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)

Piperidine derivatives of hemicholinium-3 were synthesized, which included the following spacing groups between cationic heads: trans-trans-bicyclohexyl, phenanthrene, naphthalene, and biphenyl. Relatively minor structural alterations in these series of compounds resulted in several different types of pharmacological actions related to cholinergic transmission. Structural requirements of the compounds are discussed and include internitrogen distance, structural planarity, spacing groups, and positional isomerism of the quaternary cationic heads. Selected quaternary piperidine derivatives with 14 A inter-atomic distance between the cationic heads exhibit potent HC-3 like activity which is enhanced if a molecule has a nonpolar space filling group (4-methyl piperidine) approximately 3.7 A from the corresponding quaternary cationic head. With selected piperidine ring substitutions, active tertiary amines were also identified. Compounds containing C = O in the spacing moiety were active inhibitors of cholinesterase with some derivatives being nearly as active as physostigmine. When the C = O moiety was reduced to -CH2 and a 2 or 3-CH3 piperidine ring was present, potent non-depolarizing, short acting neuromuscular blocking agents were obtained.
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PMID:Pharmacologic evaluation and structure activity relationships of a series of hemicholinium-3 (HC-3) analogs. 282 40

Piperidine derivatives of hemicholinium-3 were synthesized and included the following spacing groups between the bis-cationic heads: trans,trans-bicyclohexyl, phenanthrene, naphthalene and biphenyl. Anticholinesterase activity was determined using rat striatal synaptosomal cholinesterase, bovine erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase. Hemicholinium-3 has little anticholinesterase activity but when the choline moiety of hemicholinium-3 is replaced with selected heterocyclic amine ring systems active inhibitors can be obtained. Results in this communication identify several quaternary amines which are equipotent with physostigmine for inhibition of cholinesterase. Several tertiary amines were also found to be active. Optimal anticholinesterase activity of these piperidine derivatives appear to be related to the necessity of 14 A interatomic distance between the cationic heads as well as C = O substitution in the phenylethyl spacing moiety. Reduction of C = O to secondary alcohol or CH2 results in decreased activity. The anticholinesterase activity is not only related to internitrogen distance and C = O substitution but also structural planarity and positional isomerism of the quaternary cationic head.
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PMID:Anticholinesterase activity and structure activity relationships of a new series of hemicholinium-3 analogs. 302 35

Decrease in electrophoretic mobility of erythrocytes, increase in Km of erythrocyte membrane acetylcholinesterase and decrease in the binding constant of 8-anilino-1-naphthalene sulfonate to erythrocyte membranes demonstrate a decrease in surface charge density of bovine erythrocytes during in vivo aging. This phenomenon seems to be species-specific; it may be due to a diminution of the sialic acid content but may also be contributed by conformational changes of membrane proteins.
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PMID:Aging of the erythrocyte. XIX. Decrease in surface charge density of bovine erythrocytes. 669 39

1. Microsomes of rat liver and brain and mitochondria of rat liver and guinea-pig brown adipose tissue were solubilized with the nonionic detergent Lubrol-WX and the solubilized material was incorporated into liposomes of various phospholipid composition. In proteoliposomes thus formed the kinetics of arylsulphatase, glycerol-3-phosphate dehydrogenase, monoamine oxidase and acetylcholinesterase were measured. 2. It was shown that the apparent Km values of arylsulphatase and glycerol-3-phosphate dehydrogenase were higher in liposomes prepared with negatively charged phospholipids and lower in liposomes containing positively charged organic amines, as compared with th Km value of enzymes incorporated into liposomes prepared from phosphatidylcholine alone. The opposite was true for monoamine oxidase and acetylcholinesterase, i.e. enzymes possessing cationic substrates. Phospholipid composition did not essentially influence the activity of the enzymes extrapolated for infinite substrate concentration (V values). 3. As compared with proteoliposomes made from phosphatidylcholine, the binding constant (Ka) of 8-anilino-1-naphthalene sulphonate was higher when the vesicles contained acidic phospholipids or bis(hexadecanyl)phosphate and lower when they contained organic amines. 4. A correlation between changes of the surface potential calculated from Ka values of anilino-naphthalene sulphonate and variations in apparent Km values of the four enzymes under investigation indicates that the activity of membrane-bound enzymes may be modulated by charged phospholipids due to decreasing or increasing substrate concentration in the unstirred layer, as predicted from the Boltzmann distribution.
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PMID:Effect of phospholipid composition on the surface potential of liposomes and the activity of enzymes incorporated. 677 95

The interaction of the cholinergic fluorescent probes, 1-(5-dimethyl-aminoaphthalene-1-sulfonamido) ethane-2-trimethylammonium perchlorate, 1-(5-dimethylaminoaphthalene-1-sulfonamido) pentane-5-trimethylammonium tartarate and 1-(5-dimethylaminonaphthalene-1-sulfonamido) decane-10- trimethylammonium tartarate with horse serum cholinesterase has been examined by fluorescence and n.m.r. methods. Fluorescence titrations show binding of the decane derivative to two sites on the protein whereas the lower homologs bind largely to one site. Active site inhibitors like carbamylcholine and decamethonium abolish binding of the decane derivative to the high affinity site. The inhibitors are largely without effect on the binding of the lower homologs. N.m.r. studies clearly establish immobilization of both ends of the molecule on binding in the case of the decane derivative, whereas in the lower homologs the dimethylamino group on the naphthalene ring is significantly more affected in the presence of enzyme. The probes are effective inhibitors of the enzyme with the decane derivative being two orders of magnitude more effective than its lower homologs. Based on the n.m.r., fluorescence and inhibition studies, a model for probe binding to the enzyme is advanced. It appears that the decane derivative binds with high affinity to the catalytic anionic site while the lower affinity site is assigned to a peripheral anionic site. The lower homologs probe only the peripheral site. A comparison of fluorescence, n.m.r. and inhibition studies with acetylcholinesterases from electric eel and bovine erythrocytes is presented.
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PMID:Fluorescence and N.M.R. studies of the binding of cholinergic fluorescent probes to horse serum cholinesterase. 722 95

Effects of arsenic exposure on offspring development were studied in pregnant mice. The results showed arsenic contents of the body and brain tissue increased and the structure of neural cells in cerebral cortex became abnormal after exposure. The offspring neurobehavioral development appeared retardant and the proportion of their peripheral lymphocytes with alpha-naphthalene acetate enzyme (ANAE) declined in a mice group with exposure to 0.75 mg/kg arsenic, and the offspring body weight gain slowed after weaning, blood cholinesterase activity and serum level of haemolysin declined significantly in a group with 4.50 mg/kg. It indicated arsenic could affect embryonic and offspring development in mice through pregnant exposure.
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PMID:[Effects of arsenic on the offspring development in mice]. 808 54

Exposure of purified acetylcholinesterase from Torpedo california to a system generating oxygen radicals (viz. ascorbic acid/Fe(EDTA)2/H2O2) inactivated the enzyme. The enzyme retained its native dimeric form, but electrophoresis under denaturing conditions showed some cleavage of peptide bonds. Spectroscopic characterization revealed a shift to the red in the intrinsic fluorescence emission peak, a large decrease in molar ellipticity in the near UV with a much smaller decrease in the far UV, and increased binding of the amphiphilic probe, 1-anilino-8-naphthalene sulfonate, all relative to native enzyme. The treated enzyme was also highly susceptible to proteolysis. These data show that oxygen radical treatment converts acetylcholinesterase to a partially unfolded state, which retains most of its secondary structure but lacks substantial tertiary structure, thus resembling a 'molten globule' state. This model system may offer a mechanism for explaining the consequences of oxidative stress in vivo: partially unfolded proteins generated by oxidative stress may interact with molecular chaperons of the heat shock family, thus activating the heat-shock factor and, thereby, activating heat-shock genes.
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PMID:Oxidative stress transforms acetylcholinesterase to a molten-globule-like state. 811 96

Exposure of purified hydrophilic tetramers of acetylcholinesterase (AChE) from fetal bovine serum to various guanidinium chloride (Gdn) concentrations led to inactive tetramers (2 M Gdn) and dimers (6 M Gdn). The native tetramers were almost fully monomerized by reduction, a minor fraction of the released monomers remaining active. Sedimentation analysis and hydrophobic chromatography showed that the modified tetramers, dimers and monomers had amphiphilic properties. Intrinsic fluorescence spectra and binding of the amphiphilic probe, 1-anilino-8-naphthalene sulfonate (ANS), revealed that AchE subunit in the modified tetramers were in a 'molten globule' structure, the dimers in a denatured stated, and the inactive monomers in a 'native-like' structure. These data show that AChE subunits possess a flexible conformation, which may be important for generating a full set of molecular forms. In addition, the behavior of the active monomers with amphiphiles may explain the interactions of type II AChE forms with membranes.
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PMID:Conversion of acetylcholinesterase hydrophilic tetramers into amphiphilic dimers and monomers. 861 26

Polycyclic aromatic hydrocarbons (PAHs) are formed during the incomplete combustion of fossil fuels, wood and municipal waste incineration, from internal combustion engines, and from various food cooking operations and are common environmental contaminants which have been detected in surface waters, sediments, soils, plants, and both rural and urban air. In this study, we have shown that, for the first time, in vitro addition of PAHs dose-dependently inhibited the activity of acetylcholinesterase purified from electric eel in a competitive manner. The PAHs containing 3 or higher aromatic rings showed the highest inhibitory effect with the IC50 values between 2 and 6 ppm. Among the PAHs tested, chrysene and pyrene exhibit the highest and lowest potency with IC50 values of 2. 40+/-0.04 and 5.22+/-0.38 ppm, respectively. PAHs with lower number of aromatic rings, such as naphthalene, acenaphthylene and fluorene, and oxygenated PAHs, such as anthraquinone and xanthone, showed no or slight inhibition of the acetylcholinesterase activity.
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PMID:Polycyclic aromatic hydrocarbons inhibit the activity of acetylcholinesterase purified from electric eel. 929 14

Biochemical indices were investigated for their potential use as variables of sublethal toxicity in Daphnia (cholinesterase) and Chironomus (cholinesterase and biotransformation enzymes). Parathion, dichlorvos, and aldicarb caused dose-related inhibition of cholinesterase (ChE) in 24-h bioassays with both species. Ratios of Daphnia and Chironomus ChE IC50 values to corresponding immotility EC50 values derived from the same experiment covered the range 0.26 to 1.2. Estimates of the ChE inhibition caused by the immotility EC50 were in the range 53-99% below control activity. ChE IC50 values of dichlorvos, parathion, and aldicarb were 0.17, 0.61, and 95 microg/liter in Daphnia and 6.2, 2.9, and 27 microg/liter in Chironomus, respectively. Cytochrome P450-dependent monooxygenase activities (ethoxyresorufin-O-deethylase, methoxyresorufin-O-deethylase, and ethoxycoumarin-O-deethylase) were detectable in Chironomus but not in Daphnia. Chironomus monooxygenase activities were significantly inhibited to about 30% of control values after 4 days of exposure to 50 microg/liter 3, 4-dichloroaniline but remained unchanged by 0.5 microg/liter parathion. An approximately 1.3-fold induction of monooxygenase activities was caused by the model inducer naphthalene (0.1mg/liter). These results suggest that cytochrome P450-dependent monooxygenase activities may be useful variables in toxicity tests with aquatic insects.
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PMID:Altered cholinesterase and monooxygenase levels in Daphnia magna and Chironomus riparius exposed to environmental pollutants. 993 Dec 32


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