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acetylcholinesterase (Yt blood group)

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Target not currently curated in GtoImmuPdb

Target id: 2465

Nomenclature: acetylcholinesterase (Yt blood group)

Abbreviated Name: AChE

Family: Acetylcholine turnover, Hydrolases & Lipases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 614 7q22.1 ACHE acetylcholinesterase (Yt blood group)
Mouse - 614 5 76.32 cM Ache acetylcholinesterase
Rat - 614 12q12 Ache acetylcholinesterase
Previous and Unofficial Names Click here for help
acetylcholinesterase | acetylcholinesterase (Cartwright blood group)
Database Links Click here for help
Alphafold P22303 (Hs), P21836 (Mm), P37136 (Rn)
BRENDA 3.1.1.7
CATH/Gene3D 3.40.50.1820
ChEMBL Target CHEMBL220 (Hs), CHEMBL3198 (Mm), CHEMBL3199 (Rn)
DrugBank Target P22303 (Hs)
Ensembl Gene ENSG00000087085 (Hs), ENSMUSG00000023328 (Mm), ENSRNOG00000050841 (Rn)
Entrez Gene 43 (Hs), 11423 (Mm)
Human Protein Atlas ENSG00000087085 (Hs)
KEGG Enzyme 3.1.1.7
KEGG Gene hsa:43 (Hs), mmu:11423 (Mm)
OMIM 100740 (Hs)
Pharos P22303 (Hs)
RefSeq Nucleotide NM_015831 (Hs), NM_009599 (Mm), NM_172009 (Rn)
RefSeq Protein NP_056646 (Hs), NP_033729 (Mm), NP_742006 (Rn)
SynPHARM 78555 (in complex with donepezil)
78675 (in complex with galantamine)
UniProtKB P22303 (Hs), P21836 (Mm), P37136 (Rn)
Wikipedia ACHE (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Recombinant Human Acetylcholinesterase in Complex with Donepezil
PDB Id:  4EY7
Ligand:  donepezil
Resolution:  2.35Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 3.1.1.7 Acetylcholine + H2O = acetic acid + choline + H+

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tacrine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pKi 2
⤷ pKi 7.5 (Ki 3x10-8 M) [2]
edrophonium Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibition 6.7 pKi 1
⤷ pKi 6.7 (Ki 2x10-7 M) [1]
Description: Using the chloride salt
compound 2f [Jiang et al., 2018] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pIC50 8
⤷ pIC50 8.2 (IC50 6.5x10-9 M) [8]
donepezil Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition 7.7 – 8.3 pIC50 3,6,11
⤷ pIC50 7.7 – 8.3 [3,6,11]
donecopride Small molecule or natural product Hs Inhibition 7.8 pIC50 10
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [10]
physostigmine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 – 7.8 pIC50 11
⤷ pIC50 7.6 – 7.8 [11]
BW284C51 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pIC50 7
⤷ pIC50 7.7 [7]
neostigmine Small molecule or natural product Approved drug Hs Inhibition 7.3 pIC50 9
⤷ pIC50 7.3 (IC50 4.5x10-8 M) [9]
Description: Inhibition of ACHE activity in human serum.
pyridostigmine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.4 pIC50 14
⤷ pIC50 6.4 (IC50 3.6x10-7 M) [14]
Description: Inhibition of human erythrocyte ACHE activity by a modified Ellman assay.
galantamine Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibition 6.3 pIC50 5
⤷ pIC50 6.3 (IC50 5x10-7 M) [5]
rivastigmine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.4 pIC50 11
⤷ pIC50 5.4 (IC50 4.15x10-6 M) [11]
pralidoxime Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition 3.1 pIC50 12
⤷ pIC50 3.1 (IC50 8.78x10-4 M) [12]
Description: Inhibition of human recombinant AChE by modified Ellman's method.
echothiophate Small molecule or natural product Approved drug Hs Inhibition - -
⤷
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AChE reactivator 2 Small molecule or natural product Hs - 5.6 pIC50 13
⤷ pIC50 5.6 (IC50 2.3x10-6 M) [13]
Description: Measuring reactivation of hAChE.
Immuno Process Associations
Immuno Process:  Antigen presentation
General Comments
Acetylcholinesterase (AChE) is found at cholinergic synapses throughout the nervous system and at neuromuscular junctions where it rapidly hydrolyses the neurotransmitter acetylcholine (ACh) and in so doing terminates synaptic transmission. AChE is the primary target of organophosphorus (OP) pesticides and nerve agents. PO agents inhibit enzymatic activity by attaching a phosphyl group at AChE's active-site serine. OP nerve agent antidotes work by displacing the blocking phosphyl group and thus reactivate the enzyme.
It has been shown that ACHE corresponds to the Yt blood group antigen. For more details see the OMIM entry 112100.

References

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1. Boyle NA, Talesa V, Giovannini E, Rosi G, Norton SJ. (1997) Synthesis and study of thiocarbonate derivatives of choline as potential inhibitors of acetylcholinesterase. J Med Chem, 40 (19): 3009-13. [PMID:9301662]

2. Butini S, Campiani G, Borriello M, Gemma S, Panico A, Persico M, Catalanotti B, Ros S, Brindisi M, Agnusdei M et al.. (2008) Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors. J Med Chem, 51 (11): 3154-70. [PMID:18479118]

3. Cardozo MG, Iimura Y, Sugimoto H, Yamanishi Y, Hopfinger AJ. (1992) QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase. J Med Chem, 35 (3): 584-9. [PMID:1738151]

4. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ. (2012) Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem, 55 (22): 10282-6. [PMID:23035744]

5. Clark JK, Cowley P, Muir AW, Palin R, Pow E, Prosser AB, Taylor R, Zhang MQ. (2002) Quaternary salts of E2020 analogues as acetylcholinesterase inhibitors for the reversal of neuromuscular block. Bioorg Med Chem Lett, 12 (18): 2565-8. [PMID:12182861]

6. Galli A, Mori F, Benini L, Cacciarelli N. (1994) Acetylcholinesterase protection and the anti-diisopropylfluorophosphate efficacy of E2020. Eur J Pharmacol, 270 (2-3): 189-93. [PMID:8039548]

7. Giacobini E. (2003) Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem Res, 28 (3-4): 515-22. [PMID:12675140]

8. Jiang XY, Chen TK, Zhou JT, He SY, Yang HY, Chen Y, Qu W, Feng F, Sun HP. (2018) Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery. ACS Med Chem Lett, 9 (3): 171-176. [PMID:29541355]

9. Kavitha CV, Gaonkar SL, Narendra Sharath Chandra JN, Sadashiva CT, Rangappa KS. (2007) Synthesis and screening for acetylcholinesterase inhibitor activity of some novel 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-ones: derivatives of irbesartan key intermediate. Bioorg Med Chem, 15 (23): 7391-8. [PMID:17888667]

10. Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, Bouet V, Ballandonne C, Corvaisier S, Malzert Fréon A et al.. (2014) Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment. Proc Natl Acad Sci USA, 111 (36): E3825-30. [PMID:25157130]

11. Luo W, Yu QS, Kulkarni SS, Parrish DA, Holloway HW, Tweedie D, Shafferman A, Lahiri DK, Brossi A, Greig NH. (2006) Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine. J Med Chem, 49 (7): 2174-85. [PMID:16570913]

12. Musilek K, Komloova M, Holas O, Horova A, Pohanka M, Gunn-Moore F, Dohnal V, Dolezal M, Kuca K. (2011) Mono-oxime bisquaternary acetylcholinesterase reactivators with prop-1,3-diyl linkage-Preparation, in vitro screening and molecular docking. Bioorg Med Chem, 19 (2): 754-62. [PMID:21215642]

13. Santoni G, de Sousa J, de la Mora E, Dias J, Jean L, Sussman JL, Silman I, Renard PY, Brown RCD, Weik M et al.. (2018) Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents. J Med Chem, 61 (17): 7630-7639. [PMID:30125110]

14. Yu QS, Holloway HW, Luo W, Lahiri DK, Brossi A, Greig NH. (2010) Long-acting anticholinesterases for myasthenia gravis: synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine. Bioorg Med Chem, 18 (13): 4687-93. [PMID:20627738]

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