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Literature summary for 2.3.2.5 extracted from

  • Vijayan, D.K.; Zhang, K.Y.J.
    Human glutaminyl cyclase Structure, function, inhibitors and involvement in Alzheimers disease (2019), Pharmacol. Res., 147, 104342 .
    View publication on PubMed

Application

Application Comment Organism
medicine hQC isozymes, sQC and gQC, inhibition is considered to be an attractive strategy to prevent the formation of pGlu-Abeta and to reduce neuroinflammation and provides an opportunity for the treatment of Alzheimer disease Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of wild-type and mutant isozyme sQC Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
analysis of 23 human sQC structures, diverse PDB IDs, overview Homo sapiens
analysis of several human gQC structures, i.e. PDB IDs 3PB4, 3PB6, 3PB7, 3PB8, and 3PB9, overview Homo sapiens

Protein Variants

Protein Variants Comment Organism
D305A site-directed mutagenesis, in the mutant structure, the hydrogen bonding network between the acidic residues is demolished after incorporating the Ala residue at position 305 Homo sapiens
E201L site-directed mutagenesis, the mutant is inactive, the side chain of L201 has oriented away from the D305 in the mutant structure Homo sapiens
E201Q site-directed mutagenesis, the mutant is almost inactive, the side chain of L201 has oriented away from the D305 in the mutant structure Homo sapiens
S160G site-directed mutagenesis, mutation S160G disrupts the hydrogen bond network at the active site by inducing a swing to the side chain of D248 Homo sapiens
Y115E/Y117E site-directed mutagenesis, the double mutation improves the protein solubility compared to wild-type Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(E)-N1-(5-methyl-1H-imidazol-1-yl)-2-nitro-N'1-[4-(trifluoromethyl)phenyl]ethene-1,1-diamine
-
Homo sapiens
1-(3,4-dimethoxyphenyl)-N-(1H-imidazol-1-yl)cyclopropane-1-carbothioamide
-
Homo sapiens
1-(3,4-dimethoxyphenyl)-N-(4-methyl-1H-imidazol-1-yl)cyclopropane-1-carbothioamide
-
Homo sapiens
1-(3,4-dimethoxyphenyl)-N-(5-methyl-1H-imidazol-1-yl)cyclopropane-1-carbothioamide
-
Homo sapiens
2-(4-ethoxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one
-
Homo sapiens
3-(5-methyl-1H-imidazol-1-yl)-6-phenyl-2-sulfanylidene-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one
-
Homo sapiens
5,7-dihydroxy-2-(5-methylthiophen-2-yl)-4H-1-benzopyran-4-one
-
Homo sapiens
5,7-dihydroxy-2-(thiophen-2-yl)-4H-1-benzopyran-4-one
-
Homo sapiens
additional information structure-function analysis of enzyme inhibitors, overview; structure-function analysis of enzyme inhibitors, overview. Natural products and their derivatives belonging to the sulfolipid family and isolated from methanol extracts of different algae species (such as Scenedesmus rubescens, Scenedesmus producto-capitatus, Scenedesmus accuminatus, Scenedesmus pectinatus, Tetradesmus wisconsinensis, and Eustigmatos magnusa) act as inhibitors of sQC. Synthesis and evaluation of benzimidazole based inhibitors, overview Homo sapiens
N''-cyano-N-(5-methyl-1H-imidazol-1-yl)-N'-(3,4,5-trimethoxyphenyl)guanidine
-
Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-(4-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-1H-imidazol-1-ylthiourea
-
Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-[3-(1H-imidazol-1-yl)propyl]thiourea
-
Homo sapiens
N-(4'-fluoro[1,1'-biphenyl]-2-yl)-4-methyl-1H-imidazol-1-amine
-
Homo sapiens
N-(4-[(1E)-3-[4-(2-aminoethyl)piperazin-1-yl]-3-oxoprop-1-en-1-yl]phenyl)-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-[3-(1H-imidazol-1-yl)propyl]-N'-phenylthiourea
-
Homo sapiens
N-[3-methoxy-4-[(piperidin-4-yl)methoxy]phenyl]-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-[4-(2-aminoethoxy)-3-methoxyphenyl]-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-[4-(3-aminopropoxy)-3-methoxyphenyl]-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-[4-(4-aminobutoxy)-3-methoxyphenyl]-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
N-[4-[3-(2-aminopyridin-4-yl)propoxy]-3-methoxyphenyl]-N'-(5-methyl-1H-imidazol-1-yl)thiourea
-
Homo sapiens
SEN-177 the triazole based inhibitor, SEN177 coordinates with the catalytically important Zn2+ ion of sQC and has made several hydrophobic interactions with active site residues such as W207, F325, and W329 Homo sapiens
SEN-180
-
Homo sapiens
SEN-817
-
Homo sapiens
SEN177
-
Homo sapiens
Sen180
-
Homo sapiens
Sen817
-
Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
extracellular
-
Homo sapiens
-
-
Golgi apparatus
-
Homo sapiens 5794
-

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+ active site bound and involved in catalysis Homo sapiens
Zn2+ involved in catalysis, the Zn2+ ion located at the active site of QC polarizes the gamma-amide group of the substrate Gln residue and stabilizes the oxyanion formed by the nucleophilic attack of the alpha-nitrogen on the scissile gamma-carbonyl carbon Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
L-glutaminyl-peptide Homo sapiens
-
5-oxoprolyl-peptide + NH3
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q16769
-
-
Homo sapiens Q9NXS2
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
glycoprotein glycosylated structures of sQC are reported in PDB which exhibit divergence in the structures especially at the loop regions constituted by F146-V153 and Q295-I303. A disulfide bridge between C139 and C164 has also been observed in the glycosylated sQC. In the glycosylated structures, the position of W207 resembles the enzyme structure Conf-B Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
brain
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
L-glutaminyl-peptide
-
Homo sapiens 5-oxoprolyl-peptide + NH3
-
?

Synonyms

Synonyms Comment Organism
glutaminyl cyclase
-
Homo sapiens
Golgi resident glutaminyl cyclase
-
Homo sapiens
gQC
-
Homo sapiens
hQC
-
Homo sapiens
secretory glutaminyl cyclase
-
Homo sapiens
sQC
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000013
-
pH and temperature not specified in the publication Homo sapiens SEN177
0.000053
-
pH and temperature not specified in the publication Homo sapiens SEN-177
0.000058
-
pH and temperature not specified in the publication Homo sapiens Sen180
0.00017
-
pH and temperature not specified in the publication Homo sapiens SEN-180
0.0018
-
pH and temperature not specified in the publication Homo sapiens SEN-817
0.0023
-
pH and temperature not specified in the publication Homo sapiens Sen817

General Information

General Information Comment Organism
additional information active site structure of gQC, residue W231 in gQC has adopted an outward positioning of the indole ring and is involved in hydrogen bonding with one of the neighboring amino acid P256. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Catalytic reaction mechanism Homo sapiens
additional information two active site conformations are reported for sQC (Conf-A and Conf-B) and these are mainly associated with the orientation of W207. In Conf-A (open), the orientation of the indole ring of W207 is towards the surface of the molecule and in Conf-B (closed), the orientation is towards the Zn2+ ion. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Residues C139 and C164 are not involved in catalysis. Catalytic reaction mechanism Homo sapiens
physiological function human glutaminyl cyclase (hQC) is an important enzyme for post-translational modification by converting the N-terminal glutaminyl and glutamyl into diglutamate (pGlu) through cyclization. The two isoforms of hQC, secretory glutaminyl cyclase (sQC) and Golgi resident glutaminyl cyclase (gQC), are involved in various pathological conditions especially in Alzheimer's disease (AD). The sQC is known to mediate the formation of diglutamate containing amyloid beta (pGlu-Abeta) peptides while gQC mediates the maturation of C-C motif chemokine ligand 2 (CCL2) Homo sapiens