Fenteany G, Standaert R F, Lane W S, Choi S, Corey E J, Schreiber S L
Howard Hughes Medical Institute, Department of Chemistry, Harvard University, Cambridge, MA 02138.
Science. 1995 May 5;268(5211):726-31. doi: 10.1126/science.7732382.
Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces neurite outgrowth in a murine neuroblastoma cell line. Tritium-labeled lactacystin was used to identify the 20S proteasome as its specific cellular target. Three distinct peptidase activities of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities) were inhibited by lactacystin, the first two irreversibly and all at different rates. None of five other proteases were inhibited, and the ability of lactacystin analogs to inhibit cell cycle progression and induce neurite outgrowth correlated with their ability to inhibit the proteasome. Lactacystin appears to modify covalently the highly conserved amino-terminal threonine of the mammalian proteasome subunit X (also called MB1), a close homolog of the LMP7 proteasome subunit encoded by the major histocompatibility complex. This threonine residue may therefore have a catalytic role, and subunit X/MB1 may be a core component of an amino-terminal-threonine protease activity of the proteasome.
乳胞素是一种链霉菌代谢产物，它能抑制细胞周期进程，并在小鼠神经母细胞瘤细胞系中诱导神经突生长。用氚标记的乳胞素确定20S蛋白酶体是其特定的细胞靶点。该酶复合物的三种不同的肽酶活性（胰蛋白酶样、糜蛋白酶样和肽基谷氨酰肽水解活性）均被乳胞素抑制，前两种活性被不可逆地抑制，且抑制速率不同。其他五种蛋白酶均未被抑制，乳胞素类似物抑制细胞周期进程和诱导神经突生长的能力与其抑制蛋白酶体的能力相关。乳胞素似乎共价修饰了哺乳动物蛋白酶体亚基X（也称为MB1）高度保守的氨基末端苏氨酸，MB1是主要组织相容性复合体编码的LMP7蛋白酶体亚基的紧密同源物。因此，这个苏氨酸残基可能具有催化作用，亚基X/MB1可能是蛋白酶体氨基末端苏氨酸蛋白酶活性的核心成分。
