摘要
降脂药物前蛋白转化酶枯草溶菌素9(PCSK9)为一类抑制Kexin样前转化酶枯草杆菌蛋白酶家族第9个成员的化合物,属于肝源性分泌蛋白,是目前一类降脂新药。其主要在内质网中合成,首先生成75kDa前体,在前体成熟前包含一个N端信号肽序列、一个催化结构域、一个前结构域以及一个含半光氨酸的C端结构域,经第152位残基处发生一次自动催化性裂解,形成14kDa前结构域片段以及包含C端结构域、催化结构的成熟57kDa片段,经过裂解后成熟片段以非共价键结合在催化结构域上的前结构域形成复合体,并作为分子伴侣结合成熟片段离开内质网,进入到高尔基体中,经过乙酰化等修饰后在血液中分泌。独特的分子结构使PCSK9在血脂调节方面发挥出独特的作用机制,其通过加速降解低密度脂蛋白受体(LDLR)进行血浆低密度脂蛋白胆固醇(LDL-C)的调节,降低其表达水平,因此其独特的降脂靶点受到临床研究的高度关注。本次综述对PCSK9在人体发挥的功能、人体代谢中对血脂的作用以及目前现有研究成本展开论述,以期充分认识其临床价值,发挥推广作用,并为PCSK9抑制剂的研发与临床应用研究提供新方向、新思路。
Lipid-lowering drug preprotein invertase subtilisin 9(PCSK9)is a compound that inhibits the 9th member of Kexin like preprotein subtilisin family.It belongs to liver derived secretory protein and is a new lipid-lowering drug.It is mainly synthesized in the endoplasmic reticulum.First,a 75kDa precursor is generated.Before the precursor is mature,it contains an N-terminal signal peptide sequence,a catalytic domain,a pre domain and a C-terminal domain containing hemi-phenylalanine.After an automatic catalytic cleavage at residue 152,it forms a 14kDa pre domain fragment and a mature 57kDa fragment containing C-terminal domain and catalytic structure.After cleavage,the mature fragment forms a complex by non covalent binding to the pre domain on the catalytic domain,and as a molecular chaperone,the mature fragment leaves the endoplasmic reticulum,enters the Golgi apparatus,and is secreted in the blood after acetylation and other modifications.The unique molecular structure makes PCSK9 play a unique role in blood lipid regulation.It regulates plasma low density lipoprotein cholesterol(LDL-C)with accelerated degradation of low density lipoprotein receptor(LDLR)and reduces its expression level.Therefore,its unique lipid-lowering target has attracted great attention in clinical research.This review discusses the function of PCSK9 in human body,the role of PCSK9 in human metabolism on blood lipid and the current research cost,in order to fully understand its clinical value,promote it,and provide new directions and ideas for the research and development and clinical application of PCSK9 inhibitors.
作者
赵益霞
冯娜
刘林芳
ZHAO Yi-xia;FENG Na;LIU Lin-fang(Department of Pharmacy,Tianjin Dongli Hospital,Tianjin 300300,China)
出处
《中国城乡企业卫生》
2022年第7期73-75,共3页
Chinese Journal of Urban and Rural Enterprise Hygiene
