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Literature summary for 3.4.15.1 extracted from

  • Watermeyer, J.M.; Kroeger, W.L.; ONeill, H.G.; Sewell, B.T.; Sturrock, E.D.
    Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril (2010), Biochem. J., 428, 67-74.
    View publication on PubMed

Application

Application Comment Organism
drug development important drug target because of its role in the regulation of blood pressure via the renin-angiotensin-aldosterone system Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant mutant tACE-G13 in complex with inhibitor lisW-S, microseeding, 1.45 mg/ml tACE-G13 with 0.250 mM lisW-S over precipitant solution comprising 15% w/v PEG 4000, 0.010 mM ZnSO4, and 10 mM sodium acetate, pH 4.7, 2 weeks, X-ray diffraction structure determination and analysis at 2.3 A resolution, modelling Homo sapiens

Protein Variants

Protein Variants Comment Organism
D377Q site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
D453E site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
E162D site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
E376D site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
F391Y site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
additional information construction of a minimally glycosylated tACE mutant, tACE-G13, truncated after Ser625 and lacking 36 O-glycosylated N-terminal residues as well as all but two N-glycosylation sites. Mutation of C-domain-specific active-site residues to their N-domain equivalents Homo sapiens
T282S site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
V379S site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
V380T site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens
V518T site-directed mutagenesis, altered inhibition kinetics with inhibitor lisW-S compared to the wild-type enzyme Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(5S)-5-[(N-benzoyl)-amino]-4-oxo-6-phenyl-hexanoyl-L-phenylalanine phosphinic peptide inhibitor kAF Homo sapiens
(5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenylhexanoyl-L-tryptophan phosphinic peptide inhibitor kAW Homo sapiens
lisinopril the compound shows a 4fold domain-selectivity for the C-domain compared to the N-domain. Active site binding structure, overview Homo sapiens
lisW-S a C-domain-selective derivative of the drug lisinopril. The compound shows a 258fold domain-selectivity for the C-domain compared to the N-domain, that is largely due to the co-operative effect of C-domain-specific residues in the S2' subsite. Interactions in the active site: comparison between N- and C-domain residues, overview Homo sapiens
RXPA380
-
Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+
-
Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P12821
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
glycoprotein
-
Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
testis
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information ACE comprises two homologous domains, that differ in their substrate preferences, overview Homo sapiens ?
-
?
o-aminobenzoyl-Phe-Arg-Lys(2,4-dinitrophenyl)-Pro-hydroxide + H2O
-
Homo sapiens ?
-
?

Subunits

Subunits Comment Organism
More ACE comprises two homologous domains, that differ in their substrate preferences, overview. Has a similar binding mode like its parent compound lisinopril, but the P2' tryptophan moiety takes a different conformation to that seen in other inhibitors having a tryptophan residue in this position Homo sapiens

Synonyms

Synonyms Comment Organism
ACE
-
Homo sapiens
angiotensin-converting enzyme
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
25
-
assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
6.8
-
assay at Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
additional information
-
additional information inhibition kinetics of point exchange mutants with lisinopril and lisW-S, the mutants show highly decreased Ki for inhibitor lisW-S with their N-domain, overview Homo sapiens
0.0000012
-
lisinopril pH 6.8, 25°C, recombinant testis ACE C-domain Homo sapiens
0.0000048
-
lisinopril pH 6.8, 25°C, recombinant testis ACE N-domain Homo sapiens
0.0000066
-
lisW-S pH 6.8, 25°C, recombinant testis ACE C-domain Homo sapiens
0.0017
-
lisW-S pH 6.8, 25°C, recombinant testis ACE N-domain Homo sapiens