Small Peptide Inhibitors of Acetyl-Peptide Hydrolase Having an Uncommon Mechanism of Inhibition and a Stable Bent Conformation
Small Peptide Inhibitors of Acetyl-Peptide Hydrolase Having an Uncommon Mechanism of Inhibition and a Stable Bent Conformation
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DOI：
10.1021/jm2013375
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发表时间：
2012-03-08
影响因子：
7.3
通讯作者：
Ruvo, M.
中科院分区：
文献类型：
--
作者：
Sandomenico, A.;Russo, A.;Ruvo, M.
酰基肽水解酶（APEH）催化从肽和细胞质蛋白的n端去除乙酰氨基酸。由于APEH在多种疾病中的作用，以及对n端乙酰化的兴趣日益浓厚，对APEH结构、功能和抑制的研究越来越受到重视。因此，我们筛选了一个随机的四肽库，用选定的基团进行n帽，并鉴定出一个三氟乙酰化的四肽（CF3-lmph），其抑制酶的K-i为24.0 +/- 0.8 μ m。该抑制剂对APEH具有选择性，表现出罕见的非竞争性抑制机制，并且在溶液中呈稳定的弯曲构象。CF3-lmph能有效穿过细胞膜，阻断APEH的胞质活性；然而，与其他竞争性和非竞争性抑制剂相比，它触发轻微的促凋亡作用。不同寻常的抑制机制和稳定的结构使新化合物成为研究酶功能的新工具和开发更有效抑制剂的有用支架。
Acyl peptide hydrolase (APEH) catalyzes the removal of acetylamino acids from the N-terminus of peptides and cytoplasmic proteins. Due to the role played in several diseases, and to the growing interest around N-terminal acetylation, studies on APEH structure, function, and inhibition are attracting an ever increasing attention. We have therefore screened a random tetrapeptide library, N-capped with selected groups, and identified a trifluoroacetylated tetrapeptide (CF3-lmph) which inhibits the enzyme with a K-i of 24.0 +/- 0.8 mu M. The inhibitor' is selective for APEH, shows an uncommon uncompetitive mechanism of inhibition, and in solution adopts a stable bent conformation. CF3-lmph efficiently crosses cell membranes, blocking the cytoplasmic activity of APEH; however, it triggers a mild proapoptotic effect as compared to other competitive and noncompetitive inhibitors. The unusual inhibition mechanism and the stable structure make the new compound a novel tool to investigate enzyme functions and a useful scaffold to develop more potent inhibitors.