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 Alzheimer's disease. 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) 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) GAL, an alkaloid from the flower common snowdrop (Galanthus nivalis), shows anticholinesterase activity. The X-ray crystal structure of GAL bound in the active site of TcAChE 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, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu199.
AChE bivalent inhibitors
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Among the most interesting drugs that have been designed to inhibit acetylcholinesterase are those that have two binding sites that bind both the peripheral and catatylic sites simultaneously. Such drugs bind highly specificly and strongly. A good example is .
It appears that the principal interaction between the aceylcholine and the enzyme is relatively newly discovered cation-pi interactions between the cationic moiety of the substrate and the many aromatic residues lining the catalytic gorge. Unlike most interatomic interactions in chemistry, cation-pi interactions are unusual in that their energy hardly changes as the cationic and aromatic ring centers vary between 4 and 7 Angstroms apart, and for a wide variety of relative orientations of the aromatic rings. This gives the substrate an energetically smooth ride down the gorge with few bumps or barriers to impede passage down the gorge.
Most acetylcholinesterases have a net negative charge and a large patch of negative potential around the entrance to the active site gorge, which may be useful to attract the positively charged acetycholine substrate to the site. As one travels down the gorge, this potential becomes increasingly more and more negative, reaching a peak at the active site at the base. Because of this potential, the peripherial site is thought to act like a substrate trap, that forces practically molecule of substrate that reaches the peripheral site to travel down the gorge to the active site, that probably contributes greatly to the extremely rapid rate of degrading the substrate. This whole enzyme therefore acts like a brilliantly designed natural vacuum cleaner that clears the neurotransmitter out of the synapse extremely quickly. Yet to be solved, however, is how the products clear the active site rapidly, whether back through the gorge, or out a back door on the other side of the protein that quickly opens each catalytic cycle (Try 84 is actually near the surface of the 'underside' of the protein.)
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.
- 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
Proteopedia Page Contributors and Editors (what is this?)
Alexander Berchansky, Joel L. Sussman, Michal Harel, Jaime Prilusky, David Canner
