Jiang Xi, Yang Qing
Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China; State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
Bioorg Chem. 2023 Oct 5;142:106870. doi: 10.1016/j.bioorg.2023.106870.
Glycoside hydrolase family 20 (GH20) β-N-acetyl-d-hexosaminidase (Hex) catalyzes the cleavage of glycosidic linkages in glycans, glycolipids and glycoproteins, and is involved in glycoprotein modification, metabolism of glycoconjugate and the degradation of chitin in fungal cell walls and arthropod exoskeletons. GH84 O-β-N-acetyl-d-glucosaminidase (OGA), which is mechanistically similar related to GH20, participates in the O-GlcNAcylation modification, hydrolyzing the O-GlcNAc moiety from protein acceptors. Hex and OGA are of interest due to their potential for the treatment of disorder diseases and plant protection. Hex inhibitors act as molecular chaperones to treat lysosomal storage disease and as growth regulators to arrest insect molting. Inhibition of OGA is a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease. However, since Hex and OGA exhibit similar active sites, there are challenges in designing highly selective inhibitors. The elucidation of the structural basis of the catalytic mechanism and substrate binding mode of Hex and OGA has provided core information for virtual screening and rational design of inhibitors. A large number of high-potency and selective inhibitors have been developed in the last five years. In this review, we focus on the recent advances in the structural modification, inhibitory activity, binding mechanisms and biological evaluation of Hex and OGA inhibitors, which will facilitate the development of new drugs and agrochemicals.
糖苷水解酶家族20（GH20）β-N-乙酰基-D-己糖胺酶（Hex）催化聚糖、糖脂和糖蛋白中糖苷键的裂解，并参与糖蛋白修饰、糖缀合物代谢以及真菌细胞壁和节肢动物外骨骼中几丁质的降解。GH84 O-β-N-乙酰基-D-葡糖胺酶（OGA）在机制上与GH20相似，参与O-GlcNAcylation修饰，从蛋白质受体上水解O-GlcNAc部分。Hex和OGA因其在治疗疾病和植物保护方面的潜力而备受关注。Hex抑制剂可作为分子伴侣治疗溶酶体贮积病，并作为生长调节剂阻止昆虫蜕皮。抑制OGA是治疗神经退行性疾病（如阿尔茨海默病）中tau病理的一种有前景的治疗方法。然而，由于Hex和OGA具有相似的活性位点，设计高选择性抑制剂存在挑战。阐明Hex和OGA催化机制和底物结合模式的结构基础，为虚拟筛选和抑制剂的合理设计提供了核心信息。在过去五年中，已经开发出了大量高效和选择性的抑制剂。在这篇综述中，我们重点关注Hex和OGA抑制剂在结构修饰、抑制活性、结合机制和生物学评价方面的最新进展，这将有助于新药和农用化学品的开发。
