Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Replacement of both the acyl pocket residue Phe295 as well as residue Phe338, adjacent to the catalytic His447 in human acetylcholinesterase (HuAChE), resulted in a 680-fold decline in catalytic activity due to conformational destabilization of the histidine side chain [Barak et al. (2002) Biochemistry 41, 8245]. A possible restriction of this catalytically nonproductive mobility of His447 in a series of F295X/F338A HuAChEs was examined in silico followed by site-directed mutagenesis. Simulations suggested that of the 12 aliphatic residues substituted at position 295, including hydrophobic and polar amino acids, only methionine was capable of maintaining the catalytically viable conformation of His447. Examination of the reactivities of the actual F295X/F338A HuAChEs showed that indeed the F295M/F338A enzyme was only 2-fold less reactive than the F338A mutant toward acetylthiocholine, while enzymes substituted by the similarly bulky residues leucine and isoleucine were catalytically impaired. Furthermore, only the F295M/F338A enzyme exhibited wild-type-like reactivity toward covalent modifiers of the catalytic Ser203 including the methylphosphonate soman and transition state analogue m-(N,N,N-trimethylammonio)trifluoroacetophenone (TMTFA), as well as a facile dealkylation of the F295M/F338A-soman adduct. A different behavior was observed for bulkier ligands which introduce a deformation in the acyl pocket, and therefore their activity seems only marginally affected by the positioning of His447. The findings emphasize the importance of the precise positioning of His447 for catalysis and indicate that, in the absence of aromatic "trapping", restriction of the histidine mobility in F295X/F338A HuAChEs requires a combination of steric interference and a specific polar interaction. The results also underscore the role of the acyl pocket subsite of cholinesterases in maintaining the catalytically viable conformation of the catalytic histidine.
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PMID:Is aromaticity essential for trapping the catalytic histidine 447 in human acetylcholinesterase? 1502 64

Studies have implicated aspartame (ASP) with neurological problems. The aim of this study was to evaluate acetylcholinesterase (AChE) activity in human erythrocyte membranes after incubation with the sum of ASP metabolites, phenylalanine (Phe), methanol (met) and aspartic acid (aspt), or with each one separately. Erythrocyte membranes were obtained from 12 healthy individuals and were incubated with ASP hydrolysis products for 1 h at 37 degrees C. AChE was measured spectrophotometrically. Incubation of membranes with ASP metabolites corresponding with 34 mg/kg, 150 mg/kg or 200 mg/kg of ASP consumption resulted in an enzyme activity reduction by -33%, -41%, and -57%, respectively. Met concentrations 0.14 mM, 0.60 mM, and 0.80 mM decreased the enzyme activity by -20%, -32% or -40%, respectively. Aspt concentrations 2.80 mM, 7.60 mM or 10.0 mM inhibited membrane AChE activity by -20%, -35%, and -47%, respectively. Phe concentrations 0.14 mM, 0.35 mM or 0.50mM reduced the enzyme activity by -11%, -33%, and -35%, respectively. Aspt or Phe concentrations 0.82 mM or 0.07 mM, respectively, did not alter the membrane AChE activity. It is concluded that low concentrations of ASP metabolites had no effect on the membrane enzyme activity, whereas high or toxic concentrations partially or remarkably decreased the membrane AChE activity, respectively. Additionally, neurological symptoms, including learning and memory processes, may be related to the high or toxic concentrations of the sweetener metabolites.
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PMID:The effect of aspartame metabolites on human erythrocyte membrane acetylcholinesterase activity. 1612 18

The human epidermis holds the capacity for autocrine cholinergic signal transduction, but the presence of butyrylcholinesterase (BchE) has not been shown so far. Our results demonstrate that this compartment transcribes a functional BchE. Its activity is even higher compared to acetylcholinesterase (AchE). Moreover, we show that BchE is subject to regulation by H(2)O(2) in a concentration-dependent manner as it was recently described for AchE. Epidermal BchE protein expression and enzyme activities are severely affected by H(2)O(2) in vitiligo as previously demonstrated for AchE. Removal/reduction of H(2)O(2) by a pseudocatalase PC-KUS yields normal/increased protein expression and activities. H(2)O(2)-mediated oxidation of methionine residues in BchE was confirmed by FT-Raman spectroscopy. Computer simulation supported major alteration of the enzyme active site and its tetramerisation domain suggesting deactivation of the enzyme due to H(2)O(2)-mediated oxidation. Based on our results we conclude that H(2)O(2) is a major player in the regulation of the cholinergic signal via both AchE and BchE and this signal is severely affected in the epidermis of patients with active vitiligo.
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PMID:Butyrylcholinesterase is present in the human epidermis and is regulated by H2O2: more evidence for oxidative stress in vitiligo. 1696 96

The human epidermis is especially vulnerable to oxidative stress, which in turn leads to oxidation of important antioxidant enzymes, other proteins, and peptides. Molecular dynamic computer modelling is a new powerful tool to predict or confirm oxidative stress-mediated structural changes consequently altering the function of enzymes/proteins/peptides. Here we used examples of important epidermal antioxidant enzymes before and after hydrogen peroxide (H(2)O(2))-mediated oxidation of susceptible amino-acid residues (i.e. tryptophan, methionine, cysteine, and selenocysteine), which can affect enzyme active sites, cofactor binding, or dimerization/tetramerization domains. Computer modelling predicts that enzyme active sites are altered by H(2)O(2)-mediated oxidation in thioredoxin reductase (TR) and acetylcholinesterase (AchE), whereas cofactor nicotinamide adenine dinucleotide phosphate (reduced form) binding is affected in both catalase and TR but not in glutathione peroxidase. Dimerization is prevented in catalase. These structural changes lead to impaired functionality. Fourier transform-Raman- and Fluorescence spectroscopy together with enzyme kinetics support the results. There are limitations of modelling as demonstrated on the AchE substrate-binding domain, where the computer predicted deactivation, which could not be confirmed by enzyme kinetics. Computer modelling coupled with classical biochemical techniques offers a new powerful tool in cutaneous biology to explore oxidative stress-mediated metabolic changes in the skin.
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PMID:Computer simulation of native epidermal enzyme structures in the presence and absence of hydrogen peroxide (H2O2): potential and pitfalls. 1710 4

The human epidermis holds the full capacity for autocrine synthesis, transport and degradation of acetylcholine as well as the muscarinic (m1-m5) and nicotinic signal transduction in keratinocytes and melanocytes. This cholinergic cascade is severely affected in patients with the depigmentation disorder vitiligo due to accumulation of hydrogen peroxide (H(2)O(2)) in the mM range as shown by in vivo FT-Raman spectroscopy. These high levels can oxidise susceptible amino acid residues such as methionine, tryptophan, cysteine and selenocysteine in the structure of proteins and peptides which in turn can severely affect the function. Here the effect of this reactive oxygen species was followed on the production and degradation of acetylcholine using immunofluorescence, enzyme kinetics, in vivo and in vitro FT-Raman and fluorescence spectroscopy as well as computer modelling. The results showed that both epidermal acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) are target to H(2)O(2)-mediated oxidation of methionine and tryptophan residues close to the catalytic triad, while cholineacetyltransferase (chAT) is not affected. Enzyme kinetics revealed concentration dependent activation/deactivation of both degrading enzymes by H(2)O(2). Oxidation of methionine to methionine sulfoxide was confirmed by FT-Raman spectroscopy while oxidation of tryptophan to 5OH-tryptophan was identified by fluorescence spectroscopy. H(2)O(2)-mediated oxidation of both enzymes takes place in acute vitiligo yielding accumulation of acetylcholine in the epidermis of these patients. This process is reversible with a narrowband UVB activated pseudocatalase PC-KUS leading to recovery of epidermal and systemic enzyme activities as well as restoration of the lost skin colour.
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PMID:Hydrogen peroxide regulates the cholinergic signal in a concentration dependent manner. 1733 54

In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34-2.68 micromol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 micromol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients.
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PMID:Hypermethioninemia increases cerebral acetylcholinesterase activity and impairs memory in rats. 1770 48

Although the primary function of AChE (acetylcholinesterase) is the synaptic hydrolysis of acetylcholine, it appears that the protein is also able to promote various non-cholinergic activities, including cell adhesion, neurite outgrowth and amyloidosis. We have observed previously that AChE is able to bind to mouse laminin-111 in vitro by an electrostatic mechanism. We have also observed that certain mAbs (monoclonal antibodies) recognizing AChE's PAS (peripheral anionic site) inhibit both laminin binding and cell adhesion in neuroblastoma cells. Here, we investigated the interaction sites of the two molecules, using docking, synthetic peptides, ELISAs and conformational interaction site mapping. Mouse AChE was observed on docking to bind to a discontinuous, largely basic, structure, Val(2718)-Arg-Lys-Arg-Leu(2722), Tyr(2738)-Tyr(2739), Tyr(2789)-Ile-Lys-Arg-Lys(2793) and Val(2817)-Glu-Arg-Lys(2820), on the mouse laminin alpha1 G4 domain. ELISAs using synthetic peptides confirmed the involvement of the AG-73 site (2719-2729). This site overlaps extensively with laminin's heparin-binding site, and AChE was observed to compete with heparan sulfate for laminin binding. Docking showed the major component of the interaction site on AChE to be the acidic sequence Arg(90)-Glu-Leu-Ser-Glu-Asp(95) on the omega loop, and also the involvement of Pro(40)-Pro-Val(42), Arg(46) (linked to Glu(94) by a salt bridge) and the hexapeptide Asp(61)-Ala-Thr-Thr-Phe-Gln(66). Epitope analysis, using CLiPS technology, of seven adhesion-inhibiting mAbs (three anti-human AChE, one anti-Torpedo AChE and three anti-human anti-anti-idiotypic antibodies) showed their major recognition site to be the sequence Pro(40)-Pro-Met-Gly-Pro-Arg-Arg-Phe(48) (AChE human sequence). The antibodies, however, also reacted with the proline-containing sequences Pro(78)-Gly-Phe-Glu-Gly-Thr-Glu(84) and Pro(88)-Asn-Arg-Glu-Leu-Ser-Glu-Asp(95). Antibodies that recognized other features of the PAS area but not the Arg(90)-Gly-Leu-Ser-Glu-Asp(95) motif interfered neither with laminin binding nor with cell adhesion. These results define sites for the interaction of AChE and laminin and suggest that the interaction plays a role in cell adhesion. They also suggest the strong probability of functional redundancy between AChE and other molecules in early development, particularly heparan sulfate proteoglycans, which may explain the survival of the AChE-knockout mouse.
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PMID:Interaction of acetylcholinesterase with the G4 domain of the laminin alpha1-chain. 1821 27

The biochemical and histological changes following 60 days administration of daily doses equivalent to 1/20 LD(50) of lithium lactate and hydrochlorothiazide, as such and in association, were studied in male Wistar rats. No mortality or overt signs of toxicity were observed during the experiment and the serum activities of transaminases, alkaline phosphatase and cholinesterase were not significantly modified compared to controls. The histopathological examination of all the investigated organs: kidney, liver, brain and spleen, revealed significant lesions which were time-dependant and more pronounced in the association group. Although the changes were mostly inflammatory and conqestive, it was proved that the concomitant administration of lithium and hydrochlorothiazid is potentially dangerous, increasing lithium's nephrotoxicity and the thiazide diuretic's hepatotoxicity.
Met Based Drugs 1999
PMID:Effects of long-term administration of lithium and hydrochlorothiazide in rats. 1847 86

Features of pesticide synergism and acetylcholinesterase (AChE) inhibition (in vitro) were studied using a selected range of organotin compounds against the early 4th instar larvae of a highly resistant strain of the diamondback moth (DBM), Plutella xylostella, a major universal pest of cruciferous vegetables.Fourteen triorganotin compounds were evaluated for their ability to enhance the toxicity of the microbial insecticide, Bacillus thuringiensis (BT) and of the commercial insecticide, Malathion to Plutella xylostella larvae. Supplemental synergism was observed with triphenyl- and tricyclopentyltin hydroxides in combinations with Bacillus thuringiensis. Increased synergism was observed with an increase in the number of cyclopentyl groups on tin in the mixed series, Cyp(n) Ph(3-n) SnX, where X = OH, and 1-(1,2,4-triazolyl). The combination of (p-chlorophenyl)diphenyltin N,N-dimethyldithiocarbamate at LD(10) and LD(25) concentrations with sublethal concentrations of Malathion as well as of tricyclohexyltin methanesulphonate at the 0.01% (w/v) concentration with Malathion exerted strong synergistic effects (supplemental synergism) with toxicity index (T.I) values of 7.2, 19.8 and 10.1, respectively.Studies on the in vitro inhibition of acetylcholinesterase prepared from the DBM larvae showed that while most of the triorganotin Compounds tested were without effect on the enzyme, compounds containing the thiocarbamylacetate or the dithiocarbamylacetate moieties demonstrated appreciable levels of inhibition, being comparable in efficacy to commercial grades of Malathion and Methomyl.
Met Based Drugs 1994
PMID:Insecticidal Effects of Organotin(IV) Compounds on Plutella Xylostella (L.) Larvae. II. Inhibitory Potencies Against Acetylcholinesterase and Evidence for Synergism in Tests With Bacillus Thuringiensis(BER.) and Malathion. 1847 13

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.
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PMID:Involvement of paraoxonase 1 genetic variants in Alzheimer's disease neuropathology. 1986 53


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