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Oksana Lockridge - One of the best experts on this subject based on the ideXlab platform.
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The proline-rich tetramerization peptides in equine serum Butyrylcholinesterase.
The FEBS journal, 2012Co-Authors: Kevser Biberoglu, Ozden Tacal, Lawrence M. Schopfer, Oksana LockridgeAbstract:Soluble, tetrameric, plasma Butyrylcholinesterase from horse has previously been shown to include a non-covalently attached polyproline peptide in its structure. The polyproline peptide matched the polyproline-rich region of human lamellipodin. Our goal was to examine the tetramer-organizing peptides of horse Butyrylcholinesterase in more detail. Horse Butyrylcholinesterase was denatured by boiling, thus releasing a set of polyproline peptides ranging in mass from 1173 to 2098 Da. The peptide sequences were determined by fragmentation in MALDI-TOF-TOF and linear ion trap quadrupole Orbitrap mass spectrometers. Twenty-seven polyproline peptides grouped into 13 families were identified. Peptides contained a minimum of 11 consecutive proline residues and as many as 21. Many of the peptides had a non-proline amino acid at the N-terminus. A search of the protein databanks matched peptides to nine proteins, although not all peptides matched a known protein. It is concluded that polyproline peptides of various lengths and sequences are included in the tetramer structure of horse Butyrylcholinesterase. The function of these polyproline peptides is to serve as tetramer-organizing peptides.
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Butyrylcholinesterase for protection from organophosphorus poisons; catalytic complexities and hysteretic behavior
Archives of biochemistry and biophysics, 2009Co-Authors: Patrick Masson, Oksana LockridgeAbstract:Butyrylcholinesterase is a promiscuous enzyme that displays complex kinetic behavior. It is toxicologically important because it detoxifies organophosphorus poisons (OP) by making a covalent bond with the OP. The OP and the Butyrylcholinesterase are both inactivated in the process. Inactivation of Butyrylcholinesterase has no adverse effects. However, inactivation of acetylcholinesterase in nerve synapses can be lethal. OP-inhibited Butyrylcholinesterase and acetylcholinesterase can be reactivated with oximes provided the OP has not aged. Strategies for preventing the toxicity of OP include (a) treatment with an OP scavenger, (b) reaction of non-aged enzyme with oximes, (c) reactivation of aged enzyme, (d) slowing down aging with peripheral site ligands, and (e) design of mutants that rapidly hydrolyze OP. Option (a) has progressed through phase I clinical trials with human Butyrylcholinesterase. Option (b) is in routine clinical use. The others are at the basic research level. Butyrylcholinesterase displays complex kinetic behavior including activation by positively charged esters, ability to hydrolyze amides, and a lag time (hysteresis) preceding hydrolysis of benzoylcholine and N-methylindoxyl acetate. Mass spectrometry has identified new OP binding motifs on tyrosine and lysine in proteins that have no active site serine. It is proposed, but not yet proven, that low dose exposure involves OP modification of proteins that have no active site serine.
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Carbamates with differential mechanism of inhibition toward acetylcholinesterase and Butyrylcholinesterase.
Journal of medicinal chemistry, 2008Co-Authors: Darvesh, Oksana Lockridge, Robert S. Mcdonald, Katherine V. Darvesh, Diane Mataija, Ryan Walsh, Sam Mothana, Earl MartinAbstract:Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of Butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to π−π interaction of the phenothiazine moiety with F329 and Y332 in Butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of Butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the Butyrylcholinesterase active site gorge, such as the peripheral anionic site and the π-cationic site of the Ω-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dem...
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acetylcholinesterase knockouts establish central cholinergic pathways and can use Butyrylcholinesterase to hydrolyze acetylcholine
Neuroscience, 2002Co-Authors: Marsel M Mesulam, Angela L Guillozet, Pamela L Shaw, Andrew S Levey, Ellen G Duysen, Oksana LockridgeAbstract:Abstract Acetylcholinesterase is one of the most prominent constituents of central cholinergic pathways. It terminates the synaptic action of acetylcholine through hydrolysis and yields the choline moiety that is necessary for transmitter recycling. Despite these pivotal relationships, mice nullizygous for acetylcholinesterase established all principal anatomical components of central cholinergic pathways. No compensatory increase in the distribution of Butyrylcholinesterase was detected. However, both the wild-type and nullizygous mice showed that Butyrylcholinesterase enzyme activity extended to all parts of the brain receiving cholinergic innervation and that it could hydrolyze the acetylcholine surrogate acetylthiocholine. As opposed to acetylcholinesterase which was mostly of neuronal origin, Butyrylcholinesterase appeared to be mostly of glial origin. These experiments lead to the unexpected conclusion that acetylcholinesterase is not necessary for the establishment of cholinergic pathways. They also show that Butyrylcholinesterase can potentially substitute for acetylcholinesterase and that this enzyme is likely to play a constitutive (rather than just back-up) role in the hydrolysis of acetylcholine in the normal brain. The inhibition of Butyrylcholinesterase may therefore provide a desirable feature of cholinergic therapies, including those aimed at treating Alzheimer’s disease.
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Endogenous Butyrylcholinesterase in SV40 transformed cell lines: COS-1, COS-7, MRC-5 SV40, and WI-38 VA13
In Vitro Cellular & Developmental Biology - Animal, 1994Co-Authors: Morena Kris, Omar Jbilo, Cynthia F. Bartels, Patrick Masson, Solon Rhode, Oksana LockridgeAbstract:Comparison of proteins expressed by SV40 transformed cell lines and untransformed cell lines is of interest because SV40 transformed cells are immortal, whereas untransformed cells senesce after about 50 doublings. In MRC-5 SV40 cells, only seven proteins have previously been reported to shift from undetectable to detectable after transformation by SV40 virus. We report that Butyrylcholinesterase is an 8th protein in this category. Butyrylcholinesterase activity in transformed MRC-5 SV40 cells increased at least 150-fold over its undetectable level in MRC-5 parental cells. Other SV40 transformed cell lines, including COS-1, COS-7, and WI-38 VA13, also expressed endogenous Butyrylcholinesterase, whereas the parental, untransformed cell lines, CV-1 and WI-38, had no detectable Butyrylcholinesterase activity or mRNA. Infection of CV-1 cells by SV40 virus did not result in expression of Butyrylcholinesterase, showing that the Butyrylcholinesterase promoter was not activated by the large T antigen of SV40. We conclude that Butyrylcholinesterase expression resulted from events related to cell immortalization and did not result from activation by the large T antigen.
Changiz Geula - One of the best experts on this subject based on the ideXlab platform.
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Rivastigmine is a potent inhibitor of acetyl- and Butyrylcholinesterase in Alzheimer's plaques and tangles.
Brain research, 2005Co-Authors: Mariam F Eskander, Nicholas G Nagykery, Elaine Y Leung, Bahiyyih Khelghati, Changiz GeulaAbstract:Acetylcholinesterase and Butyrylcholinesterase activities emerge in association with plaques and tangles in Alzheimer's disease. These pathological cholinesterases, with altered properties, are suggested to participate in formation of plaques. The present experiment assessed the ability of rivastigmine, a clinically utilized agent that inhibits acetylcholinesterase and Butyrylcholinesterase activities, to inhibit cholinesterases in plaques and tangles. Cortical sections from cases of Alzheimer's disease were processed using cholinesterase histochemistry in the presence or absence of rivastigmine. Optical densities of stained sections were utilized as a measure of inhibition. The potency of rivastigmine was compared with those of other specific inhibitors. Optimum staining for cholinesterases in neurons and axons was obtained at pH 8.0. Cholinesterases in plaques, tangles and glia were stained best at pH 6.8. Butyrylcholinesterase-positive plaques were more numerous than acetylcholinesterase-positive plaques. Rivastigmine inhibited acetylcholinesterase in all positive structures in a dose-dependent manner (10(-6)-10(-4) M). However, even at the highest concentration, faint activity remained. In contrast, rivastigmine resulted in complete inhibition of Butyrylcholinesterase in all structures at 10(-5) M. Rivastigmine was equipotent to the specific acetylcholinesterase inhibitor BW284C51 and more potent than the Butyrylcholinesterase inhibitors iso-OMPA and ethopropazine. In conclusion, rivastigmine is a potent inhibitor of acetylcholinesterase and a more potent inhibitor of Butyrylcholinesterase in plaques and tangles. Unlike other cholinesterase inhibitors tested, rivastigmine inhibited cholinesterases in normal and pathological structures with the same potency. Thus, at the therapeutic concentrations used, rivastigmine is likely to result in inhibition of pathological cholinesterases, with the potential of interfering with the disease process.
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Butyrylcholinesterase, cholinergic neurotransmission and the pathology of Alzheimer's disease.
Drugs of today (Barcelona Spain : 1998), 2004Co-Authors: Changiz Geula, DarveshAbstract:Butyrylcholinesterase is a serine hydrolase biochemically related to the cholinergic enzyme acetylcholinesterase. It is capable of hydrolyzing esters of choline. Butyrylcholinesterase has unique enzymatic properties and is widely distributed in the nervous system, raising the possibility of its involvement in neural function. In particular, recent evidence indicates that along with acetylcholinesterase, Butyrylcholinesterase catalyzes the hydrolysis of acetylcholine, and thus serves as a co-regulator of cholinergic transmission. Accumulating evidence also indicates that Butyrylcholinesterase is likely to be involved in neurodegenerative disorders such as Alzheimer's disease. Therefore, inhibition of Butyrylcholinesterase will not only lead to enhanced cholinergic transmission but also has the potential to interfere with the disease process in Alzheimer's disease and other dementing disorders.
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neurobiology of Butyrylcholinesterase
Nature Reviews Neuroscience, 2003Co-Authors: Sultan Darvesh, David A Hopkins, Changiz GeulaAbstract:Butyrylcholinesterase is a serine hydrolase related to acetylcholinesterase that catalyses the hydrolysis of esters of choline, including acetylcholine. Butyrylcholinesterase has unique enzymatic properties and is widely distributed in the nervous system, pointing to its possible involvement in neural function. Here, we summarize the biochemical properties of Butyrylcholinesterase and review the evidence that this enzyme has important roles in cholinergic neurotransmission and could be involved in other nervous system functions and in neurodegenerative diseases.
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Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia
Annals of neurology, 1994Co-Authors: M.-marsel Mesulam, Changiz GeulaAbstract:In a sample of consecutively received, 4 demented and 4 age-matched nondemented brains, the total cortical area covered by plaque-like A beta amyloid and Butyrylcholinesterase deposits was measured at two regions of the temporal cortex with the help of computed densitometry. Demented as well as age-matched nondemented brains contained A beta and Butyrylcholinesterase-positive plaques. The total cortical area covered by the A beta precipitates was higher in demented individuals but there was overlap with the values seen in the specimens from nondemented individuals. The proportional plaque area displaying Butyrylcholinesterase reactivity was very significantly and five fold to sixfold higher in the demented than in the nondemented group and there was no overlap between the two populations. Diffuse A beta deposits in nondemented elderly brains may represent a benign or preclinical stage of plaque deposition with relatively little pathological effect on brain tissue and mental function. Our results suggest that the progressively more extensive Butyrylcholinesterase reactivity of plaques may participate in their transformation from a relatively benign form to pathogenic structures associated with neuritic degeneration and dementia.
Earl Martin - One of the best experts on this subject based on the ideXlab platform.
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Carbamates with differential mechanism of inhibition toward acetylcholinesterase and Butyrylcholinesterase.
Journal of medicinal chemistry, 2008Co-Authors: Darvesh, Oksana Lockridge, Robert S. Mcdonald, Katherine V. Darvesh, Diane Mataija, Ryan Walsh, Sam Mothana, Earl MartinAbstract:Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of Butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to π−π interaction of the phenothiazine moiety with F329 and Y332 in Butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of Butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the Butyrylcholinesterase active site gorge, such as the peripheral anionic site and the π-cationic site of the Ω-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dem...
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Selective reversible inhibition of human Butyrylcholinesterase by aryl amide derivatives of phenothiazine.
Bioorganic & medicinal chemistry, 2007Co-Authors: Darvesh, Robert S. Mcdonald, Katherine V. Darvesh, Diane Mataija, Sarah Conrad, Geraldine Gomez, Ryan Walsh, Earl MartinAbstract:Abstract Evidence suggests that specific inhibition of Butyrylcholinesterase may be an appropriate focus for the development of more effective drugs to treat dementias such as Alzheimer’s disease. Butyrylcholinesterase is a co-regulator of cholinergic neurotransmission and its activity is increased in Alzheimer’s disease, and is associated with all neuropathological lesions in this disease. Some selective Butyrylcholinesterase inhibitors have already been reported to increase acetylcholine levels and to reduce the formation of abnormal amyloid found in Alzheimer’s disease. Synthesized N -(10)-aryl and N -(10)-alkylaryl amides of phenothiazine are specific inhibitors of Butyrylcholinesterase. In some cases, inhibition constants in the nanomolar range are achieved. Enzyme specificity and inhibitor potency of these molecules can be related to molecular volumes, steric and electronic factors. Computed log P values indicate high potential for these compounds to cross the blood–brain barrier. Use of such Butyrylcholinesterase inhibitors could provide direct evidence for the importance of this enzyme in the normal nervous system and in Alzheimer’s disease.
Valdeci J Pomblum - One of the best experts on this subject based on the ideXlab platform.
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Butyrylcholinesterase activity is reduced in haemodialysis patients: is there association with hyperhomocysteinemia and/or oxidative stress?
Clinical biochemistry, 2008Co-Authors: Solange C Garcia, Angela T S Wyse, Juliana Valentini, Miguel Roehrs, Angela M Moro, Clóvis Paniz, Gabriela Schmitt, Denise Grotto, Valdeci J PomblumAbstract:To quantify serum Butyrylcholinesterase activity in haemodialysis patients and to evaluate if the homocysteine levels and/or oxidative stress biomarkers have an effect on Butyrylcholinesterase. Blood samples were collected from patients and healthy subjects (control). The plasma homocysteine and TBARS levels; serum Butyrylcholinesterase activity; blood delta aminolevulinic acid dehydratase (ALA-D) activity and methahaemoglobin were analyzed. The mortality of the patients was also evaluated after 3 years. The homocysteine was increased and Butyrylcholinesterase decreased compared to control (p<0.05). TBARS and methahaemoglobin were increased and ALA-D decreased (p<0.05). The following correlations were found: homocysteine with Butyrylcholinesterase (-0.44); methahaemoglobin (0.41); ALA-D (-0.68); and TBARS (0.66). The partial correlation between homocysteine with Butyrylcholinesterase, withdrawn the effect of TBARS, was -0.30; all p<0.05. Moreover, it was observed that 22% of the patients died due to cardiovascular problems. Thus, our findings support a direct association between the reduction of Butyrylcholinesterase by the increase of homocysteine and an indirect effect by increase in oxidative stress.
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Butyrylcholinesterase activity is reduced in haemodialysis patients: is there association with hyperhomocysteinemia and/or oxidative stress?
Clinical Biochemistry, 2008Co-Authors: Solange C Garcia, Angela T S Wyse, Juliana Valentini, Miguel Roehrs, Angela M Moro, Clóvis Paniz, Denise Grotto, Gabriela Cristina Schmitt, Valdeci J PomblumAbstract:Objectives: To quantify serum Butyrylcholinesterase activity in haemodialysis patients and to evaluate if the homocysteine levels and/or oxidative stress biomarkers have an effect on Butyrylcholinesterase. Materials and methods: Blood samples were collected from patients and healthy subjects (control). The plasma homocysteine and TBARS levels; serum Butyrylcholinesterase activity; blood δ aminolevulinic acid dehydratase (ALA-D) activity and methahaemoglobin were analyzed. The mortality of the patients was also evaluated after 3 years. Results: The homocysteine was increased and Butyrylcholinesterase decreased compared to control (p
Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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Why acetylcholinesterase reactivators do not work in Butyrylcholinesterase.
Journal of enzyme inhibition and medicinal chemistry, 2009Co-Authors: Jiří Wiesner, Daniel Jun, Kamil Kuca, Zdeněk Kříž, Jaroslav KočaAbstract:The pyridinium oxime therapy for treatment of organophosphate poisoning is a well established, but not sufficient method. Recent trends also focus on prophylaxis as a way of preventing even the entrance of organophosphates into the nervous system. One of the possible prophylactic methods is increasing the concentration of Butyrylcholinesterase in the blood with the simultaneous administration of Butyrylcholinesterase reactivators, when the enzyme is continuously reactivated by oxime. This article summarizes and sets forth the structural differences between Butyrylcholinesterase and acetylcholinesterase, essential for the future design of Butyrylcholinesterase reactivators. Butyrylcholinesterase lacks the reactivator aromatic binding pocket found in acetylcholinesterase, which is itself a part of the acetylcholinesterase peripheral anionic site. This difference finally renders the current acetylcholinesterase reactivators, when used in Butyrylcholinesterase, non-functional.
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In vitro reactivation of trichlorfon-inhibited Butyrylcholinesterase using HI-6, obidoxime, pralidoxime and K048
Journal of enzyme inhibition and medicinal chemistry, 2009Co-Authors: Miroslav Pohanka, Daniel Jun, Kamil KucaAbstract:Trichlorfon is a specific inhibitor of cholinesterases. It was typically used as an insecticide; however, trichlorfon was described as useful for symptomatic treatment of Alzheimer’s disease some years ago. The presented study is aimed at reactivation of trichlorfon-inhibited Butyrylcholinesterase since this enzyme play an important role in Alzheimer’s disease as deputy for acetylcholinesterase and furthermore it could be applied as a scavenger in case of overdosing. We used in vitro reactivation test for considering only reactivation efficacy of Butyrylcholinesterase that is inhibited by trichlorfon and not reactivation of Butyrylcholinesterase inhibited by trichlorfon metabolic products. Four reactivators were used: HI-6, pralidoxime, obidoxime, and K048. Although all of the reactivators seem to be effective at 1 mM concentration, a lower concentration was not able ensure sufficient reactivation. There was also an observed lowering of reactivation efficacy when Butyrylcholinesterase was exposed to trichlorfon for a longer time interval.
