School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266071, China.
College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266071, China.
Eur J Pharmacol. 2022 Sep 15;931:175178. doi: 10.1016/j.ejphar.2022.175178. Epub 2022 Aug 7.
Glutaminyl cyclases (QC) catalyze the cyclization of proteins and turn N-terminal glutamine or glutamic acid into N-terminal pyroglutamate, resulting in protection of proteins from aminopeptidases and an increase of their stabilities. The aberrant N-terminal pyroglutamate has been found in various diseases, including Alzheimer's disease (AD), Huntington's disease (HD) and cancer. Two kinds of human QC, the secretory sQC and the Golgi resident gQC, are identified to date. Several substrates of sQC involving beta amyloid (Aβ), Huntington (HTT) protein and certain inflammatory mediators such as CCL2 and CX3CL1 have been observed to associate with neurodegenerative diseases and cancers. The Golgi resident gQC can modify N-terminus of CD47 that directly influences the interaction of CD47 and SIRPα resulting in the modulations of the immunological surveillance related mechanisms in cancer. Additionally, inflammatory chemokines CCL2 and CX3CL1 can also be modified by gQC. Several QC inhibitors with differential scaffold structures have been developed and investigated. Among these QC inhibitors, PQ912, a benzimidazole-based inhibitor, has been studied in a phase II clinical trial to treat AD. In this review, we will summarize the current knowledge about QCs' tissue expression patterns, their potential cellular substrates in the context of cancers, AD and HD. After introducing QCs' molecular structures and catalysis mechanisms, the structures and efficacies of the currently reported QCs' inhibitors will also be summarized.
谷氨酰胺环化酶（QC）催化蛋白质的环化作用，将蛋白质的 N 端谷氨酰胺或谷氨酸转化为 N 端焦谷氨酸，从而保护蛋白质免受氨肽酶的作用，并增加其稳定性。在各种疾病中都发现了异常的 N 端焦谷氨酸，包括阿尔茨海默病（AD）、亨廷顿病（HD）和癌症。迄今为止，已经鉴定出两种人类 QC，即分泌型 sQC 和高尔基体驻留型 gQC。已经观察到 sQC 的几种底物，包括β淀粉样蛋白（Aβ）、亨廷顿（HTT）蛋白和某些炎症介质，如 CCL2 和 CX3CL1，与神经退行性疾病和癌症有关。高尔基体驻留型 gQC 可以修饰 CD47 的 N 端，直接影响 CD47 和 SIRPα 的相互作用，从而调节癌症中与免疫监视相关的机制。此外，炎症趋化因子 CCL2 和 CX3CL1 也可以被 gQC 修饰。已经开发和研究了几种具有不同支架结构的 QC 抑制剂。在这些 QC 抑制剂中，苯并咪唑基抑制剂 PQ912 已在 II 期临床试验中用于治疗 AD。在这篇综述中，我们将总结 QC 在组织表达模式方面的最新知识，以及它们在癌症、AD 和 HD 背景下的潜在细胞底物。在介绍 QC 的分子结构和催化机制之后，还将总结目前报道的 QC 抑制剂的结构和功效。
