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)

A 45-year-old man was hospitalized because of acute hepatitis. His serum cholinesterase (ChE) was below 10 IU/l (normal range: 105-240 IU/l) during the disease course and after his recovery. The patient was suspected of having familial hypocholinesterasemia. His family members were healthy except that his father had hypertension and gall stones. Analysis of ChE gene in the propositus and his family revealed three point mutations at nucleotides 298 (CCA to TCA), 1,410 (CGT to CGG) and 1,615 (GCA to ACA). The first mutation caused an amino acid change at codon 100 from proline to serine, which was a new mutation not previously reported, but the second one was a silent mutation. The third mutation resulted in an amino acid alteration from alanine to threonine at codon 539 in exon 4 of the ChE gene. The mode of transmission of these mutations is described.
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PMID:Familial hypocholinesterasemia found in a family and a new confirmed mutation. 905 91

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50 mg three times daily, taken before meals; this was increased to 100 mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7 +/- 18.6 mg/dl (mean +/- SE) at entry, and was significantly decreased to 132.9 +/- 7.5 mg/dl (P < 0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2 +/- 0.3% at entry to 6.3 +/- 0.2% (P < 0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3 +/- 10.7 micrograms/dl to 71.1 +/- 9.6 micrograms/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124 micrograms/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.
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PMID:Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose. 943 16

The contribution of the oxyanion hole to the functional architecture and to the hydrolytic efficiency of human acetylcholinesterase (HuAChE) was investigated through single replacements of its elements, residues Gly-121, Gly-122 and the adjacent residue Gly-120, by alanine. All three substitutions resulted in about 100-fold decrease of the bimolecular rate constants for hydrolysis of acetylthiocholine; however, whereas replacements of Gly-120 and Gly-121 affected only the turnover number, mutation of residue Gly-122 had an effect also on the Michaelis constant. The differential behavior of the G121A and G122A enzymes was manifested also toward the transition state analog m-(N,N, N-trimethylammonio)trifluoroacetophenone (TMTFA), organophosphorous inhibitors, carbamates, and toward selected noncovalent active center ligands. Reactivity of both mutants toward TMTFA was 2000-11, 000-fold lower than that of the wild type HuAChE; however, the G121A enzyme exhibited a rapid inhibition pattern, as opposed to the slow binding kinetics shown by the G122A enzyme. For both phosphates (diethyl phosphorofluoridate, diisopropyl phosphorofluoridate, and paraoxon) and phosphonates (sarin and soman), the decrease in inhibitory activity toward the G121A enzyme was very substantial (2000-6700-fold), irrespective of size of the alkoxy substituents on the phosphorus atom. On the other hand, for the G122A HuAChE the relative decline in reactivity toward phosphonates (500-460-fold) differed from that toward the phosphates (12-95-fold). Although formation of Michaelis complexes with substrates does not seem to involve significant interaction with the oxyanion hole, interactions with this motif are a major stabilizing element in accommodation of covalent inhibitors like organophosphates or carbamates. These observations and molecular modeling suggest that replacements of residues Gly-120 or Gly-121 by alanine alter the structure of the oxyanion hole motif, abolishing the H-bonding capacity of residue at position 121. These mutations weaken the interaction between HuAChE and the various ligands by 2.7-5.0 kcal/mol. In contrast, variations in reactivity due to replacement of residue Gly-122 seem to result from steric hindrance at the active center acyl pocket.
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PMID:Functional characteristics of the oxyanion hole in human acetylcholinesterase. 967 73

Chronic occupational exposure to organophosphorus and carbamate-type pesticides significantly inhibits acetylcholinesterase activity and causes morbidity. This study on mice was designed to evaluate their amino profile and to identify signs of hepatic dysfunction following their chronic exposure to mixtures of organophosphorus pesticides. Laboratory mice were exposed to a formulated mixture of the six organophosphorus pesticides (Dimethoate, Chlorpyrifos, Profenofos, Pirimiphos methyl, Triazophos and Dimethoate) most commonly used in agriculture in this region of the Middle East. Doses (10% of LD50 of the mixture) were given once a week by gavage in corn oil for 7 weeks; the control group was given only corn oil. At the end of the exposure period, mice were culled and blood samples were collected to determine erythrocyte acetylcholinesterase activity, biochemical markers of liver function and concentrations of serum amino acids. Erythrocyte acetylcholinesterase activity and total serum proteins decreased significantly in the exposed group. Serum concentrations of alanine aminotransferase and aspartate aminotransferase, alanine, glutamic acid, glycine, isoleucine, leucine, methionine, ornithine, proline, serine, threonine and valine were significantly increased in the exposed mice, while serum levels of cystine were decreased significantly. There were also non-significant increases in serum alkaline phosphatase, gama-glutamyl transpeptidase and some of the other amino acids. Chronic exposure to mixtures of organophosphorus pesticides is associated with decreased acetylcholinesterase activity, hepatic dysfunction and disturbance of amino acids profile. Biochemical indices of hepatocellular injury and disturbed amino acid metabolism may be of value as markers of chronic exposure to such pesticides.
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PMID:Hepatic injury and disturbed amino acid metabolism in mice following prolonged exposure to organophosphorus pesticides. 1002 66

Nasonovia ribisnigri, a main pest of salad crops, has developed resistance to various insecticides in southern France, including the carbamate pirimicarb and the cyclodiene endosulfan, two insecticides widely used to control this aphid. Here we have investigated the mechanisms of resistance to these two insecticides by studying cross-resistance, synergism, activity of detoxifying enzymes, and possible modifications of the target proteins. Resistance to pirimicarb was shown to be mainly due to a decreased sensitivity of the target acetylcholinesterase; this modification conferred also, resistance to propoxur but not to methomyl and the two tested organophosphates (acephate and paraoxon). Endosulfan resistance was associated with a moderate level of resistance to dieldrin, and resistance to both insecticides was due, in part, to increased detoxification by glutathione S-transferases (GST). The endosulfan resistant strain displayed the same amino acid at position 302 of the Rdl gene (GABA receptor) as susceptible aphids (e.g. Ala), indicating that the Ala to Ser (or to Gly) mutation observed among dieldrin resistant strains of other insect species was not present.
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PMID:Mechanisms of insecticide resistance in the aphid Nasonovia ribisnigri (Mosley) (Homoptera: Aphididae) from France. 1033 76

Alzheimer's disease (AD) is a neurodegenerative disorder whose hallmark is the presence of senile plaques and neurofibrillary tangles. Senile plaques are mainly composed of amyloid beta-peptide (Abeta) fibrils and several proteins including acetylcholinesterase (AChE). AChE has been previously shown to stimulate the aggregation of Abeta1-40 into amyloid fibrils. In the present work, the neurotoxicity of different amyloid aggregates formed in the absence or presence of AChE was evaluated in rat pheochromocytoma PC12 cells. Stable AChE-Abeta complexes were found to be more toxic than those formed without the enzyme, for Abeta1-40 and Abeta1-42, but not for amyloid fibrils formed with AbetaVal18-Ala, a synthetic variant of the Abeta1-40 peptide. Of all the AChE-Abeta complexes tested the one containing the Abeta1-40 peptide was the most toxic. When increasing concentrations of AChE were used to aggregate the Abeta1-40 peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results show that AChE-Abeta1-40 aggregates are more toxic than those of AChE-Abeta1-42 and that the neurotoxicity depends on the amount of AChE bound to the complexes, suggesting that AChE may play a key role in the neurodegeneration observed in Alzheimer brain.
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PMID:Neurotoxicity of acetylcholinesterase amyloid beta-peptide aggregates is dependent on the type of Abeta peptide and the AChE concentration present in the complexes. 1035 75

In order to identify amino acids involved in the interaction of acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8) with carbamates, the time course of inhibition of the recombinant mouse enzymes BChE wild-type (w.t.), AChE w.t. and of 11 site-directed AChE mutants by Ro 02-0683 and bambuterol was studied. In addition, the reversible inhibition of cholinesterases by terbutaline, the leaving group of bambuterol, was studied. The bimolecular rate constant of AChE w.t. inhibition was 6.8 times smaller by Ro 02-0683 and 16000 times smaller by bambuterol than that of BChE w.t. The two carbamates were equipotent BChE inhibitors. Replacement of tyrosine-337 in AChE with alanine (resembling the choline binding site of BChE) resulted in 630 times faster inhibition by bambuterol. The same replacement decreased the inhibition by Ro 02-0683 ten times. The difference in size of the choline binding site in the two w.t. enzymes appeared critical for the selectivity of bambuterol and terbutaline binding. Removal of the charge with the mutation D74N caused a reduction in the reaction rate constants for Ro 02-0683 and bambuterol. Substitution of tyrosine-124 with glutamine in the AChE peripheral site significantly increased the inhibition rate for both carbamates. Substitution of phenylalanine-297 with alanine in the AChE acyl pocket decreased the inhibition rate by Ro 02-0683. Computational docking of carbamates provided plausible orientations of the inhibitors inside the active site gorge of mouse AChE and human BChE, thus substantiating involvement of amino acid residues in the enzyme active sites critical for the carbamate binding as derived from kinetic studies.
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PMID:Amino acid residues involved in the interaction of acetylcholinesterase and butyrylcholinesterase with the carbamates Ro 02-0683 and bambuterol, and with terbutaline. 1044 76

We evaluated the focal therapeutic effect of oily carcinostatic agents administered by transcatheter arterial infusion (TAI) as the initial therapy in patients with hepatocellular carcinoma in a randomized controlled clinical trial. Group A (19 patients) received 4 mg of styrene maleic acid neocarzinostatin in 4 ml of Lipiodol, and group B (18 patients) received 100 mg of epirubicin in 4 ml of Lipiodol via the tumor feeding arteries as peripherally as possible. The grade of Lipiodol accumulation and the tumor regression rate were determined 2 weeks after TAI by computerized tomography. Adverse effects within 2 weeks after TAI were evaluated by subjective signs and symptoms such as fever (maximum body temperature) and the frequency of shaking chills and abdominal pain, and by biochemical parameters such as albumin, prothrombin time, and aspartate and alanine aminotransferases. Lipiodol accumulation in the tumor was significantly greater in group A (12/19; 63.2% showing grade IV Lipiodol accumulation) than in group B (3/18; 16.7% showing grade IV) (P<0.05). The tumor regression rate was also significantly greater in group A (8/17; 47.1% showing more than 25% tumor regression) than in group B (1/13; 7.7% showing more than 25% tumor regression) (P<0.05). Although clinically significant elevations of aminotransferases and reductions of cholinesterase, and shaking chills were observed more often in group A than in group B (P<0.0001), these factors had little influence on the clinical outcome. Our results suggest that styrene maleic acid neocarzinostatin in Lipiodol exerts a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of hepatocellular carcinoma.
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PMID:Focal therapeutic efficacy of transcatheter arterial infusion of styrene maleic acid neocarzinostatin for hepatocellular carcinoma. 1063 37

This study was conducted to investigate the effect of a new phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) on membrane bound target enzymes aspartate amino transferase (ASAT), alanine amino transferase (ALAT) and RBC acetylcholinesterase (AChE) in different tissues of male and female albino wistar rats when treated orally with 0.014 (low), 0.028 (medium) and 0.042 (high) mg/kg daily for a period of 90 days. Repeated administration of RPR-II caused significant increase of ASAT and ALAT enzymes in serum, liver and kidney and significant decrease was recorded in lung in both male and female rats when measured after 45 and 90 days of treatment. This compound also caused significant inhibition of RBC AChE indicating its effect on nerve synapsis. Females were more susceptible than males with regard to ASAT and ALAT levels in serum and liver and also in kidney ASAT, whereas reverse trend was recorded in lung ALAT, suggesting sexual dimorphism in the treated rats. These studies also indicated that the levels of these affected enzymes were recovered to normal conditions after 28 days of post treatment (withdrawal study). Positive correlation was observed with regard to these enzymes between serum, liver and kidney, whereas in case of serum and lung a negative correlation was recorded. These enzymes profile elucidates lung necrosis whereas in other tissues the level of enzymes increased showing an adaptive mechanism due to the chemical stress.
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PMID:Biochemical alterations induced by a new phosphorothionate (RPR-II) in tissues of male and female rats. 1064 Nov 86

To examine the influence of individual side chains in governing rates of ligand entry into the active center gorge of acetylcholinesterase and to characterize the dynamics and immediate environment of these residues, we have conjugated reactive groups with selected charge and fluorescence characteristics to cysteines substituted by mutagenesis at specific positions on the enzyme. Insertion of side chains larger than in the native tyrosine at position 124 near the constriction point of the active site gorge confers steric hindrance to affect maximum catalytic throughput (k(cat)/K(m)) and rates of diffusional entry of trifluoroketones to the active center. Smaller groups appear not to present steric constraints to entry; however, cationic side chains selectively and markedly reduce cation ligand entry through electrostatic repulsion in the gorge. The influence of side chain modification on ligand kinetics has been correlated with spectroscopic characteristics of fluorescent side chains and their capacity to influence the binding of a peptide, fasciculin, which inhibits catalysis peripherally by sealing the mouth of the gorge. Acrylodan conjugated to cysteine was substituted for tyrosine at position 124 within the gorge, for histidine 287 on the surface adjacent to the gorge and for alanine 262 on a mobile loop distal to the gorge. The 124 position reveals the most hydrophobic environment and the largest hypsochromic shift of the emission maximum with fasciculin binding. This finding likely reflects a sandwiching of the acrylodan in the complex with the tip of fasciculin loop II. An intermediate spectral shift is found for the 287 position, consistent with partial occlusion by loops II and III of fasciculin in the complex. Spectroscopic properties of the acrylodan at the 262 position are unaltered by fasciculin addition. Hence, combined spectroscopic and kinetic analyses reveal distinguishing characteristics in various regions of acetylcholinesterase that influence ligand association.
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PMID:Probing the active center gorge of acetylcholinesterase by fluorophores linked to substituted cysteines. 1077 3


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