The proteasome: structure, function, and role in the cell
The proteasome: structure, function, and role in the cell
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DOI：
10.1016/s0305-7372(03)00081-1
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发表时间：
2003-05-01
影响因子：
11.8
通讯作者：
Adams, J
中科院分区：
文献类型：
--
作者：
Adams, J
蛋白酶体是一种多亚基酶复合物，在控制细胞周期进程和细胞凋亡的蛋白质的调节中发挥核心作用，因此已成为抗癌治疗的重要靶点。在蛋白质被降解之前，它首先被标记为被泛素缀合系统破坏，这最终导致多聚泛素链附着在靶蛋白上。蛋白酶体的19 S调节帽结合聚泛素链，使蛋白质变性，并将蛋白质送入蛋白酶体的蛋白水解核心。蛋白水解核心由2个内部β环和2个外部α环组成。2个β环各自含有3个蛋白水解位点，以其胰蛋白酶样、谷氨酰后肽水解酶样（PGPH）命名（即，半胱天冬酶样）或胰凝乳蛋白酶样活性。蛋白酶体的抑制导致细胞周期停滞和凋亡。在体外和体内动物研究中，通过硼替佐米（万珂;以前称为PS-341、LDP-341和MLN 341）抑制蛋白酶体，单独或与常规化疗药物联合治疗对多种肿瘤类型具有抗肿瘤活性;这些结果为广泛的临床试验项目提供了依据。硼替佐米目前正处于骨髓瘤的III期临床试验中。在许多其他肿瘤类型的早期临床开发中。(C)2003爱思唯尔科技有限公司版权所有。
The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein. The proteasome's 19S regulatory cap binds the polyubiquitin chain, denatures the protein, and feeds the protein into the proteasome's proteolytic core. The proteolytic core is composed of 2 inner beta rings and 2 outer alpha rings. The 2 beta rings each contain 3 proteolytic sites named for their trypsin-like, post-glutamyl peptide hydrolase-like (PGPH) (i.e., caspase-like), or chymotrypsin-like activity. Inhibition of the proteasome results in cell-cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition of the proteasome via bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341) had antitumor activity against numerous tumor types either alone or in combination with conventional chemotherapeutic agents; these results provided the rationale for a broad clinical trial program. Bortezomib is currently in phase III trials for myeloma and is.-in early clinical development for numerous other tumor types. (C) 2003 Elsevier Science Ltd. All rights reserved.