Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket

Ordentlich, Arie; Barak, Dov; Kronman, Chanoch; Flashner, Yehuda; Leitner, Moshe; Segall, Yoffi; Ariel, Naomi; Cohen, Sara; Velan, Baruch; Shafferman, Avigdor

doi:10.1016/s0021-9258(19)85305-x

Cited by 303 publications

(160 citation statements)

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“…The G119S mutation occurs in the oxyanion hole of acetylcholinesterase 1 which aids in substrates trafficking [ 84 , 85 ]. The F290V mutation involves substrate specificity and the F331W mutation has been denoted as being involved in substrate guidance and binding [ 80 , 86 , 87 ].…”

Section: Mechanisms Of Insecticide Resistancementioning

confidence: 99%

Dengue fever and insecticide resistance in Aedes mosquitoes in Southeast Asia: a review

et al. 2021

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Dengue fever is the most important mosquito-borne viral disease in Southeast Asia. Insecticides remain the most effective vector control approach for Aedes mosquitoes. Four main classes of insecticides are widely used for mosquito control: organochlorines, organophosphates, pyrethroids and carbamates. Here, we review the distribution of dengue fever from 2000 to 2020 and its associated mortality in Southeast Asian countries, and we gather evidence on the trend of insecticide resistance and its distribution in these countries since 2000, summarising the mechanisms involved. The prevalence of resistance to these insecticides is increasing in Southeast Asia, and the mechanisms of resistance are reported to be associated with target site mutations, metabolic detoxification, reduced penetration of insecticides via the mosquito cuticle and behavioural changes of mosquitoes. Continuous monitoring of the status of resistance and searching for alternative control measures will be critical for minimising any unpredicted outbreaks and improving public health. This review also provides improved insights into the specific use of insecticides for effective control of mosquitoes in these dengue endemic countries.

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Section: Mechanisms Of Insecticide Resistancementioning

confidence: 99%

Dengue fever and insecticide resistance in Aedes mosquitoes in Southeast Asia: a review

et al. 2021

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“…This position ensures its contact with most non-covalent AChE ligands [5]. The amino acid Trp-286 present in PAS as well as the previously mentioned Trp-86 are important in the mechanism of inhibition by peripheral anionic site ligand, thus providing plasticity to the AChE active site [7]. As for the function of PAS, it is considered that it may act as an initial binding site for substrate entry to the acylation site or that it may modulate cation clearance and product release [4].…”

Section: Introductionmentioning

confidence: 97%

“…The Phe-295 and Phe-297 residues are responsible for the substrate specificity of the acyl pocket for covalent adducts. The Phe-295 residue is also responsible for substrate specificity in the non-covalent enzyme substrate complex [7]. The oxyanion hole is constructed from the N-H groups of the backbone peptides, viz., Gly-121, Gly-122 and Ala-204.…”

Section: Introductionmentioning

confidence: 99%

Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis

Walczak-Nowicka

Herbet

2021

IJMS

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Acetylcholinesterase (AChE) plays an important role in the pathogenesis of neurodegenerative diseases by influencing the inflammatory response, apoptosis, oxidative stress and aggregation of pathological proteins. There is a search for new compounds that can prevent the occurrence of neurodegenerative diseases and slow down their course. The aim of this review is to present the role of AChE in the pathomechanism of neurodegenerative diseases. In addition, this review aims to reveal the benefits of using AChE inhibitors to treat these diseases. The selected new AChE inhibitors were also assessed in terms of their potential use in the described disease entities. Designing and searching for new drugs targeting AChE may in the future allow the discovery of therapies that will be effective in the treatment of neurodegenerative diseases.

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“…It has been reported that the X-ray analysis of the structural features of AChE has a narrow, long, hydrophobic gorge which is about 20 Å deep [11,12]. The AChE has a catalytic triad consisting of His447, Ser203, and Glu334 [22] situated in the active site of the narrow deep gorge, the lining of which contains mostly aromatic residues that form a narrow access to the catalytic Ser203 [22]. In addition to that a peripheral anionic site containing an additional set of aromatic residues Trp286, Tyr124, Tyr72, Tyr341, and Asp74 [22] was reported which is located at the border of the gorge and affords a binding site for allosteric inhibitors and modulators.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

“…The AChE has a catalytic triad consisting of His447, Ser203, and Glu334 [22] situated in the active site of the narrow deep gorge, the lining of which contains mostly aromatic residues that form a narrow access to the catalytic Ser203 [22]. In addition to that a peripheral anionic site containing an additional set of aromatic residues Trp286, Tyr124, Tyr72, Tyr341, and Asp74 [22] was reported which is located at the border of the gorge and affords a binding site for allosteric inhibitors and modulators. The binding between the acetylcholine and the four inhibitors with the enzyme is characterized by cation-π interactions between the protonated nitrogen's and the preserved aromatic residues, phenylalanine and tryptophan.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

Potential Molecular Docking of Four Acetylcholinesterase Inhibitors

Elmaki

Sadawi

Hermann

et al. 2018

DDIPIJ

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Acetylcholinesterase has extremely high catalytic activity and each molecule of AChE hydrolyze about twenty-five thousand molecules of acetylcholine (ACh) per second. The active site of AChE contains two subsites which are the anionic site and the esteratic subsite [10,11]. The mechanism of action and structure of AChE have been obtained from the crystal structure of the enzyme which were studies by different research groups [12][13][14]. The anionic subsite housing the positive quaternary amine of the acetylcholine in addition to other cationic inhibitors and

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Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket

Cited by 303 publications

References 1 publication

Dengue fever and insecticide resistance in Aedes mosquitoes in Southeast Asia: a review

Dengue fever and insecticide resistance in Aedes mosquitoes in Southeast Asia: a review

Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis

Potential Molecular Docking of Four Acetylcholinesterase Inhibitors

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