Recent developments in catalysis and inhibition of the Jumonji histone demethylases.
Recent developments in catalysis and inhibition of the Jumonji histone demethylases.
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DOI：
10.1016/j.sbi.2023.102707
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发表时间：
2023-12
影响因子：
6.8
通讯作者：
Fujimori, Danica Galonic
中科院分区：
文献类型：
--
作者：
Sarah, Letitia;Fujimori, Danica Galonic
组蛋白甲基化是最常见的组蛋白修饰之一，在调节基于染色质的过程中具有重要作用。 Jumonji 组蛋白赖氨酸去甲基化酶 (JMJC KDM) 通过其去甲基化和染色质支架功能影响基因转录的调节。最近已经证明，JMJC KDM 的失调会导致包括癌症在内的多种疾病的发病机制和进展。这些观察结果引起了人们对调节赖氨酸甲基化酶的兴趣增加。在这里，我们重点介绍 JMJC KDM 催化作用的最新进展。具体来说，我们重点关注 JMJC KDM 底物识别和相互作用组阐明的最新研究进展。我们还重点介绍了最近报道的 JMJC KDM 抑制剂，并描述了它们的治疗潜力和挑战。最后，我们讨论了针对这些酶的替代策略，这些策略依赖于针对 JMJC KDM 辅助结构域以及利用靶向蛋白质降解策略。
Histone methylation, one of the most common histone modifications, has fundamental roles in regulating chromatin-based processes. Jumonji histone lysine demethylases (JMJC KDMs) influence regulation of gene transcription through both their demethylation and chromatin scaffolding functions. It has recently been demonstrated that dysregulation of JMJC KDMs contributes to pathogenesis and progression of several diseases, including cancer. These observations have led to an increased interest in modulation of enzymes that regulate lysine methylation. Here, we highlight recent progress in understanding catalysis of JMJC KDMs. Specifically, we focus on recent research advances on elucidation of JMJC KDM substrate recognition and interactomes. We also highlight recently reported JMJC KDM inhibitors and describe their therapeutic potentials and challenges. Finally, we discuss alternative strategies to target these enzymes, which rely on targeting JMJC KDMs accessory domains as well as utilization of the targeted protein degradation strategy.
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