Acetylcholinesterase peripheral anionic site degeneracy conferred by amino acid arrays sharing a common core.

Barak, Dov; Kronman, Chanoch; Ordentlich, Arie; Ariel, Naomi; Bromberg, A.; Marcus, Dino; Lazar, Arye; Velan, Baruch; Shafferman, Avigdor

doi:10.1016/s0021-9258(17)37371-4

Cited by 174 publications

(65 citation statements)

References 28 publications

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“…Analysis of the kinetics through stepwise replacement of Trp by Tyr, Phe, and then Ala suggests that subtle changes in alignment of the associated carboxyl ester are sufficient to dramatically decrease catalysjs, Moreover, occupation of the peripheral site by FAS may affect the alignment of the substrate through an allosteric influence mediated between the lip of the gorge and its base. Support for this linkage comes from previous studies of AChE structure involving circular dichroism, fluorescence spectroscopy, and site-specific mutagenesis when propidium is bound to the peripheral site (24)(25)(26). Efficient catalysis requires an optimal alignment of substrate, and FAS exhibits its most dramatic effects on inhibition parameters for the fast substrate.…”

Section: Fasciculin-acetylcholinesterase Interactionsmentioning

confidence: 95%

Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin

Radić

Quinn

Vellom

et al. 1995

Journal of Biological Chemistry

110

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The interaction of fasciculin 2 was examined with wild-type and several mutant forms of acetylcholinesterase (AChE) where Trp86, which lies at the base of the active center gorge, is replaced by Tyr, Phe, and Ala. The fasciculin family of peptides from snake venom bind to a peripheral site near the rim of the gorge, but at a position which still allows substrates and other inhibitors to enter the gorge. The interaction of a series of charged and uncharged carboxyl esters, alkyl phosphoryl esters, and substituted trifluoroacetophenones were analyzed with the wild-type and mutant AChEs in the presence and absence of fasciculin. We show that Trp86 is important for the alignment of carboxyl ester substrates in the AChE active center. The most marked influence of Trp86 substitution in inhibiting catalysis is seen for carboxyl esters that show rapid turnover. The extent of inhibition achieved with bound fasciculin is also greatest for efficiently catalyzed, charged substrates. When Ala is substituted for Trp86, fasciculin becomes an allosteric activator instead of an inhibitor for certain substrates. Analysis of the kinetics of acylation by organophosphates and conjugation by trifluoroacetophenones, along with deconstruction of the kinetic constants for carboxyl esters, suggests that AChE inhibition by fasciculin arises from reductions of both the commitment to catalysis and diffusional entry of substrate into the gorge. The former is reflected in the ratio of the rate constant for substrate acylation to that for dissociation of the initial complex. The action of fasciculin appears to be mediated allosterically from its binding site at the rim of the gorge to affect the orientation of the side chain of Trp86 which lies at the gorge base.

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Section: Fasciculin-acetylcholinesterase Interactionsmentioning

confidence: 95%

Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin

Radić

Quinn

Vellom

et al. 1995

Journal of Biological Chemistry

110

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“…Site-directed mutagenesis of mouse recombinant AChE pointed to an important role for three conserved aromatic residues, namely Tyr70, Tyrl21 and Trp279, in the interaction with FAS-II [32]. All three are located near the top of the gorge, with their aromatic rings pointing into it, and have been assigned to the peripheral site also on the basis of their involvement in interactions with other peripheral-site-specific inhibitors [19,[37][38][39][40]. Our 3D structure shows that two of these residues, Tyr70 and Trp279, interact with residues in FAS-II.…”

Section: Role Of Aromatic Residuesmentioning

confidence: 99%

“…site for the toxin was assigned on the basis of the Tyrl21--Gln mutation, which reduced affinity towards FAS -100-fold [32]. However, mutation of the corresponding residue to alanine, in human recombinant AChE, slightly increased affinity for the peripheral-site ligand, propidium [40]. The introduction of a polar glutamine residue into the aromatic cluster lining the wall of the gorge probably has an indirect effect on the geometry of the binding site for FAS.…”

Section: Role Of Aromatic Residuesmentioning

confidence: 99%

Crystal structure of an acetylcholinesterase–fasciculin complex: interaction of a three-fingered toxin from snake venom with its target

Harel¹,

Kleywegt

Ravelli³

et al. 1995

Structure

230

202

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Two conserved aromatic residues in the AChE peripheral anionic site make important contacts with FAS. The absence of these residues from chicken and insect AChEs and from butyrylcholinesterase explains the very large reduction in the affinity of these enzymes for FAS. Several basic residues in FAS make important contacts with AChE. The complementarity between FAS and AChE is unusual, inasmuch as it involves a number of charged residues, but lacks any intermolecular salt linkages.

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“…Furthermore, it has been recently demonstrated that a secondary noncholinergic function of AChE, associated with the peripheral anionic site (PAS), is involved in the pathogenesis of AD. PAS is formed by aromatic amino acid residues such as Tyr70, Asp72, Tyr121, Trp279, and Tyr334 lining the rim of the gorge [37]. Through its PAS, AChE co-localizes with Aβ peptide deposits in patients with AD and forms a stable Aβ-AChE complex, which in turn promotes fibrillogenesis and aggregation [38,39].…”

Section: Analysis Of the Interaction Between Ache And F0850-4777mentioning

confidence: 99%

High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach

et al. 2021

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Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.

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Acetylcholinesterase peripheral anionic site degeneracy conferred by amino acid arrays sharing a common core.

Cited by 174 publications

References 28 publications

Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin

Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin

Crystal structure of an acetylcholinesterase–fasciculin complex: interaction of a three-fingered toxin from snake venom with its target

High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach

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