Gregoretti Ivan V, Lee Yun-Mi, Goodson Holly V
Walther Cancer Center and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46628, USA.
J Mol Biol. 2004 Apr 16;338(1):17-31. doi: 10.1016/j.jmb.2004.02.006.
Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic agents against cancer and a variety of other diseases. Thus far, 11 members of the HDAC family have been identified in humans, but few have been characterized in detail. To better define the biological function of these proteins, make maximal use of studies performed in other systems, and assist in drug development efforts, we have performed a phylogenetic analysis of all HDAC-related proteins in all fully sequenced free-living organisms. Previous analyses have divided non-sirtuin HDACs into two groups, classes 1 and 2. We find that HDACs can be divided into three equally distinct groups: class 1, class 2, and a third class consisting of proteins related to the recently identified human HDAC11 gene. We term this novel group "class 4" to distinguish it from the unrelated "class 3" sirtuin deacetylases. Analysis of gene duplication events indicates that the common ancestor of metazoan organisms contained two class 1, two class 2, and a single class 4 HDAC. Examination of HDAC characteristics in light of these evolutionary relationships leads to functional predictions, among them that self-association is common among HDAC proteins. All three HDAC classes (including class 4) exist in eubacteria. Phylogenetic analysis of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against non-histone substrates.
组蛋白去乙酰化酶（HDACs）修饰核心组蛋白，并参与抑制和增强转录的大型调控复合物。最近的研究表明，一些HDACs也可以作用于非组蛋白。对这些酶的兴趣与日俱增，因为HDAC抑制剂似乎是对抗癌症和多种其他疾病的有前景的治疗药物。迄今为止，已在人类中鉴定出HDAC家族的11个成员，但对其中很少成员进行了详细表征。为了更好地界定这些蛋白质的生物学功能，充分利用在其他系统中进行的研究，并协助药物开发工作，我们对所有完全测序的自由生活生物体中所有与HDAC相关的蛋白质进行了系统发育分析。先前的分析已将非沉默调节蛋白HDACs分为两组，即1类和2类。我们发现HDACs可分为三个同样不同的组：1类、2类，以及由与最近鉴定的人类HDAC11基因相关的蛋白质组成的第三组。我们将这个新组称为“4类”，以将其与无关的“3类”沉默调节蛋白去乙酰化酶区分开来。基因复制事件分析表明，后生动物的共同祖先包含两个1类、两个2类和一个单一的4类HDAC。根据这些进化关系对HDAC特征进行研究可得出功能预测，其中包括HDAC蛋白之间的自我缔合很常见。所有三类HDAC（包括4类）都存在于真细菌中。对细菌HDAC亲属的系统发育分析表明，所有三类HDAC都先于组蛋白的进化，并增加了一些“组蛋白去乙酰化酶”酶的主要活性针对非组蛋白底物的可能性。
