Acetylcholinesterase

From Proteopedia

Revision as of 02:21, 2 May 2010

3D structure of acetylcholinesterase

Key Enzyme in the Nervous System

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.

Cholinergic Synapse

The 3D structure of Torpedo californica AChE (TcAChE) (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 , lined by aromatic residues, led to a revision of the views then held concerning substrate traffic, recognition, and hydrolysis (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.

The active site gorge has , 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
1ea5, 2ace – TcAChE – trigonal – Torpedo californica
2j3d – TcAChE – monoclinic
1w75 – TcAChE – orthorhombic
1eea – TcAChE – cubic
2vt6, 2vt7 – TcAChE – different dosage
1qid to 1qim - TcAChE synchrotron radiation damage
1j06, 1maa – mAChE - mouse
1qo9 – DmAChE - Drosophila
1c2o, 1c2b – electrophorus AChE – Electric eel

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

2w9i – TcAChE + methylene blue
2wls – MosAChE + AMTS13
2vq6 – TcAChE + 2-PAM
2j3q – TcAChE + Thioflavin T
2ha0 – mAChE + ketoamyltrimethylammonium
2h9y – mAChE + TMTFA
1gpk, 1gpn, 1vot – TcAChE + huperzine
1gqr – TcAChE + rivastigmine
1gqs – TcAChE + NAP
1e66 – TcAChE + huprine
1dx4, 1qon – DmAChE + tacrine derivative
1oce – TcAChE + MF268
1ax9, 1ack – TcAChE + edrophonium
1amn – TcAChE + TMTFA
1acj – TcAChE + tacrine

AChE peripheral site inhibitors conjugating at the surface of the protein

1ku6 - mAChE + fasciculin 2
1ku6, 1mah - mAChE + fasciculin 2
1j07 - mAChE + decidium
1n5m - mAChE + gallamine
1n5r - mAChE + propidium
1b41, 1f8u - hAChE + fasciculin 2
1fss - TcAChE + fasciculin 2

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

3i6m – TcAChE + N-piperidinopropyl galanthamine
3i6z - TcAChE + saccharinohexyl galanthamine
1zgb, 1zgc – TcAChE + tacrine (10) hupyridone
2w6c – TcAChE + bis-(-)-nor-meptazinol
2ckm, 2cmf – TcAChE + bis-tacrine
2cek – TcAChE + N-[8-(1,2,3,4-tetrahydroacridin-9-ylthio)octyl]-1,2,3,4-tetrahydroacridin-9-amine
1ut6 - TcAChE + N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane
1odc - TcAChE + N-4-quinolyl-N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane
1w4l, 1w6r, 1w76, 1dx6, 1qti - TcAChE + galanthamine and derivative
1q83, 1q84 - mAChE + TZ2PA6
1h22, 1h23 – TcAChE + bis-hupyridone
1hbj – TcAChE + quinoline derivativev
1e3q – TcAChE + bw284c51
1eve – TcAChE + e2020
1acl – TcAChE + decamethonium

• 2ace This is the original solved structure for T. californica
• 1ea5 This is the highest resolution X-ray structure of AChE determined till now.
• 1eve The E2020 (Aricept) complex.
• 1ax9 Edrophonium complex.
• 1vot Complex with huperzine, a traditional Chinese folk medicine.
• 1fss Complex with the snake venom toxin, Fasciculin-II.
• 1vzj Model complex of the cholinesterase tetramer.
• 1som Complex with nerve agent soman (GD).

More structures can be obtained by searching for AChE

External Links

Acetylcholinesterase Tutorial by Karl Oberholser, Messiah College

PDB Molecule of the Month - Acetylcholinesterase

Movies: X-ray Damage in ACh & Nature's Vacuum Cleaner by R. Gillilan, Cornell Univ