Neuropeptide Y (NPY) cleaving enzymes:: Structural and functional homologues of dipeptidyl peptidase 4
Neuropeptide Y (NPY) cleaving enzymes:: Structural and functional homologues of dipeptidyl peptidase 4
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DOI：
10.1016/j.peptides.2006.09.027
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发表时间：
2007-02-01
期刊：
影响因子：
3
通讯作者：
von Hoersten, Stephan
中科院分区：
文献类型：
--
作者：
Frerker, Nadine;Wagner, Leona;von Hoersten, Stephan
NPY的N-末端截短具有重要的生理后果，因为截短的肽失去了它们激活Y1受体的能力。N-末端截短的NPY和相关肽的来源是未知的，可能涉及几种脯氨酸特异性肽酶。首先，我们因此提供了一个概述的肽酶，属于二肽基肽酶4（DP 4）以及氨基肽酶P（APP）的结构和功能的同源物，因此，代表潜在的候选人在体内的NPY裂解。第二，分别应用针对DP 4、DP 8/9和DP 2的选择性抑制剂，在活性研究中以及通过基质辅助激光解吸/电离-飞行时间（MALDI-TOF）-质谱法分析来自野生型和DP 4缺陷型F344大鼠亚株的脑提取物和人血浆样品中的酶分布。第三，用Dpp 4和Npy共转染Cos-1细胞，随后通过共聚焦激光显微镜显示，hNPY-dsRed 1-N1在大的致密核心囊泡中向膜转运，而rDP 4-GFP-C1主要在不同的囊泡中转运，因此没有提供NPY和DP 4共定位的明确证据。然而，活性和质谱研究的综述和实验结果支持这样的观点，即至少有五种肽酶（DP 4，DP 8，DP 9，XPNPEP 1，XPNPEP 2）可能参与NPY的切割，而丝氨酸蛋白酶DP 4（CD 26）可能是参与NPY的N端截短的主要肽酶。然而，DP 8和DP 9也能够裂解NPY，而DP 2不能裂解。(c)2006爱思唯尔公司All rights reserved.
N-terminal truncation of NPY has important physiological consequences, because the truncated peptides lose their capability to activate the Y1-receptor. The sources of N-terminally truncated NPY and related peptides are unknown and several proline specific peptidases may be involved. First, we therefore provide an overview on the peptidases, belonging to structural and functional homologues of dipeptidyl peptidase 4 (DP4) as well as aminopeptidase P (APP) and thus, represent potential candidates of NPY cleavage in vivo. Second, applying selective inhibitors against DP4, DP8/9 and DP2, respectively, the enzymatic distribution was analyzed in brain extracts from wild type and DP4 deficient F344 rat substrains and human plasma samples in activity studies as well as by matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry. Third, co-transfection of Cos-1 cells with Dpp4 and Npy followed by confocal lasermicroscopy illustrated that hNPY-dsRed1-N1 was transported in large dense core vesicles towards the membrane while rDP4-GFP-C1 was transported primarily in different vesicles thereby providing no clear evidence for co-localization of NPY and DP4. Nevertheless, the review and experimental results of activity and mass spectrometry studies support the notion that at least five peptidases (DP4, DP8, DP9, XPNPEP1, XPNPEP2) are potentially involved in NPY cleavage while the serine protease DP4 (CD26) could be the principal peptidase involved in the N-terminal truncation of NPY. However, DP8 and DP9 are also capable of cleaving NPY, whereas no cleavage could be demonstrated for DP2. (c) 2006 Elsevier Inc. All rights reserved.