Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fluoride variant of human butyrylcholinesterase owes its name to the observation that it is resistant to inhibition by 0.050 mM sodium fluoride in the in vitro assay. Individuals who are heterozygous for the fluoride and atypical alleles experience about 30 min of apnea, rather than the usual 3-5 min, after receiving succinyldicholine. Earlier we reported that the atypical variant has a nucleotide substitution which changes Asp 70 to Gly. In the present work we have identified two different point mutations associated with the fluoride-resistant phenotype. Fluoride-1 has a nucleotide substitution which changes Thr 243 to Met (ACG to ATG). Fluoride-2 has a substitution which changes Gly 390 to Val (GGT to GTT). These results were obtained by DNA sequence analysis of the butyrylcholinesterase gene after amplification by PCR. The subjects for these analyses were 4 patients and 21 family members.
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PMID:Identification of two different point mutations associated with the fluoride-resistant phenotype for human butyrylcholinesterase. 141 24

The properties of a cholinesterase from mucosal cells of rat intestine have been characterized. The enzyme was identified as butyrylcholinesterase because it was more sensitive to iso-OMPA (IC50 = 1.0 x 10(-6) M) than to BW284C51 (IC50 = 5.5 x 10(-5) M) and was not inhibited by substrate excess. It displayed a higher affinity for acetylthiocholine than for butyrylthiocholine. A major molecular form was observed sedimenting at 5.9 S. Two other minor molecular forms were identified as a hydrophilic tetramer (G4, sedimenting at 10.5 S) and a monomer (G1, sedimenting at 4.3 S). The 5.9 S component was referred to as "G" form (G for globular) and not "G2" as usual dimers for the following reasons: (i) the G form was unaffected by the reducing agents, beta-mercaptoethanol and dithiothreitol, which converted disulfide-linked dimers of acetylcholinesterase into monomers, (ii) the G form was shifted from 5.9 to 3.4 S when the sucrose gradient contained Triton X-100. This value of 3.4 S (in Triton X-100) appeared too low for a typical G2 form. The shift in the S value was partly reversible: the 3.4 S form resedimented at 5.2 S in the absence of detergent. The behavior of the G form in sucrose gradients indicated that it was amphiphilic. This was confirmed in nondenaturing electrophoreses and also by quantitative binding of the G form to octyl-Sepharose. The hydrophobic domain of the G form was not a glycolipid, as shown by its insensitivity to Bacillus thuringiensis phosphatidylinositol-specific phospholipase C and its nonaggregating properties in the absence of nondenaturing detergent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amphiphilic forms of butyrylcholinesterase in mucosal cells of rat intestine. 142 Feb 1

Heptyl-physostigmine (heptyl-Phy), a new carbamate derivative of physostigmine (Phy), has been assessed for potential clinical value by evaluating its in vitro activity against human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE), its duration of in vivo activity against rat plasma AChE, and its effects on attenuating a scopolamine-induced impairment in learning performance of young rats in a 14-unit T-maze. Heptyl-Phy demonstrated potent cholinesterase inhibition, with activity similar to that of Phy against AChE, IC50 values 21.7 +/- 2.0 nM and 27.9 +/- 2.4 nM, respectively, and significantly greater than that of Phy against BChE, IC50 values 5.0 +/- 0.1 nM and 16.0 +/- 2.9 nM, respectively. Heptyl-Phy achieved maximum AChE inhibition of 92.5% at 60 min and maintained a high and relatively constant inhibition for more than 8 h. For analysis of effects on learning performance, heptyl-Phy at 1.0, 1.5, 2.0 or 3.0 mg/kg, or vehicle was administered i.p. to 52 3-month-old male Fischer-344 rats 60 min prior to maze training. Thirty minutes prior to training, each animal received either 0.9% NaCl or scopolamine hydrochloride (0.75 mg/kg). Only a 2.0 mg/kg dose of heptyl-Phy significantly reduced the number of errors in scopolamine-treated rats. The other doses did not improve any aspect of maze performance. Although the therapeutic window of heptyl-Phy did not appear wide enough for clinical use, the longer duration of action of heptyl-Phy would appear beneficial.
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PMID:The long-acting cholinesterase inhibitor heptyl-physostigmine attenuates the scopolamine-induced learning impairment of rats in a 14-unit T-maze. 143 16

Torpedo acetylcholinesterase (AcChoEase, EC 3.1.1.7) and human butyrylcholinesterase (BtChoEase, EC 3.1.1.8), while clearly differing in substrate specificity and sensitivity to inhibitors, possess 53% sequence homology; this permitted modeling human BtChoEase on the basis of the three-dimensional structure of Torpedo AcChoEase. The modeled BtChoEase structure closely resembled that of AcChoEase in overall features. However, six conserved aromatic residues that line the active-site gorge, which is a prominent feature of the AcChoEase structure, are absent in BtChoEase. Modeling showed that two such residues, Phe-288 and Phe-290, replaced by leucine and valine, respectively, in BtChoEase, may prevent entrance of butyrylcholine into the acyl-binding pocket. Their mutation to leucine and valine in AcChoEase, by site-directed mutagenesis, produced a double mutant that hydrolyzed butyrylthiocholine almost as well as acetylthiocholine. The mutated enzyme was also inhibited well by the bulky, BtChoEase-selective organophosphate inhibitor (tetraisopropylpyrophosphoramide, iso-OMPA). Trp-279, at the entrance of the active-site gorge in AcChoEase, is absent in BtChoEase. Modeling designated it as part of the "peripheral" anionic site, which is lacking in BtChoEase. The mutant W279A displayed strongly reduced inhibition by the peripheral site-specific ligand propidium relative to wild-type Torpedo AcChoEase, whereas inhibition by the catalytic-site inhibitor edrophonium was unaffected.
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PMID:Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis. 143 84

Differences in glycosylation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in human brain, plasma and cerebrospinal fluid (CSF) have been investigated by means of their interaction with agarose-immobilized lectins. Most of the AChE in brain and CSF was associated to concanavalin A (Con A), Lens culinaris (LCA) and Triticum vulgaris (WGA) agglutinins, but little activity was adsorbed to Ricinus communis agglutinin I (RCAI). Brain, plasma and CSF BuChE was almost fully bound to Con A, LCA and WGA-agarose. Brain BuChE was unable to react with RCA (RCA-BuChE), the plasma enzyme was completely bound to the lectin (RCA+BuChE) and BuChE from CSF of normal children was partially fixed to RCA (RCA +/- BuChE). BuChE in CSF of children with meningitis fully reacts with the lectin. The data suggest that the proportion of RCA+BuChE in CSF of children with meningitis is increased, this enzyme probably coming from plasma.
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PMID:Ricinus communis agglutinin I reacting and non-reacting butyrylcholinesterase in human cerebrospinal fluid. 146 69

Previous studies have used a sensitive histochemical technique to demonstrate acetylcholinesterase and butyrylcholinesterase within the pathological lesions of Alzheimer's disease. In this study, we used this technique to show that acetylcholinesterase localized in either frozen or fixed neocortical tissue sections is removed after treatment with various glycosaminoglycans, heparinases or proteases. Heparan sulphate, heparinase lyase type I and to a lesser degree, heparin and chondroitin sulphate were effective in solubilizing a large part of the cholinesterase activity. At physiological concentrations, the protease papain or trypsin readily removed activity but collagenase or pronase were relatively less effective. Peptide protease inhibitors and divalent metals did not exhibit any clear effect. The specificity of these observations was shown by inhibition of activity with various anticholinesterases including diisofluorophosphate. Our results suggest that acetylcholinesterase is anchored to and may be released from the heparan sulphate glycosaminoglycans shown to be contained in the lesions. We further suggest that the localization of cholinesterases is closely associated with the accumulation of the glycosaminoglycans in amyloid plaques and neurofibrillary tangles.
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PMID:Acetylcholinesterase and its association with heparan sulphate proteoglycans in cortical amyloid deposits of Alzheimer's disease. 146 81

A sensitive histochemical method for the visualization of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity was used to determine the laminar distribution of cholinesterase-positive cortical tangles in Alzheimer's disease (AD). In many cortical areas AChE- and BChE-positive tangles displayed a completely overlapping distribution. In other areas the most superficial layers contained only AChE-positive tangles whereas the deepest layers contained only BChE-positive tangles. These observations suggest that some cholinesterase-positive tangles have a predominantly (if not exclusively) AChE-like reactivity whereas others have a reactivity that is predominantly BChE-like. The intermingling of AChE- and BChE-positive tangles in most cortical areas and layers suggests that there may also be a third population in which the two enzymes are equally prominent in the same tangle.
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PMID:Differential laminar distribution of acetylcholinesterase and butyrylcholinesterase containing tangles in the cerebral cortex of Alzheimer's disease. 146 98

Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities of cerebrospinal fluid (CSF) collected post mortem from the lateral ventricles, cisterna magna, and lumbar regions of the spinal cord of patients with a histologically confirmed diagnosis of Alzheimer's disease were compared with those of normal, age matched control patients, patients with dementia of non-Alzheimer aetiology, and patients with non-dementing neurological disorders. The AChE activity of the ventricular CSF of patients with Alzheimer's disease was 48% lower (p < 0.005) than that of age matched controls or patients with other types of dementia, and the AChE activity of CSF sampled from the basal cistern was 40% lower (p < 0.005) in patients with Alzheimer's disease. There were no significant differences between the AChE activity in Alzheimer's disease and control patients in CSF collected from the lumbar cistern. AChE activity was lower in CSF sampled from the basal and lumbar cistern of patients with dementia of non-Alzheimer aetiology, while ventricular activity was in the normal range. BuChE activity in ventricular CSF of Alzheimer's disease patients was 41% lower than normal (p < 0.05) and in the normal range in all other samples. The secretion of AChE from forebrain and hindbrain regions is reduced in Alzheimer's disease patients, leading to decreased ventricular and cisternal levels of the enzyme. Secretion from more caudal regions of the central nervous system seems to be unaffected by the disease, resulting in AChE in the lumbar CSF of patients with Alzheimer's disease being in the control range. Such altered secretion of AChE in the brain could have profound implications not only for cholinergic transmission in these patients but also for the proposed noncholinergic modulatory actions of AChE.
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PMID:Acetylcholinesterase and butyrylcholinesterase activities in cerebrospinal fluid from different levels of the neuraxis of patients with dementia of the Alzheimer type. 146 5

Purified fetal bovine serum acetylcholinesterase (FBS AChE) and horse serum butyrylcholinesterase (BChE) were successfully used as single pretreatment drugs for the prevention of pinacolyl methylphosphonofluoridate (soman) toxicity in nonhuman primates. Eight rhesus monkeys, trained to perform Primate Equilibrium Platform (PEP) tasks, were pretreated with FBS AChE or BChE and challenged with a cumulative level of five median lethal doses (LD50) of soman. All ChE-pretreated monkeys survived the soman challenge and showed no symptoms of soman toxicity. A quantitative linear relation was observed between the soman dose and the neutralization of blood ChE. None of the four AChE-pretreated animals showed PEP task decrements, even though administration of soman irreversibly inhibited nearly all of the exogenously administered AChE. In two of four BChE-pretreated animals, a small transient PEP performance decrement occurred when the cumulative soman dose exceeded 4 LD50. Performance decrements observed under BChE protection were modest by the usual standards of organophosphorus compound toxicity. No residual or delayed performance decrements or other untoward effects were observed during 6 weeks of post-exposure testing with either ChE.
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PMID:Use of cholinesterases as pretreatment drugs for the protection of rhesus monkeys against soman toxicity. 147 Nov 50

Biochemical responses of animals to environmental chemicals (biochemical biomarkers) can give measures of exposure, and sometimes also toxic effect. They are particularly valuable where they can be used to measure the toxic effects of chemicals in the field, employing non-destructive sampling methods. Measurements of exposure are useful in the case of non-persistent chemicals (e.g. organophosphorus, carbamate, or pyrethroid insecticides) which are difficult or impossible to detect by chemical analysis. They can also be useful to provide an integrated measure of the level of exposure to a group of related chemicals. Biochemical biomarkers are likely to provide a measure of toxic effect, where they are based upon a molecular mechanism which underlies toxicity. A widely-used biochemical biomarker is cholinesterase depression, which may involve destructive sampling (brain acetylcholinesterase) or non-destructive sampling (serum butyrylcholinesterase). For genotoxic chemicals, techniques which measure DNA damage (e.g. detection of DNA adducts) provide a powerful tool in measuring environmental effects. The detection of biochemical changes caused by anticoagulant rodenticides (e.g. abnormal levels of clotting proteins in blood) provides another example of this approach. In general, the development of simple, sensitive, and specific assays that are 'user-friendly' would open the way for much wider use of biochemical biomarkers in environmental monitoring.
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PMID:Biochemical responses as indicators of toxic effects of chemicals in ecosystems. 147 Dec 5


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