Premium
Reduced activity of the hypertension‐associated Lys528Arg mutant of human adipocyte‐derived leucine aminopeptidase (A‐LAP)/ER‐aminopeptidase‐1
Author(s) -
Goto Yoshikuni,
Hattori Akira,
Ishii Yasuhiro,
Tsujimoto Masafumi
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.02.041
Subject(s) - aminopeptidase , leucine , enzyme , leucyl aminopeptidase , adipocyte , enzyme assay , mutant , biochemistry , chemistry , biology , amino acid , endocrinology , medicine , gene , adipose tissue
The adipocyte‐derived leucine aminopeptidase (A‐LAP)/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.