Mechanism, Structure, and Inhibition of O-GlcNAc Processing Enzymes.
Mechanism, Structure, and Inhibition of O-GlcNAc Processing Enzymes.
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DOI：
10.2174/157436210790226537
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发表时间：
2010-01
影响因子：
--
通讯作者：
Vocadlo DJ
中科院分区：
文献类型：
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作者：
Gloster TM;Vocadlo DJ
O-连接的 2-乙酰氨基-2-脱氧-d-吡喃葡萄糖 (O-GlcNAc) 对核细胞质蛋白的翻译后修饰是一个备受关注的话题，并吸引了大量的研究工作。 O-GlcNAc 酰化是一个动态过程，在蛋白质的生命周期中可能发生多次，有时与磷酸化呈相互关系。数百种参与多种细胞过程的蛋白质已被鉴定为用单糖修饰的。 O-GlcNAc 修饰状态对不同蛋白质靶标的控制似乎在许多疾病的病因学中很重要，包括 II 型糖尿病、神经退行性疾病和癌症。有两种酶负责 O-GlcNAc 修饰的添加和去除：分别是尿苷二磷酸-N-乙酰葡糖胺：多肽 β-N-乙酰葡糖胺基转移酶 (OGT) 和 O-GlcNAcase (OGA)。在过去的十年中，关于这两种酶的已知信息量显着增加。特别是，OGA 的机制研究与 OGA 细菌同系物的结构研究相结合，促进了抑制剂的设计，并为某些有效和选择性抑制剂的结合提供了理论基础。关于 OGT 的机制信息稍微落后于 OGA，但最近对 OGT 细菌同源物结构的推论现在应该会推动这些研究向前发展。
The post-translational modification of nucleocytoplasmic proteins with O-linked 2-acetamido-2-deoxy-d-glucopyranose (O-GlcNAc) is a topic of considerable interest and attracts a great deal of research effort. O-GlcNAcylation is a dynamic process which can occur multiple times over the lifetime of a protein, sometimes in a reciprocal relationship with phosphorylation. Several hundred proteins, which are involved in a diverse range of cellular processes, have been identified as being modified with the monosaccharide. The control of the O-GlcNAc modification state on different protein targets appears to be important in the aetiology of a number of diseases, including type II diabetes, neurodegenerative diseases and cancer. Two enzymes are responsible for the addition and removal of the O-GlcNAc modification: uridine diphospho-N-acetylglucosamine:polypeptide β-N-acetylglucosaminyltransferase (OGT) and O-GlcNAcase (OGA), respectively. Over the past decade the volume of information known about these two enzymes has increased significantly. In particular, mechanistic studies of OGA, in conjunction with structural studies of bacterial homologues of OGA have stimulated the design of inhibitors and offered a rationale for the binding of certain potent and selective inhibitors. Mechanistic information about OGT lags a little way behind OGA, but the recent deduction of the structure of an OGT bacterial homologue should now drive these studies forward.