嘌呤霉素敏感的氨肽酶结构与功能研究进展  

Advances on research of structure and function of puromycin sensitive aminopeptidase

作　　者：焦晨阳 李艳[1] 徐强[1] 郭文洁[1] JIAO Chen-yang;LI Yan;XU Qiang;GUO Wen-jie(State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing 210023,China)

机构地区：[1]南京大学生命科学学院,医药生物技术国家重点实验室,江苏南京210023

出　　处：《药学学报》2023年第8期2130-2138,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上资助项目(82073856).

摘　　要：嘌呤霉素敏感的氨肽酶(puromycin-sensitive aminopeptidase,PSAP)是一种M1氨肽酶(M1 amino‐peptidases),具有对嘌呤霉素敏感的特性。其结构包括N端底物结合序列GAMEN、酶活中心HEXXH(X)18E基序以及C端ERAP-1样超家族(ERAP like superfamily)结构域。作为M1型氨肽酶中的重要亚型,PSAP由定位于17q21.32的基因NPEPPS编码,全长为919个氨基酸。PSAP广泛分布于人体各组织,在脑中表达最高,其次是心脏和骨骼肌。同时,PSAP也在肝脏、肾小管上皮、小肠和大肠上皮以及胃上皮细胞中表达。通过其水解活性,PSAP可以清除一些毒性蛋白聚集体,如微管相关蛋白Tau、多聚谷氨酰胺(poly Q)及铜锌超氧化物歧化酶(SOD1)等,参与阿尔茨海默症、亨廷顿舞蹈病、肿瘤等疾病的发生发展过程。现有PSAP酶活抑制剂包括bestatin、amastatin、leuhistin、actinonin和嘌呤霉素等,其中一些已经成药或者正在进行临床试验。本文总结了M1氨肽酶特别是PSAP的生物学功能、结构和相关药物研究进展,旨在为深入研究PSAP的结构、功能及靶向药物的开发提供依据。Puromycin-sensitive aminopeptidase(PSAP)belongs to the M1 family of aminopeptidases,characterized by the N-terminal substrate binding sequence GAMEN,the enzyme activity center HEXXH(X)18E motif,and the C-terminal ERAP-1-like superfamily structural domain.Encoded by the gene NPEPPS located at 17q21.32,PSAP consists of 919 amino acids and is widely distributed throughout the human body,with the highest expression in the brain,followed by the heart and skeletal muscle.It is also found in the liver,renal tubular epithelium,small intestine,large intestine epithelium,and gastric epithelial cells.PSAP primarily relies on its aminopeptidase hydrolytic activity to remove toxic protein aggregates such as Tau,poly Q,and Cu,Zn-superoxide dismutase 1,making it an important factor in the development of diseases such as Alzheimer's disease,Huntington's chorea,and tumors.Existing PSAP inhibitors include bestatin,amastatin,leuhistin,actinonin,and purinomycin,some of which are already available or in clinical trials.This review provides an overview of the structural and biological functions of M1 family aminopeptidases,with a focus on PSAP,to facilitate further research and targeted drug development.

关 键 词：M1氨肽酶 嘌呤霉素敏感的氨肽酶 结构与功能 疾病 抑制剂 

分 类 号：R966[医药卫生—药理学]