N端规则途径的药理学调节及其治疗意义。
Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications.
作者信息
Lee Jung Hoon, Jiang Yanxialei, Kwon Yong Tae, Lee Min Jae
机构信息
Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Protein Metabolism Medical Research Center, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
出版信息
Trends Pharmacol Sci. 2015 Nov;36(11):782-797. doi: 10.1016/j.tips.2015.07.004. Epub 2015 Oct 1.
Abstract
The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N-end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action.
摘要
N端规则途径是一种蛋白水解系统，其中短命底物的单个N端氨基酸决定其代谢半衰期。该途径的底物与许多疾病的发病机制有关，包括恶性肿瘤、神经退行性疾病和心血管疾病。本文综述了关于N端规则途径的机制和功能的当前知识的全面概述。还综述了调节靶底物降解的药理学策略，重点是它们在体内的意义。鉴于对N端规则途径的识别成分（N识别蛋白）的结构和生化理解的迅速进展，N识别蛋白的小分子抑制剂和激活配体成为具有新作用机制的治疗剂。
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