Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1
Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1
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DOI：
10.1016/j.febslet.2006.02.041
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发表时间：
2006-03-20
期刊：
影响因子：
3.5
通讯作者：
Tsujimoto, M
中科院分区：
文献类型：
--
作者：
Goto, Y;Hattori, A;Tsujimoto, M
脂肪细胞来源的亮氨酸氨肽酶（阿拉普）/ER氨肽酶-1是属于氨肽酶M1家族的多功能酶。有研究表明，人类A-Arg基因Lys 528 Arg多态性与原发性高血压相关。在这项研究中，Lys 528在人A-丙氨酸的酶活性的作用进行了研究，通过定点突变。在检测的非同义多态性中，只有Lys 528 Arg降低酶活性。用包括Ala、Met、His和Arg的各种氨基酸替换Lys 528引起酶活性的显著降低。该酶的分子模拟表明，Lys 528位于底物口袋的入口附近。这些结果表明，Lys 528通过维持酶的底物口袋的适当结构而对A-actin的最大活性是重要的。A-β的酶活性降低可能导致高血压以及观察到的多态性与高血压之间的关联。(c)2006年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
The adipocyte-derived leucine aminopeptidase (ALAP)/ER aminopeptidase-1 is a multi-functional enzyme belonging to the M1 family of aminopeptidases. It was reported that the polymorphism Lys528Arg in the human A-LAP gene is associated with essential hypertension. In this study, the role of Lys528 in the enzymatic activity of human A-LAP was examined by site-directed mutagenesis. Among non-synonymous polymorphisms tested, only Lys528Arg reduced enzymatic activity. The replacement of Lys528 with various amino acids including Ala, Met, His and Arg caused a significant decrease in the enzymatic activity. Molecular modeling of the enzyme suggested that Lys528 is located near the entrance of the substrate pocket. These results suggest that Lys528 is important for maximal activity of A-LAP by maintaining the appropriate structure of the substrate pocket of the enzyme. The reduced enzymatic activity of A-LAP may cause high blood pressure and the observed association between the polymorphism and hypertension. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.