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glutaminyl-peptide cyclotransferase

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Target not currently curated in GtoImmuPdb

Target id: 2411

Nomenclature: glutaminyl-peptide cyclotransferase

Family: M28: Aminopeptidase Y

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 361 2p22.2 QPCT glutaminyl-peptide cyclotransferase
Mouse - 362 17 E3 Qpct glutaminyl-peptide cyclotransferase (glutaminyl cyclase)
Rat - 313 6q11 Qpct glutaminyl-peptide cyclotransferase
Previous and Unofficial Names Click here for help
GCT | glutaminyl cyclase | glutaminyl-tRNA cyclotransferase | QC | secretory glutaminyl cyclase (sQC)
Database Links Click here for help
Specialist databases
MEROPS M28.974 (Hs)
Other databases
Alphafold Q16769 (Hs), Q9CYK2 (Mm)
BRENDA 2.3.2.5
ChEMBL Target CHEMBL4508 (Hs), CHEMBL4105900 (Mm)
Ensembl Gene ENSG00000115828 (Hs), ENSMUSG00000024084 (Mm), ENSRNOG00000005705 (Rn)
Entrez Gene 25797 (Hs), 70536 (Mm), 313837 (Rn)
Human Protein Atlas ENSG00000115828 (Hs)
KEGG Enzyme 2.3.2.5
KEGG Gene hsa:25797 (Hs), mmu:70536 (Mm), rno:313837 (Rn)
OMIM 607065 (Hs)
Pharos Q16769 (Hs)
RefSeq Nucleotide NM_012413 (Hs), NM_027455 (Mm), NM_001134557 (Rn)
RefSeq Protein NP_036545 (Hs), NP_081731 (Mm), NP_001128029 (Rn)
SynPHARM 82033 (in complex with PBD150)
UniProtKB Q16769 (Hs), Q9CYK2 (Mm)
Wikipedia QPCT (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human glutaminyl cyclase variant Y115E-Y117E in complex with SEN177
PDB Id:  6GBX
Ligand:  SEN177
Resolution:  1.72Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human secretory glutaminyl cyclase in complex with (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (varoglutamstat, PQ912).
PDB Id:  8XGB
Ligand:  varoglutamstat
Resolution:  0.0Å
Species:  Human
References: 
Enzyme Reaction Click here for help
EC Number: 2.3.2.5
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
amyloid β Substrate is endogenous in the given species Hs - -

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
varoglutamstat Small molecule or natural product Click here for species-specific activity table Hs Binding 7.8 pKd 4
⤷ pKd 7.8 (Kd 1.7x10-8 M) [4]
Description: Binding constant determined by SPR at pH 7.6
SEN177 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pKi 7
⤷ pKi 7.7 (Ki 2x10-8 M) [7]
varoglutamstat Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pKi 4
⤷ pKi 7.6 (Ki 2.5x10-8 M) [4]
Description: Enzymatic inhibition constant determined at pH 8.0
PBD150 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.2 pKi 1
⤷ pKi 7.2 (Ki 6x10-8 M) [1]
varoglutamstat Small molecule or natural product Mm Inhibition 7.2 pKi 4
⤷ pKi 7.2 (Ki 6.2x10-8 M) [4]
Description: Enzymatic inhibition constant determined at pH 8.0
QP5038 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 8
⤷ pIC50 8.4 (IC50 4x10-9 M) [8]
BI-43 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 pIC50 5
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [5]
SEN177 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pIC50 3
⤷ pIC50 7.8 (IC50 1.67x10-8 M) [3]
sulfolipid 2 [PMID: 27827845] Small molecule or natural product Hs Inhibition - - 2
⤷ [2]
View species-specific inhibitor tables
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cellular signalling

References

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1. Buchholz M, Heiser U, Schilling S, Niestroj AJ, Zunkel K, Demuth HU. (2006) The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship. J Med Chem, 49 (2): 664-77. [PMID:16420052]

2. Hielscher-Michael S, Griehl C, Buchholz M, Demuth HU, Arnold N, Wessjohann LA. (2016) Natural Products from Microalgae with Potential against Alzheimer's Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors. Mar Drugs, 14 (11). [PMID:27827845]

3. Hoang VH, Ngo VTH, Cui M, Manh NV, Tran PT, Ann J, Ha HJ, Kim H, Choi K, Kim YH et al.. (2019) Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design. J Med Chem, 62 (17): 8011-8027. [PMID:31411468]

4. Hoffmann T, Meyer A, Heiser U, Kurat S, Böhme L, Kleinschmidt M, Bühring KU, Hutter-Paier B, Farcher M, Demuth HU et al.. (2017) Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer's Disease-Studies on Relation to Effective Target Occupancy. J Pharmacol Exp Ther, 362 (1): 119-130. [PMID:28446518]

5. Mou J, Ning XL, Wang XY, Hou SY, Meng FB, Zhou C, Wu JW, Li C, Jia T, Wu X et al.. (2024) X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model. J Med Chem, [Epub ahead of print]. [PMID:38817193]

6. Pozzi C, Di Pisa F, Benvenuti M, Mangani S. (2018) The structure of the human glutaminyl cyclase-SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders. J Biol Inorg Chem, 23 (8): 1219-1226. [PMID:30132075]

7. Xu C, Wang YN, Wu H. (2021) Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors. J Med Chem, 64 (10): 6549-6565. [PMID:34000808]

8. Yu L, Zhao P, Sun Y, Zheng Z, Du W, Zhang L, Li Y, Xie L, Xu S, Wang P. (2023) Development of a potent benzonitrile-based inhibitor of glutaminyl-peptide cyclotransferase-like protein (QPCTL) with antitumor efficacy. Signal Transduct Target Ther, 8 (1): 454. [PMID:38097557]

How to cite this page

M28: Aminopeptidase Y: glutaminyl-peptide cyclotransferase. Last modified on 05/06/2024. Accessed on 27/07/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2411.