Reduced activity of the hypertension‐associated Lys528Arg mutant of human adipocyte‐derived leucine aminopeptidase (A‐LAP)/ER‐aminopeptidase‐1
- 24 February 2006
- journal article
- Published by Wiley in FEBS Letters
- Vol. 580 (7) , 1833-1838
- https://doi.org/10.1016/j.febslet.2006.02.041
Abstract
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.Keywords
This publication has 26 references indexed in Scilit:
- Crystal Structures of the Tricorn Interacting Factor F3 from Thermoplasma acidophilum, a Zinc Aminopeptidase in Three Different ConformationsJournal of Molecular Biology, 2005
- Contribution of Molecular Modeling and Site-Directed Mutagenesis to the Identification of a New Residue, Glutamate 215, Involved in the Exopeptidase Specificity of Aminopeptidase ABiochemistry, 2003
- Human Leukocyte-derived Arginine AminopeptidasePublished by Elsevier ,2003
- An Aminopeptidase, ARTS-1, Is Required for Interleukin-6 Receptor SheddingJournal of Biological Chemistry, 2003
- An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptidesNature Immunology, 2002
- ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulumNature, 2002
- Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase APublished by Elsevier ,2002
- Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertensionHuman Mutation, 2002
- Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation.Nature Structural & Molecular Biology, 2001
- Characterization of Glu350 as a Critical Residue Involved in the N-Terminal Amine Binding Site of Aminopeptidase N (EC 3.4.11.2): Insights into Its Mechanism of ActionBiochemistry, 1998