Glutaminyl cyclases, the potential targets of cancer and neurodegenerative diseases
Glutaminyl cyclases, the potential targets of cancer and neurodegenerative diseases
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谷氨酰胺酰环化酶，癌症和神经退行性疾病的潜在靶标。
DOI：
10.1016/j.ejphar.2022.175178
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发表时间：
2022-08-10
影响因子：
5
通讯作者：
Zhao，Chenyang
中科院分区：
文献类型：
--
作者：
Zhang，Yidan;Wang，Yifan;Zhao，Chenyang
谷氨酰胺酰环化酶 (QC) 催化蛋白质环化，将 N 末端谷氨酰胺或谷氨酸转化为 N 末端焦谷氨酸，从而保护蛋白质免受氨肽酶的影响并提高其稳定性。异常的 N 末端焦谷氨酸已在多种疾病中被发现，包括阿尔茨海默病 (AD)、亨廷顿病 (HD) 和癌症。迄今为止，已鉴定出两种人类 QC，即分泌型 sQC 和高尔基体驻留型 gQC。 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（例如 CCL2 和 CX3CL1）已被观察到与神经退行性疾病和癌症相关。高尔基体 gQC 可以修饰 CD47 的 N 末端，直接影响 CD47 和 SIRPα 的相互作用，从而调节癌症中的免疫监视相关机制。此外，炎症趋化因子 CCL2 和 CX3CL1 也可以通过 gQC 进行修饰。几种具有不同支架结构的 QC 抑制剂已经被开发和研究。在这些 QC 抑制剂中，PQ912（一种基于苯并咪唑的抑制剂）已在治疗 AD 的 II 期临床试验中进行了研究。在这篇综述中，我们将总结目前关于 QC 的组织表达模式及其在癌症、AD 和 HD 背景下的潜在细胞底物的知识。在介绍QCs的分子结构和催化机制后，还将总结目前报道的QCs抑制剂的结构和功效。
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.