Literature summary for 2.3.2.5 extracted from

Xu, A.; He, F.; Yu, C.; Qu, Y.; Zhang, Q.; Lv, J.; Zhang, X.; Ran, Y.; Wei, C.; Wu, J.
The development of small molecule inhibitors of glutaminyl cyclase and isoglutaminyl cyclase for Alzheimers disease (2019), ChemistrySelect, 4, 10591-10600 .

No PubMed abstract available

Application

Application	Comment	Organism
drug development	development of small molecule inhibitors of glutaminyl cyclase and isoglutaminyl cyclase for Alzheimers disease	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
1,2-di-O-palmitoyl-3-O-(6'-deoxy-6'-sulfo-D-glycopyranosyl)-glycerol	-	Homo sapiens
1-(3,4-dimethoxyphenyl)-N-[3-(1H-imidazol-1-yl)propyl]cyclopropane-1-carbothioamide	-	Homo sapiens
1-O-linolyl-2-O-palmitoyl-3-O-(6'-deoxy-6'-sulfo-D-glucopyranosyl)-glycerol	-	Homo sapiens
1-O-palmitoyl-2-O-linolenyl-3-O-(6'-deoxy-6'-sulfo-D-glucopyranosyl)-glycerol	-	Homo sapiens
3-fluoro-3',4'-dimethoxy-N-[3-(4-methyl-1H-imidazol-1-yl)propyl][1,1'-biphenyl]-2-amine	-	Homo sapiens
3-[(1H-imidazol-1-yl)methyl]aniline	-	Homo sapiens
3-[3-(5-methyl-1H-imidazol-1-yl)propyl]-2-sulfanylidene-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-one	-	Homo sapiens
3-[3-(5-methyl-1H-imidazol-1-yl)propyl]-2-sulfanylidene-2,3-dihydroquinazolin-4(1H)-one	-	Homo sapiens
3-[4-(1H-imidazol-1-yl)butoxy]benzaldehyde	-	Homo sapiens
4'-fluoro-N-[3-(4-methyl-1H-imidazol-1-yl)propyl][1,1'-biphenyl]-2-amine	-	Homo sapiens
4-[2-(1H-imidazol-1-yl)ethoxy]benzaldehyde	-	Homo sapiens
4-[2-[4-([1-[(3-aminophenyl)methyl]-1H-imidazol-2-yl]methyl)-1H-imidazol-1-yl]ethoxy]benzaldehyde	-	Homo sapiens
5,7-dihydroxy-2-(3-methylphenyl)-4H-1-benzopyran-4-one	-	Homo sapiens
5-(5-[[(3,4-dimethoxyphenyl)sulfanyl]methyl]-1,3,4-oxadiazol-2-yl)-1H-benzimidazole	-	Homo sapiens
5-(5-[[(pyridin-4-yl)methyl]sulfanyl]-1,3,4-oxadiazol-2-yl)-1H-benzimidazole	-	Homo sapiens
5-[5-(2-phenylethyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole	-	Homo sapiens
apigenin	-	Homo sapiens
cysteamine	-	Homo sapiens
additional information	development of small molecule inhibitors of glutaminyl cyclase and isoglutaminyl cyclase for Alzheimers disease, overview; development of small molecule inhibitors of glutaminyl cyclase and isoglutaminyl cyclase for Alzheimers disease, overview. Weak inhibition by imidazole derivatives	Homo sapiens
N''-cyano-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]guanidine	-	Homo sapiens
N''-cyano-N-methyl-N'-[3-(4-methyl-1H-imidazol-1-yl)propyl]guanidine	-	Homo sapiens
N''-cyano-N-methyl-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]guanidine	-	Homo sapiens
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-[3-(1H-imidazol-1-yl)-2-methylpropyl]thiourea	-	Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-[3-(1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
N-(3,4-dimethoxyphenyl)-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
N-(3-methoxy-4-[[4-(piperidin-4-yl)phenyl]methoxy]phenyl)-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
N-(4-chlorophenyl)-N'-[3-(1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
N-[3-(4-aminobutoxy)-4-methoxyphenyl]-N'-[3-(2-methyl-1H-imidazol-1-yl)propyl]thiourea	-	Homo sapiens
PBD150	-	Homo sapiens
PQ912	-	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
extracellular	the isozyme is secreted	Homo sapiens	-	-
Golgi membrane	-	Homo sapiens	139	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Zn2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
L-glutaminyl-Abeta3-40/42	Homo sapiens	amyloid-beta peptide Abeta3-40/42	5-oxoprolyl-Abeta3-40/42 + NH3	-	r
L-glutaminyl-CCL2	Homo sapiens	i.e. monocyte chemoattractant protein (MCP-1)	5-oxoprolyl-CCL2 + NH3	-	r
L-glutaminyl-peptide	Homo sapiens	-	5-oxoprolyl-peptide + NH3	-	r

Organism

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

Source Tissue

Source Tissue	Comment	Organism	Textmining
Hep-G2 cell	-	Homo sapiens	-
hepatoma cell	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
L-glutaminyl-Abeta3-40/42	amyloid-beta peptide Abeta3-40/42	Homo sapiens	5-oxoprolyl-Abeta3-40/42 + NH3	-	r
L-glutaminyl-CCL2	i.e. monocyte chemoattractant protein (MCP-1)	Homo sapiens	5-oxoprolyl-CCL2 + NH3	-	r
L-glutaminyl-CCL2	i.e. monocyte chemoattractant protein (MCP-1), CCL2 is a specific substrate for h-isoQC but not for h-QC	Homo sapiens	5-oxoprolyl-CCL2 + NH3	-	r
L-glutaminyl-peptide	-	Homo sapiens	5-oxoprolyl-peptide + NH3	-	r
L-glutaminyl-Phe-Ala	-	Homo sapiens	5-oxoprolyl-Phe-Ala + NH3	-	r
additional information	cyclization reaction of glutamate and glutamine residues, overview	Homo sapiens	?	-	-
additional information	cyclization reaction of glutamate and glutamine residues, overview. CCL2 is a specific substrate for h-isoQC but not for h-QC	Homo sapiens	?	-	-

Synonyms

Synonyms	Comment	Organism
glutaminyl cyclase	-	Homo sapiens
golgi resident enzyme	-	Homo sapiens
gQC	-	Homo sapiens
h-isoQC	-	Homo sapiens
h-QC	-	Homo sapiens
isoGlutaminyl cyclase	-	Homo sapiens
secretory glutaminyl cyclase	-	Homo sapiens
sQC	-	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.000006	-	N-(3,4-dimethoxyphenyl)-N'-[3-(1H-imidazol-1-yl)propyl]thiourea	pH and temperature not specified in the publication	Homo sapiens
0.000023	-	5-(5-[[(3,4-dimethoxyphenyl)sulfanyl]methyl]-1,3,4-oxadiazol-2-yl)-1H-benzimidazole	pH and temperature not specified in the publication	Homo sapiens
0.000638	-	5-[5-(2-phenylethyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole	pH and temperature not specified in the publication	Homo sapiens
0.00101	-	5-(5-[[(pyridin-4-yl)methyl]sulfanyl]-1,3,4-oxadiazol-2-yl)-1H-benzimidazole	pH and temperature not specified in the publication	Homo sapiens
0.00124	-	N-(4-chlorophenyl)-N'-[3-(1H-imidazol-1-yl)propyl]thiourea	pH and temperature not specified in the publication	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.0000062	-	pH and temperature not specified in the publication	Homo sapiens	N-(3-methoxy-4-[[4-(piperidin-4-yl)phenyl]methoxy]phenyl)-N'-[3-(5-methyl-1H-imidazol-1-yl)propyl]thiourea
0.0000088	-	pH and temperature not specified in the publication	Homo sapiens	N-[3-(4-aminobutoxy)-4-methoxyphenyl]-N'-[3-(2-methyl-1H-imidazol-1-yl)propyl]thiourea
0.00007	-	pH and temperature not specified in the publication	Homo sapiens	5-(5-[[(3,4-dimethoxyphenyl)sulfanyl]methyl]-1,3,4-oxadiazol-2-yl)-1H-benzimidazole
0.00396	-	pH and temperature not specified in the publication	Homo sapiens	5-[5-(2-phenylethyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole

General Information

General Information	Comment	Organism
evolution	glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) belong to the family of the metalloenzymes	Homo sapiens
malfunction	loss of the pE-modification and N-terminal charge leads to accelerated aggregation of Abeta3(pE) compared with unmodified Abeta	Homo sapiens
physiological function	glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into diglutamic acid (pGlu). The amyloid protein and the monocyte chemoattractant protein (MCP-1) also known as CCL2 that promotes a cascade of inflammation-related responses are two representative substrates. The diglutamated Abeta and CCL2 exhibit more severe neurotoxicity than normal Abeta and CCL2. The Abeta1-40/42 peptides start with an L-aspartate at the N-terminus. Under pathological conditions, the Abeta1-40/42 peptides are truncated to expose the glutamate at position 3 or 11 of the Abeta peptides. Then the N-terminal glutamate (E) will be cyclized by QC to form the pyroglutamate (pE) and the products are termed as Abeta3(pE)-40/42 or Abeta11(pE)-40/42. The pE-modification of Abeta confers unique properties, such as proteolytic resistance. pGlu-Abeta peptides exhibit enhanced toxicity compared to the unmodified Abeta peptide and promote the formation of tau tangles. In Alzheimer's disease (AD) patients and animal AD models, the level and activity of QC are significantly increased	Homo sapiens
physiological function	glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into diglutamic acid (pGlu). The level of CCL2 and h-isoQCmRNA in Alzheimer disease (AD) patients is significantly higher than that of healthy subjects	Homo sapiens