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O-GlcNAcase: Emerging Mechanism, Substrate Recognition and Small-Molecule Inhibitors.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-06-04 , DOI: 10.1002/cmdc.202000077
Ahmed A Elbatrawy 1, 2 , Eun Ju Kim 3 , Ghilsoo Nam 1, 2
Affiliation  

O‐GlcNAcylation is the dynamic and ubiquitous post‐translational glycosylation of nucleocytoplasmic proteins on serine/threonine residues; it is implicated in regulation of the cell cycle. This protein modification is mainly governed by a pair of enzymes: O‐GlcNAc transferase (OGT) adds the N‐acetylglucosamine moiety to acceptor proteins, and O‐GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation to be investigated. However, the design of highly potent and selective inhibitors faces several challenges as no full structural data of human OGA has been discovered to date. Moreover, there are a number of mechanistically similar related enzymes such as β‐hexosaminidases (Hex), and the concomitant inhibition of these enzymes leads to undesirable lysosomal‐storage disorders. This review highlights recent insights into the structure of human O‐GlcNAcase and its isoforms. We focus on the catalytic mechanism and substrate recognition by OGA. In addition, it presents an updated overview of small‐molecule OGA inhibitors, with either carbohydrate or noncarbohydrate scaffolds. We discuss inhibitor structures, binding modes, and selectivity towards the enzyme, and potential outcomes in probing O‐GlcNAcylation at cellular levels.

中文翻译:

O-GlcNAcase:新兴机制,底物识别和小分子抑制剂。

O-GlcNAcylation是丝氨酸/苏氨酸残基上胞质蛋白的动态且普遍存在的翻译后糖基化作用;它与细胞周期的调节有关。这种蛋白质修饰主要由一对酶控制:O-GlcNAc转移酶(OGT)在受体蛋白质上添加N-乙酰氨基葡糖部分,O-GlcNAcase(OGA)从蛋白质受体上水解糖部分。不规则的O-GlcNAcylation与多种疾病有关,包括癌症,糖尿病和神经变性。最近,小分子OGA抑制剂的发现使O-GlcNAcylation的生理功能得以研究。然而,由于迄今为止尚未发现人OGA的完整结构数据,因此设计高效和选择性抑制剂面临若干挑战。此外,在机械上有许多类似的相关酶,例如β-己糖胺酶(Hex),这些酶的同时抑制会导致不良的溶酶体贮积病。这篇综述强调了对人O-GlcNAcase及其同工型结构的最新见解。我们专注于OGA的催化机理和底物识别。此外,它还提供了带有碳水化合物或非碳水化合物支架的小分子OGA抑制剂的最新概述。我们讨论了抑制剂的结构,结合模式和对酶的选择性,以及在细胞水平上探测O-GlcNAcylation的潜在结果。这篇综述强调了对人O-GlcNAcase及其同工型结构的最新见解。我们专注于OGA的催化机理和底物识别。此外,它还提供了带有碳水化合物或非碳水化合物支架的小分子OGA抑制剂的最新概述。我们讨论了抑制剂的结构,结合模式,对酶的选择性以及在细胞水平上探测O-GlcNAcylation的潜在结果。这篇综述强调了对人O-GlcNAcase及其同工型结构的最新见解。我们专注于OGA的催化机理和底物识别。此外,它还提供了带有碳水化合物或非碳水化合物支架的小分子OGA抑制剂的最新概述。我们讨论了抑制剂的结构,结合模式,对酶的选择性以及在细胞水平上探测O-GlcNAcylation的潜在结果。
更新日期:2020-07-20
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