Acetylcholinesterase

[[Image:small_wh_ray0001.gif|left|150px]]<br />

'''Acetylcholinesterase''' (AChE) is key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, '''acetylcholine''' (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) poisons is attributed primarily to their potent AChE inhibitors.

[[Image:Synapse_Schematic.jpg|thumb|Cholinergic Synapse|300px|left]]

The 3D structure of ''Torpedo californica'' AChE (''Tc''AChE) ([http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1678899 Sussman et al. & Silman (1991)]) opened up new horizons in research on an enzyme that had already been the subject of intensive investigation. The unanticipated structure of this extremely rapid enzyme, in which the active site was found to be buried at the bottom of a

and hydrolysis ([http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10545346 Botti et al. Sussman & Silman (1999)]). To understand how those aromatic residues behave with the enzyme, see [[Flexibility of aromatic residues in acetylcholinesterase]].

Alzheimer’s disease (AD) is a debilitating brain disease that occurs in around 10% of the elderly and, as yet, there is no known cure. At present, the most widely used treatments consist are medications that attempt to increase the brain’s levels of ACh, whose levels decrease with onset of disease. These drugs work by interfering with AChE. Thus drugs that are mild inhibitors of AChE, like Tacrine, E2020 (Aricept) and the Traditonal Chinese Medicine (TCM) Huperzine appear to retard symptoms of AD.

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'''3D structure of acetylcholinesterase'''<br />

The active site gorge has <scene name='Acetylcholinesterase/New_down_gorge/6'>two binding sites</scene>, a catalytic site (consisting of the catalytic triad together with Trp84 & Phe330) and a peripheral site (including Trp 279 & Tyr 121), which helps prebind the substrate and direct it toward the active site. The 3D structure showed not only that the active site was buried deep in the enzyme, but surprisingly, there were no negatively charged residues along this gorge, as was expected to help attract the positively charged ACh substrate, rather, instead, a series of aromatic residues that are highly conserved in all AChE sequences. See: [[AChE inhibitors and substrates]]

==Selected 3D Structures of AChE ==

===Acetylcholinesterase - AChE native===

[[3lii]] – hAChE - recombinant human <br />

[[1ea5]], [[2ace]] – ''Tc''AChE – trigonal – ''Torpedo californica'' <br />

[[2j3d]] – ''Tc''AChE – monoclinic <br />

[[1w75]] – ''Tc''AChE – orthorhombic <br />

[[1eea]] – ''Tc''AChE – cubic <br />

[[2vt6]], [[2vt7]] – ''Tc''AChE – different dosage <br />

[[1qid]] to [[1qim]] - ''Tc''AChE synchrotron radiation damage <br />

[[1j06]], [[1maa]] – mAChE - mouse <br />

[[1qo9]] – ''Dm''AChE - ''Drosophila'' <br />

[[1c2o]], [[1c2b]] – electrophorus AChE – Electric eel <br />

===AChE active site inhibitors conjugating at the bottom of the active site gorge===

[[2w9i]] – ''Tc''AChE + methylene blue <br />

[[2wls]] – MosAChE + AMTS13 <br />

[[2vq6]] – ''Tc''AChE + 2-PAM <br />

[[2j3q]] – ''Tc''AChE + Thioflavin T <br />

[[2ha0]] – mAChE + ketoamyltrimethylammonium <br />

[[2h9y]] – mAChE + TMTFA <br />

[[1gpk]], [[1gpn]], [[1vot]] – ''Tc''AChE + huperzine <br />

[[1gqr]] – ''Tc''AChE + rivastigmine <br />

[[1gqs]] – ''Tc''AChE + NAP <br />

[[1e66]] – ''Tc''AChE + huprine <br />

[[1dx4]], [[1qon]] – ''Dm''AChE + tacrine derivative <br />

[[1oce]] – ''Tc''AChE + MF268 <br />

[[1ax9]], [[1ack]] – ''Tc''AChE + edrophonium <br />

[[1amn]] – ''Tc''AChE + TMTFA <br />

[[1acj]] – ''Tc''AChE + tacrine <br />

===AChE peripheral site inhibitors conjugating at the surface of the protein===

[[1ku6]] - mAChE + fasciculin 2 <br />

[[1ku6]], [[1mah]] - mAChE + fasciculin 2 <br />

[[1j07]] - mAChE + decidium <br />

[[1n5m]] - mAChE + gallamine <br />

[[1n5r]] - mAChE + propidium <br />

[[1b41]], [[1f8u]] - hAChE + fasciculin 2 <br />

[[1fss]] - TcAChE + fasciculin 2 <br />

===AChE bis inhibitors spanning the active site gorge and conjugating with the active site and the peripheral site===

[[3i6m]] – ''Tc''AChE + N-piperidinopropyl galanthamine <br />

[[3i6z]] - ''Tc''AChE + saccharinohexyl galanthamine <br />

[[1zgb]], [[1zgc]] – ''Tc''AChE + tacrine (10) hupyridone <br />

[[2w6c]] – ''Tc''AChE + bis-(-)-nor-meptazinol <br />

[[2ckm]], [[2cmf]] – ''Tc''AChE + bis-tacrine <br />

[[2cek]] – ''Tc''AChE + N-[8-(1,2,3,4-tetrahydroacridin-9-ylthio)octyl]-1,2,3,4-tetrahydroacridin-9-amine <br />

[[1ut6]] - ''Tc''AChE + N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane <br />

[[1odc]] - ''Tc''AChE + N-4-quinolyl-N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane <br />

[[1w4l]], [[1w6r]], [[1w76]], [[1dx6]], [[1qti]] - TcAChE + galanthamine and derivative <br />

[[1q83]], [[1q84]] - mAChE + TZ2PA6 <br />

[[1h22]], [[1h23]] – ''Tc''AChE + bis-hupyridone <br />

[[1hbj]] – ''Tc''AChE + quinoline derivativev <br />

[[1e3q]] – ''Tc''AChE + bw284c51 <br />

[[1eve]] – ''Tc''AChE + e2020 <br />

[[1acl]] – ''Tc''AChE + decamethonium <br />

===AChE organophosphate inhibitors causing irreversible inhibition===

[[2wu3]] – mAChE + fenamiphos and HI-6 <br />

[[2wu4]] – mAChE + fenamiphos and ortho-7 <br />

[[2jgf]] - mAChE + fenamiphos <br />

[[2wfz]], [[2wg0]], [[1som]] - ''Tc''AChE + soman <br />

[[2wg1]] - ''Tc''AChE + soman + 2-PAM <br />

[[2whp]], [[2whq]], [[2whr]] – mAChE + sarin and HI-6 <br />

[[2jgg]] - mAChE + sarin <br />

[[2jgl]] - mAChE + VX and sarin <br />

[[1cfj]] - ''Tc''AChE + sarin, GB <br />

[[3dl4]], [[3dl7]] – mAChE + tabun <br />

[[2jey]] – mAChE + HLO-7 <br />

[[2c0p]], [[2c0q]] - mAChE + tabun <br />

[[2jez]] - mAChE + tabun + HLO-7 <br />

[[2jf0]] - mAChE + tabun + Ortho-7 <br />

[[2jgh]] - mAChE + VX <br />

[[1vxo]], [[1vxr]] - ''Tc''AChE + VX <br />

[[2jgi]], [[2jgm]] - mAChE + DFP <br />

[[1dfp]] - ''Tc''AChE + DFP <br />

[[2jgj]], [[2jgk]], [[2jge]] - mAChE + methamidophos <br />

[[2gyu]] - mAChE + HI-6 <br />

[[2gyv]] - mAChE + Ortho-7 <br />

[[2gyw]] - mAChE + obidoxime <br />

* [[1vzj]] Model complex of the cholinesterase tetramer.

* [[1som]] Complex with nerve agent soman (GD).