School of Chemistry & Chemical Engineering , Queen's University Belfast , David Keir Building, Stranmillis Road , Belfast BT9 5AG , Northern Ireland , United Kingdom.
Department of Biocatalysis and Isotope Chemistry , Almac Sciences , Almac House, 20 Seagoe Industrial Estate , Craigavon BT63 5QD , Northern Ireland , United Kingdom.
J Phys Chem B. 2019 Sep 19;123(37):7801-7811. doi: 10.1021/acs.jpcb.9b06064. Epub 2019 Sep 10.
Histone demethylases (KDMs) catalyze histone lysine demethylation, an important epigenetic process that controls gene expression in eukaryotes, and represent important cancer drug targets for cancer treatment. Demethylation of histone is comprised of sequential reaction steps including oxygen activation, decarboxylation, and demethylation. The initial oxygen binding and activation steps have been studied. However, the information on the complete catalytic reaction cycle is limited, which has impeded the structure-based design of inhibitors targeting KDMs. Here we report the mechanism of the complete reaction steps catalyzed by a representative nonheme iron αKG-dependent KDM, PHF8 using QM/MM approaches. The atomic-level understanding on the complete reaction mechanism of PHF8 would shed light on the structure-based design of selective inhibitors targeting KDMs to intervene in cancer epigenetics.
组蛋白去甲基化酶（KDMs）催化组蛋白赖氨酸去甲基化，这是真核生物中控制基因表达的重要表观遗传过程，也是癌症治疗中癌症药物靶点的重要组成部分。组蛋白的去甲基化包括一系列反应步骤，包括氧的结合和激活、脱羧和去甲基化。已经研究了初始氧结合和激活步骤。然而，关于完整催化反应循环的信息有限，这阻碍了针对 KDM 的基于结构的抑制剂的设计。在这里，我们使用 QM/MM 方法报道了代表性的非血红素铁 αKG 依赖性 KDM PHF8 催化的完整反应步骤的机制。对 PHF8 完整反应机制的原子水平理解将为基于结构的选择性抑制剂的设计提供思路，以靶向 KDM 干预癌症表观遗传学。
