AChE inhibitors and substrates
From Proteopedia
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AChE substrate
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Solution of the three-dimensional (3D) structure of Torpedo californica acetylcholinesterase (TcAChE) in 1991 (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 (colored darkmagenta), led to a revision of the views then held concerning substrate traffic, recognition, and hydrolysis (Botti et al. Sussman & Silman (1999)). This led to a series of theoretical and experimental studies, which took advantage of recent advances in theoretical techniques for treatment of proteins, such as molecular dynamics and electrostatics, and of site-directed mutagenesis, utilizing suitable expression systems. Acetylcholinesterase hydrolysizes the neurotransmitter (ACh), producing group. directly binds (via its nucleophilic Oγ atom) within the (ACh/TcAChE structure 2ace). The residues are also important in the ligand recognition (Ref 1).
AChE monovalent inhibitors
Alzheimer's disease (AD) is a disorder that attacks the central nervous system through progressive degeneration of its neurons. Patients with this disease develop dementia which becomes more severe as the disease progresses. It was suggested that symptoms of AD caused by decrease of activity of cholinergic neocortical and hippocampal neurons. Treatment for AD by acetylcholine (ACh) precursors and cholinergic agonists was ineffective or caused side effects. ACh hydrolysize by AChE causes termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh reduced by AD. Indeed, it was shown that AChE inhibitors improve the cognitive abilities of AD patients at early stages disease development. The first generation of AD drugs were AChE inhibitors: alcaloids (-)-Huperzine A (HupA) and (-)-galanthamine (GAL, Reminyl); synthetic compounds tacrine (Cognex) and rivastigmine (Exelon).
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1) (-)-Huperzine A. is found in an extract from a club moss that has been used in Chinese folk medicine. Its action has been associated to its ability to strongly inhibit AChE (it has high binding affinity to this enzyme). The X-ray structure of the complex of TcAChE with optically pure HupA (colored blueviolet) at 2.5 Å resolution (1vot) reveals that this inhibitor also binds to TcAChE active site mentioned above (Ser200, His440, Glu327, Trp84, and Phe330; colored orange), but its observed orientation is almost orthogonal in comparison to ACh (transparent gray; 2ace) (Ref 1). Ser200 (colored transparent yellow) is from ACh/TcAChE complex 2ace).
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2) Tacrine. The X-ray crystal structure of (magenta) bound in the active site of TcAChE (1acj) was determined at 2.8 Å resolution (Ref 2). ACh (gray) is shown for comparison.
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3) Galanthamine. (red) is an alkaloid from the flower common snowdrop (Galanthus nivalis). The X-ray crystal structure of GAL bound in the active site of TcAChE (1dx6) was determined at 2.3 Å resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp84) and the acyl-binding pocket (Phe288, Phe290). The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp72. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu199 (Ref 3). ACh (gray) is shown for comparison.
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4) Galanthamine iminium derivative. The X-ray structure of Torpedo californica AChE (TcAChE) in complex with galanthamine iminium derivative (compound 5) was determined at 2.05 Å (1w6r). The binding mode of this (cyan) with TcAChE is virtually identical to that of galanthamine (red) itself (1dx6). The TcAChE residues of the galanthamine/TcAChE are colored pink, while those of compound 5/TcAChE are in lime. The main structural change is side-chain movement of Phe330 in the compound 5/TcAChE complex, in comparison to that of galanthamine. The compound 5 differs by presence of (N+; blue) instead N of galanthamine. This chemical difference causes the structural change and slightly decreases affinity of compound 5 to TcAChE in comparison to galanthamine itself (Ref 4).
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5) Edrophonium (EDR) (2ack) is stacked between the aromatic rings of , near TcAChE which consists of S200, E327, and H440.
AChE bivalent inhibitors
Please see page AChE bivalent inhibitors
Selected 3D Structures of AChE
- 2ace This is the original solved structure for Torpedo Californica
- 1ea5 This is one of the highest quality representative X-ray structures in the PDB.
- 1eve The E2020 (Aricept) complex.
- 1ax9 Endrophonium complex.
- 1vot Complex with Huperzine, a Chinese folk medicine.
- 1fss Complex with snake venum toxin Fasciculin-II.
- 1acj Complex with tacrine.
- 1dx6 Complex with galanthamine.
- 1w6r Complex with galanthamine iminium derivative.
- 2ack Complex with edrophonium.
- 1vzj Structure of the tetramerization domain of acetylcholinesterase.
More structures can be obtained by searching for
AChE
References
1) Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A., Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL, Nat Struct Biol. 1997 Jan;4(1):57-63. PMID:8989325
2) Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase., Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL, Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5. PMID:8415649
3) Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution., Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL, FEBS Lett. 1999 Dec 17;463(3):321-6. PMID:10606746
4) The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design., Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL, J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167
5) Static Laue diffraction studies on acetylcholinesterase., Ravelli RB, Raves ML, Ren Z, Bourgeois D, Roth M, Kroon J, Silman I, Sussman JL, Acta Crystallogr D Biol Crystallogr. 1998 Nov 1;54(Pt 6 Pt 2):1359-66. PMID:10089512
Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase., Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL, J Am Chem Soc. 2005 Aug 10;127(31):11029-36. PMID:16076210
Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors., Carlier PR, Du DM, Han Y, Liu J, Pang YP, Bioorg Med Chem Lett. 1999 Aug 16;9(16):2335-8. PMID:10476864
Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity., Wong DM, Greenblatt HM, Dvir H, Carlier PR, Han YF, Pang YP, Silman I, Sussman JL, J Am Chem Soc. 2003 Jan 15;125(2):363-73. PMID:12517147
Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein., Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I, Science. 1991 Aug 23;253(5022):872-9. PMID:1678899
Proteopedia Page Contributors and Editors (what is this?)
Alexander Berchansky, Joel L. Sussman, Michal Harel, Jaime Prilusky, David Canner
