Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The electrostatic potentials for the three-dimensional structures of cholinesterases from various species were calculated, using the Delphi algorithm, on the basis of the Poisson-Boltzmann equation. We used structures for Torpedo californica and mouse acetylcholinesterase, and built homology models of the human, Bungarus fasciatus, and Drosophila melanogaster acetylcholinesterases and human butyrylcholinesterase. All these structures reveal a negative external surface potential, in the area around the entrance to the active-site gorge, that becomes more negative as the rim of the gorge is approached. Moreover, in all cases, the potential becomes increasingly more negative along the central axis running down the gorge, and is largest at the base of the gorge, near the active site. Ten key acidic residues conserved in the sequence alignments of AChE from various species, both in the surface area near the entrance of the active-site gorge and at its base, appear to be primarily responsible for these potentials. The potentials are highly correlated among the structures examined, down to sequence identities as low as 35%. This indicates that they are a conserved property of the cholinesterase family, could serve to attract the positively charged substrate into and down the gorge to the active site, and may play other roles important for cholinesterase function.
J Mol Graph Model 1997 Oct
PMID:External and internal electrostatic potentials of cholinesterase models. 964 May 63

Acetylcholinesterase (AChE), the enzyme involved in the hydrolysis of the neurotransmitter acetylcholine, has been implicated in non-cholinergic actions which may play a role in neurodegenerative diseases such as Alzheimer's disease. To study the potential cytotoxicity of brain AChE, the effects of affinity purified AChE were analyzed on neuronal (Neuro 2a) and glial-like (B12) cells. LDH release and MTT reduction assays showed that AChE was toxic; the toxicity was dependent on the enzyme concentration, time of incubation and cellular density. The toxic effect of AChE was not related to its catalytic activity, since the anti-cholinesterase drug BW284C51 and heat inactivation were unable to block the effects of the enzyme. When cells were incubated at 4 degrees C, toxicity was completely blocked, in contrast to cells incubated at 37 degrees C. The presence of serum in the culture medium inhibited the toxic effects of AChE. Cytoplasmic shrinkage, condensation and fragmentation of nucleus as well as DNA strand breaks detected with the TUNEL technique indicated that apoptotic cell death is involved in the effect of AChE. Considering that we have previously shown that AChE promotes the assembly of beta-amyloid peptide into neurotoxic amyloid fibrils, it is conceivable that the neurotoxicity of AChE shown here may play a role in the neuronal degeneration observed in Alzheimer's disease.
Mol Psychiatry 1998 May
PMID:Toxic effects of acetylcholinesterase on neuronal and glial-like cells in vitro. 967

Acetylcholinesterase is the target of organophosphate and carbamate pesticides. Organophosphate resistance is widespread in the cattle tick, Boophilus microplus, in Australia. We have isolated a cDNA of acetylcholinesterase from B. microplus and show that it would encode a protein 62 kDa in size. The predicted amino acid sequence contains all the residues characteristic of an acetylcholinesterase. Alternative splicing of the transcript was detected at both the 5' and 3' ends. Alternative splicing at the 5' end would result in two proteins differing by six amino acids. This is the first report of alternative splicing of the N-terminal coding region in a cholinesterase. No point mutations were detected in the acetylcholinesterase gene from organophosphate resistant strains of B. microplus. Alternative explanations for resistance to organophosphates in B. microplus are discussed.
Insect Biochem Mol Biol 1998 Aug
PMID:Acetylcholinesterase cDNA of the cattle tick, Boophilus microplus: characterisation and role in organophosphate resistance. 975 68

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-expressing cells. A matrix metalloproteinase-like enzyme cleaves the membrane-bound FasL to produce the soluble FasL (sFasL). Since FasL has been reported to play a pivotal role in the development of hepatitis, we evaluated clinical significance of serum sFasL in acute liver injury including acute self-limited and fulminant hepatitis. Serum sFasL in 19 patients including 12 with acute self-limited hepatitis and 7 with fulminant hepatitis was measured by an enzyme-linked immunosorbent assay (ELISA). The clinical data consisted of 18 indices including age, sex, liver function tests, hepatocyte growth factor (HGF), outcome and sFasL. Serum sFasL in fulminant hepatitis is 0.06+/-0.01 ng/ml, being identical to that in acute self-limited hepatitis, Serum sFasL is positively correlated with AST and ALT (p<0.0001 and p<0.0001). The factors associated with outcome of the patients were HGF, albumin, prothrombin time, platelet count, cholinesterase and leukocyte count in this order. Serum sFasL serves as an indicator of liver injury in acute self-limited and fulminant hepatitis.
Res Commun Mol Pathol Pharmacol 1998 Jul
PMID:Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. 975 39

Recombinant alpha-D-galactosidase (rGal) from soybean (Glycine max) hydrolyzed the immunodominant alpha-D-galactose residue from the B epitope of red blood cells. This converted type B erythrocytes to type O which are "universally" transfusable. Type B red blood cells were obtained from four different donors and enzymatically converted. Cell function parameters, including red cell indices, pH, methemoglobin, carboxyhemoglobin, osmotic fragility, hemolysis, 2,3-diphosphoglycerate, cholinesterase, ATP, and antigen typing of treated cells were compared to controls. These pilot studies indicate that rGal could have potential biotechnical application in the production of universally transfusable red blood cells.
Biochem Mol Biol Int 1998 Sep
PMID:Seroconversion of type B to O erythrocytes using recombinant Glycine max alpha-D-galactosidase. 978 52

The amyloid beta-protein (Abeta) is an approximately 4 kD secreted protein normally found in human plasma and cerebrospinal fluid. Abeta is invariably deposited as insoluble amyloid fibrils in the brains of patients with Alzheimer's disease (AD), and there is increasing evidence that Abeta deposition plays an important role in AD pathogenesis. Abeta is released from the larger beta-amyloid precursor protein (betaAPP) through cleavage on the amino and carboxyl side of Abeta by proteolytic activities referred to as beta and gamma secretase, respectively. betaAPP is also cleaved at Abeta16 by a third protease, alpha secretase, which may prevent amyloid deposition by bisecting the Abeta peptide. Tacrine, a cholinesterase inhibitor, has been shown to improve memory and cognitive functions in some patients with AD, and we have previously demonstrated that it significantly reduces the levels of the secretion of soluble betaAPP fragments (sAPP) in cultured cells. In this study, we extended our studies by analysis of Abeta40 and Abeta42 and report that in a human neuroblastoma cell line tacrine reduced the levels of total Abeta, Abeta40 and Abeta42 in addition to sAPP. These inhibitory results cannot be attributed to a reduction in total betaAPP synthesis as tacrine treatment did not cause a significant change in the rate of betaAPP synthesis. Furthermore, significant toxicity was not observed in tacrine-treated cultures as determined by analysis of lactate dehydrogenase (LDH) in the conditioned media. Taken together, these results suggest that tacrine affects the processing of betaAPP by alterations in betaAPP trafficking and/or increased intracellular proteolysis. This study raises the possibility that tacrine may aid in the treatment of AD due to its effects on betaAPP processing as well as by its effects on the cholinergic pathway.
Brain Res Mol Brain Res 1998 Nov 20
PMID:The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells. 981 82

The aim of this work was to study gender differences on the physiology of the dimorphic brachial musculature involved in the clasp reflex of the toad (Bufo marinus L.). The neuromuscular transmission, the sensitivity to acetylcholine (ACh) and the cholinesterase activity were compared on the forelimb sternoradialis muscles (SR) from male and female toads. The interosseous muscles of the first finger were used to compare the properties of the nicotinic receptor/ionic channel complex (AChR). All the muscles studied were dimorphic, i.e. significantly smaller in the female than in the male frog in otherwise similar size animals. The SR of either sex contracted to bath application of ACh with similar EC50. In physiological solution the frequency of the miniature end-plate potentials (mepps) was very low (0.1 s-1) and no gender difference was detected. The mepp amplitudes were 0.62 +/- 0.03 and 0.58 +/- 0.03 mV in SR from male and female toads, respectively. To increase exocytosis the muscles were incubated in hypertonic solution (158 mM NaCl). Under this condition mepp frequency was increased by five and seven times and mepp amplitude increased by 1.3 and 1.6 times in SR from male and female toads, respectively. The cholinesterase activity measured by the colorimetric method, did not differ in SR from male and female toads. In muscle fibers dissociated from the dimorphic interosseous muscles of male and female toads, the ionic channel conductance was 43 +/- 5.3 and 44 +/- 4.5 pS, respectively. The mean channel open time was voltage-dependent and not significantly different in preparations from both genders. These observations indicate that neither the ACh-nicotinic receptor interaction, nor the AChR complex kinetics and the nicotinic excitation-contraction coupling or the cholinesterase activity differ in dimorphic muscles from Bufo genders. No gender difference was detected in neuromuscular transmission of the studied muscle. Only a slight increase in mepp frequency and amplitude could be detected when the muscles were incubated in hypertonic solution.
Comp Biochem Physiol A Mol Integr Physiol 1998 Oct
PMID:Gender does not influence neuromuscular properties in dimorphic skeletal muscles of the toad. 988 74

Succinylcholine is the most important rapid-acting depolarizing muscle relaxant during anesthesia. Its desirable short duration of action is controlled by butyrylcholinesterase, the detoxifying enzyme. There are two reported cases of prolonged paralysis from succinylcholine in patients poisoned with the organophosphorus insecticides parathion and chlorpyrifos. The present study examines the possibility that other organophosphorus and methylcarbamate pesticides might also prolong succinylcholine action by inhibiting butyrylcholinesterase using mice treated intraperitoneally as a model and relating inhibition of blood serum hydrolysis of butyrylthiocholine to potentiated toxicity (mouse mortality). The organophosphorus plant defoliant tribufos (4 h pretreatment, 160 mg/kg) and organophosphorus plant growth regulator ethephon (1 h pretreatment, 200 mg/kg) potentiate the toxicity of succinylcholine by seven- and fourfold, respectively. Some other pesticides or analogs are more potent sensitizers for succinylcholine toxicity with threshold levels of 0.5, 1.0, 1.7, 8, 10, and 67 mg/kg for phenyl saligenin cyclic phosphonate, profenofos, methamidophos, tribufos, chlorpyrifos, and ethephon, respectively. Enhanced mortality from succinylcholine is generally observed when serum butyrylcholinesterase is inhibited 55-94%. Mivacurium, a related nondepolarizing muscle relaxant also detoxified by butyrylcholinesterase, is likewise potentiated by at least threefold on 4 hour pretreatment with tribufos (25 mg/kg) or profenofos (10 mg/kg).
J Biochem Mol Toxicol 1999
PMID:Organophosphorus pesticide-induced butyrylcholinesterase inhibition and potentiation of succinylcholine toxicity in mice. 989 Jan 96

Acetylcholinesterase (AChE), a serine hydrolase, is potentially susceptible to inactivation by phenylmethylsulfonyl fluoride (PMSF) and benzenesulfonyl fluoride (BSF). Although BSF inhibits both mouse and Torpedo californica AChE, PMSF does not react measurably with the T. californica enzyme. To understand the residue changes responsible for the change in reactivity, we studied the inactivation of wild-type T. californica and mouse AChE and mutants of both by BSF and PMSF both in the presence and absence of substrate. The enzymes investigated were wild-type mouse AChE, wild-type T. californica AChE, wild-type mouse butyrylcholinesterase, mouse Y330F, Y330A, F288L, and F290I, and the double mutant T. californica F288L/F290V (all mutants given T. californica numbering). Inactivation rate constants for T. californica AChE confirmed previous reports that this enzyme is not inactivated by PMSF. Wild-type mouse AChE and mouse mutants Y330F and Y330A all had similar inactivation rate constants with PMSF, implying that the difference between mouse and T. californica AChE at position 330 is not responsible for their differing PMSF sensitivities. In addition, butyrylcholinesterase and mouse AChE mutants F288L and F290I had increased rate constants ( approximately 14 fold) over those of wild-type mouse AChE, indicating that these residues may be responsible for the increased sensitivity to inactivation by PMSF of butyrylcholinesterase. The double mutant T. californica AChE F288L/F290V had a rate constant nearly identical with the rate constant for the F288L and F290I mouse mutant AChEs, representing an increase of approximately 4000-fold over the T. californica wild-type enzyme. It remains unclear why these two positions have more importance for T. californica AChE than for mouse AChE.
Mol Pharmacol 2000 Jun
PMID:Inactivation studies of acetylcholinesterase with phenylmethylsulfonyl fluoride. 1082 96

Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.
J Mol Neurosci
PMID:Synaptogenesis and myopathy under acetylcholinesterase overexpression. 1085 41


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