鞘脂代谢关键酶丝氨酸棕榈酰转移酶的结构、功能及其相关疾病  

Structure,Function and Related Diseases of SPT,a Key Enzyme in Sphingolipid Metabolism

作　　者：赵亚楠 陈成 ZHAO Ya-Nan;CHEN Cheng(Laboratory of Structural Biology,School of Life Sciences,Tianjin University,Tianjin 300072,China)

机构地区：[1]天津大学生命科学学院结构生物学实验室,天津300072

出　　处：《中国生物化学与分子生物学报》2023年第2期165-173,共9页Chinese Journal of Biochemistry and Molecular Biology

基　　金：北京亦城合作发展基金会(No.YJXJ-JZ-2021-0014-08)资助。

摘　　要：鞘脂(sphingolipids)是生物细胞中最主要的膜脂之一,同时也作为信号分子介导细胞生长、增殖、迁移及死亡等重要的生理反应,异常鞘脂代谢经常与心血管疾病、糖尿病、癌症、神经变性病以及自身免疫性疾病等相关。丝氨酸棕榈酰转移酶(serine palmitoyltransferase,SPT)及其复合物是鞘脂从头合成途径的起始酶和关键酶,催化L-丝氨酸与棕榈酰辅酶A缩合形成3-酮二氢鞘氨醇,之后再经过一系列反应生成神经酰胺和其它重要的鞘脂,在鞘脂代谢和稳态调节方面发挥重要作用。本文基于国内外对SPT的研究,综述了SPT的构型、活性位点、底物结合位点等关键的结构信息,尤其近2年的研究发现,SPT是一种组成极其复杂的酶,各个亚基之间存在错综复杂的相互作用和高度调控。SPT具有重要的生物学功能,包括参与胚胎发育、调节内环境稳态、诱导细胞凋亡和参与机体免疫调节等。SPT还可以通过调节酶活性影响鞘脂代谢,进而影响血管疾病和肿瘤的发生发展,并有潜力成为肿瘤诊断和治疗的关键分子。此外,SPT突变体与神经变性病密切相关,本文着重介绍了遗传性感觉与自主神经病变1型(hereditary sensory and autonomic neuropathy type 1,HSAN1)和早发性肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)的病变机制及最新的治疗手段,为深入了解该酶及其参与的鞘脂代谢提供理论参考,同时也为今后的功能研究和药物研发奠定基础。Sphingolipids are one type of the most important membrane lipids in biological cells which act as signal molecules to mediate important physiological responses such as cell growth,proliferation,migration and death.Abnormal sphingolipid metabolism is often associated with cardiovascular diseases,diabetes,cancer,neurodegenerative diseases and autoimmune diseases.Serine palmitoyltransferase(SPT) and its complexes are the initial and key enzymes of sphingomyelin de novo synthesis play an important role in sphingolipid metabolism and homeostasis regulation by catalyzation of the condensation of L-serine with palmitoyl CoA to form 3-keto dihydrosphingosine,followed by a series of reactions to ceramide and other important sphingolipids.This paper reviews the studies related with key structural information of SPT,such as configuration,active site and substrate binding site.Especially in the past two years,it has been found that SPT is an extremely complex enzyme with complex interactions and regulation among subunits.SPT has important biological functions,including participating in embryonic development,regulating homeostasis,inducing apoptosis and participating in immune regulation.SPT plays important roles in the occurrence and development of vascular diseases and tumors by regulating enzymes in sphingolipid metabolism.Thus it has the potential to become a key molecule in tumor diagnosis and treatment.In addition,SPT mutants are closely related to neurodegenerative diseases.This paper focuses on the pathological mechanism and the latest treatment of hereditary sensation and autonomic neuropathy type 1(HSAN1) and early-onset amyotrophic lateral sclerosis(ALS).It not only provides a theoretical reference for further understanding of the enzyme and its participation in sphingolipid metabolism,but also lays a foundation for future functional research and drug development.

关 键 词：鞘脂代谢 丝氨酸棕榈酰转移酶 神经变性病 

分 类 号：Q71[生物学—分子生物学] R363[医药卫生—病理学]