Signal peptide peptidase and γ-secretase share equivalent inhibitor binding pharmacology
Signal peptide peptidase and γ-secretase share equivalent inhibitor binding pharmacology
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DOI：
10.1074/jbc.m707002200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Toyn, Jeremy H.
中科院分区：
文献类型：
--
作者：
Iben, Lawrence G.;Olson, Richard E.;Toyn, Jeremy H.
长期以来，伽马分泌酶一直被认为是治疗阿尔茨海默病的潜在药物靶点。早老素(γ-分泌酶的催化亚单位)和信号肽酶(SPP)是与裂解跨膜底物相关的跨膜天冬氨酸蛋白酶。SPP和伽马分泌酶在药理上是相似的，因为它们是许多相同的小分子的靶标，包括过渡态类似物、非过渡态抑制剂和淀粉样β-肽调节剂。早老素和SPP之间的一个不同之处在于，早老素的蛋白分解活性只在多亚单位复合体中起作用，而SPP不需要额外的蛋白质辅助因子来发挥活性。本研究利用γ-分泌酶抑制剂放射性配基评价SPP及其结合药理作用。我们发现，SPP酶与过渡态类似物、非过渡态抑制剂和非甾体抗炎药物舒林酸硫化物显示出明显的结合位点，与先前报道的伽马分泌酶类似。在这项研究过程中，培养细胞被发现含有丰富的SPP结合活性，很可能是由几个SPP家族蛋白贡献的。SPP结合位点的数量超过了伽马分泌酶结合位点的数量，因此在这些条件下使用选择性放射性配基来评价伽玛分泌酶结合是必要的。这项研究进一步支持了SPP是SPP/早老素蛋白家族中抑制机制和结构的有用模型的观点。
The enzyme gamma-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin ( the catalytic subunit of gamma-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and gamma-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid beta-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, gamma-secretase inhibitor radioligands were used to evaluate SPP and gamma-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for gamma-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of gamma-secretase binding sites, making it essential to use selective radioligands for evaluation of gamma-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.