substrates but also on nonhistone proteins. Dysfunction of the HATs/HDACs is associated with various diseases like cancer, diabetes, asthma, cardiac hypertrophy, retroviral pathogenesis and neurodegenerative disorders. Therefore, modulation of these enzymes is being considered as an important therapeutic strategy. Although substantial progress has been made in the area of HDAC inhibitors, we have focused this review on the HATs and their small-molecule modulators in the context of disease and therapeutics. Recent discoveries from different groups have established the involvement of HAT function in various diseases. Furthermore, several new classes of HAT modulators have been identified and their biological activities have also been reported. The scaffold of these small molecules can be used for the design and synthesis of better and efficient modulators with superior therapeutic efficacy.
真核生物基因组是一种高度动态的核蛋白复合体，由DNA、组蛋白、非组蛋白和RNA组成，被称为染色质。染色质的动态变化负责调控细胞中所有以DNA为模板的现象。包括非组蛋白染色质成分、ATP依赖的重塑因子和染色质修饰酶在内的多种因素介导了组合性的翻译后修饰，这些修饰控制着染色质的流动性，进而影响细胞功能。在这些修饰中，可逆乙酰化在高度协调的网络中起着核心作用。负责可逆乙酰化的酶，即组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs），不仅作用于组蛋白底物，也作用于非组蛋白。HATs/HDACs功能失调与多种疾病相关，如癌症、糖尿病、哮喘、心脏肥大、逆转录病毒发病机制和神经退行性疾病。因此，调节这些酶被认为是一种重要的治疗策略。尽管在HDAC抑制剂领域已经取得了重大进展，但我们在本综述中重点关注了HATs及其在疾病和治疗背景下的小分子调节剂。不同研究小组最近的发现证实了HAT功能与多种疾病有关。此外，已经鉴定出几类新的HAT调节剂，并报道了它们的生物学活性。这些小分子的支架可用于设计和合成具有更好治疗效果的高效调节剂。
