微管蛋白亲和力调节激酶4作为药物靶点的研究进展  

Research Progress of Microtubule Affinity-regulating Kinase 4 as Drug Target

作　　者：周箭 叶和杨[1] 尹秀山 李健 ZHOU Jian;YE He-Yang;YIN Xiu-Shan;LI Jian(College of Pharmaceutical Sciences,Gannan Medical University,Ganzhou 341000,China;College of Pharmacy and Bioengineering,Shenyang University of Chemical Technology,Shenyang 110142,China)

机构地区：[1]赣南医学院药学院,赣州341000 [2]沈阳化工大学制药与生物工程学院,沈阳110142

出　　处：《生物化学与生物物理进展》2022年第8期1422-1430,共9页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(81402850);高层次人才启动基金(QD201910);教育部项目心脑血管疾病专项(XN201904);江西省重点研发计划项目(20203BBG73063);江西省教育厅研究生创新专项资金(YC2021-S804)资助。

摘　　要：微管蛋白亲和力调节激酶4(microtubule affinity-regulating kinase,MARK4)是丝氨酸/苏氨酸激酶家族重要成员之一,主要功能是磷酸化微管结合蛋白(microtubule associated protein,MAP),进而导致MAP从微管中分离,从而改变细胞形状,促进细胞分裂,调控细胞周期等。研究表明,MARK4与微管束形成、神经系统发育和程序性细胞死亡等密切相关,并且参与多种疾病的发生,比如阿尔茨海默病(Alzheimer’s disease,AD)、代谢紊乱、癌症以及心衰心梗等疾病,因此MARK4被认为是极具潜力的药物靶点。本文综述了MARK4的三维结构、生物学功能以及MARK4介导的相关疾病,并且总结了MARK4抑制剂的研究进展。Microtubule affinity-regulating kinase 4(MARK4)is a Ser/Thr protein kinase,best known for its role in phosphorylating microtubule associated proteins,causing their detachment from microtubules thereby increasing microtubule dynamics and facilitating cell shape alterations,cell division,cell cycle control,regulating cell cycle,etc.The MARK4 gene encodes two alternatively spliced isoforms,L and S that differ in their C-terminal region.These isoforms are differentially regulated in human tissues including central nervous system.The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation and the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas.MARK4 exhibits are multi domain structure comprised of an N-terminal header,a catalytic kinase domain,a linker,UBA domain,spacer,and a kinase-associated domain at the C-terminal end.Over-expression of MARK4 is associated with the onset of neurodegenerative diseases such as Alzheimer’s disease,metabolism disorders and cancer.Therefore,MARK4 is being considered as a most suitable drug target for cancer,Alzheimer’s disease and other neurodegenerative diseases and its structural features are employed in the development of new therapeutic molecules.In this paper,the structure and biological functions of MARK4 and the related diseases mediated by MARK4 were reviewed,and the research progress of MARK4 inhibitors was summarized.

关 键 词：微管蛋白亲和力调节激酶4 微管结合蛋白 阿尔茨海默病 心衰心梗 代谢紊乱 药物靶点 抑制剂 

分 类 号：Q25[生物学—细胞生物学] Q51[医药卫生—肿瘤] Q71[医药卫生—临床医学] R73