Identification of two active site residues in human angiotensin I-converting enzyme.
作者：
DOI: 10.1016/S0021-9258(18)43897-5
关键词: Glutamic acid 、 Biochemistry 、 Alanine 、 Stereochemistry 、 Binding site 、 Aspartic acid 、 Active site 、 Metalloproteinase 、 Zinc 、 Amino acid 、 Chemistry
摘要: Angiotensin I-converting enzyme (ACE) contains two zinc-dependent catalytic domains (N and C domains) each bearing the motif HEXXH where histidines form of three amino acid zinc ligands. Sequence alignment ACE domain with other metalloproteases, indicates a glutamate residues which putatively constitutes third ligand an aspartate residue may indirect interaction. We investigated functional roles in (Glu987 Asp991) using cDNA encoding inactive N domain. mutated Glu987 to (E987D) or valine (E987V) Asp991 (D991E) alanine (D991A). Catalytically active mutants (E987D, D991E D991A) exhibited similar Km values for hippuryl-His-Leu compared non-mutated E987D displayed 300-fold decrease kcat 25-fold reduction sensitivity inhibitor trandolaprilat, whose binding is zinc-dependent. E987V was catalytically did not bind [3H]trandolaprilat. D991A 3.8- 22-fold kcat, respectively, Ki' trandolaprilat were increased 8- 29-fold. These results provide strong evidence that suggest role positioning site ion.
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