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)

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

The ability of acetylcholinesterase from fetal bovine serum (FBS AChE) to protect against soman, a highly toxic organophosphorus (OP) compound, was tested in rhesus monkeys. Intravenous administration of FBS AChE produced a minimal behavioral effect on the serial probe recognition task, a sensitive test of cognitive function and short-term memory. Pharmacokinetic studies of injected FBS AChE indicated a plasma half-life of 40 hr for FBS AChE in monkeys. Both in vitro and in vivo titration of FBS AChE with soman produced a 1:1 stoichiometry between organophosphate-inhibited FBS AChE and the cumulative dose of the toxic stereoisomers of soman. Administration of FBS AChE protected monkeys against the lethal effects of up to 2.7 LD50 of soman and prevented any signs of organophosphate intoxication, e.g., excessive secretions, respiratory depression, muscle fasciculations, or convulsions. In addition, monkeys pretreated with FBS AChE were devoid of any behavioral incapacitation after soman challenge, as measured by the serial probe recognition task. Compared to the current multicomponent drug treatment against soman, which does not prevent the signs or the behavioral deficits resulting from OP intoxication, use of FBS AChE as a single pretreatment drug provides significantly effective protection against both the lethal and the behavioral effects of soman.
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PMID:Protection of rhesus monkeys against soman and prevention of performance decrement by pretreatment with acetylcholinesterase. 163 92

Kinetic constants for selected phosphonate and phosphinate inhibitors of fetal bovine serum acetylcholinesterase (FBS AChE; EC 3.1.1.7), bovine caudate nucleus AChE (BCN AChE), and eel AChE have been determined. Oxime reactivation of the phosphylated enzymes has also been evaluated. In general, a rank order with respect to organophosphorus compound (OP) inhibition of the enzymes was observed: soman (pinacolyl methylphosphonofluoridate) was found to be the most potent inhibitor, and 4-nitrophenyl methyl(phenyl)phosphinate (PMP) the least potent. On average the bimolecular rate constant for soman inhibition of eel AChE was nearly twofold greater (9.3 x 10(7) M-1 s-1) than that for FBS AChE (5.5 x 10(7) M-1 s-1) and nearly fourfold greater than that for BCN AChE (2.2 x 10(7) M-1 s-1). In addition, 4-nitrophenyl chloromethyl(phenyl)phosphinate (CPMP) inhibition of eel AChE on average was nearly 10-fold greater than FBS AChE and three orders of magnitude greater than BCN AChE. The oxime HI-6 reactivated soman phosphonylated enzymes to a considerably greater extent than other oximes, and FBS AChE was notably more responsive to HI-6 than to other oximes. The individual mean values of the ki for each inhibitor in each class (phosphonate or phosphinate) were different with respect to each AChE, which may be a reflection of differences in enzyme configuration, whereas the general rank order of inhibitor potency within each class, reflected by the ki, was similar with respect to each AChE, which may be related to similar active centers. In general, oxime potency and some rank order varied with each inhibitor and with each AChE, although there was some similarity in oxime rank order between the two mammalian AChEs. Overall, the data support the selection of FBS AChE as the enzyme of choice for in vitro testing of OP inhibitors and reactivators.
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PMID:Phosphylation kinetic constants and oxime-induced reactivation in acetylcholinesterase from fetal bovine serum, bovine caudate nucleus, and electric eel. 189 Jun 90

The complete amino acid sequence of a mammalian acetylcholinesterase from fetal bovine serum (FBS AChE) is presented. This enzyme has a high degree of sequence identity with other cholinesterases, liver carboxyesterases, esterase-6, lysophospholipase, and thyroglobulin. The locations of 191 amino acids in 10 regions of the FBS enzyme were compared with corresponding sequences of Torpedo, human, and Drosophila AChEs and human serum butyrylcholinesterase (BChE). In one region there is a marked difference in both the number of amino acids and their sequence between mammalian AChE and other AChEs and the human serum BChE. The amino acid sequence of FBS AChE showed overall homologies of 90% with human AChE, 60% with T. california AChE, 50% with human serum BChE, and 39% with Drosophila AChE in these regions.
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PMID:Complete amino acid sequence of fetal bovine serum acetylcholinesterase and its comparison in various regions with other cholinesterases. 236 60

The monoclonal antibody (mAb) AE-2 decreases the rate of hydrolysis of acetylthiocholine (ATC) by fetal bovine serum acetylcholinesterase (acetylcholine acetylhydrolase EC 3.1.1.7) (FBS-AChE) (Doctor, B.P. et al. (1989) Proc. 32nd Oholo Conf., Eilat, Israel, in press), but increases the rate of hydrolysis (Vmax) of the nonpolar substrate, indophenyl acetate (IPA) approx. 15-fold. The affinity (Km) of FBS-AChE for IPA changes minimally in comparison with the increase in the rate of hydrolysis. The complex is dissociated, and the modulation of substrate hydrolysis is reversed by the active-center ligand, 1-methyl-2-hydroxyiminomethylpyridinium chloride (2-PAM).
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PMID:The monoclonal antibody AE-2 modulates fetal bovine serum acetylcholinesterase substrate hydrolysis. 276 60

Fetal bovine serum acetylcholinesterase (FBS-AChE, EC 3.1.1.7) was titrated, both in vitro and in vivo, with a highly toxic anti-ChE organophosphate, 7-(methylethoxyphosphinyloxy)-1-methyl-quinolinium iodie (MEPQ). Approximately 1:1 stoichiometry was obtained for the sequestration of MEPQ by FBS-AChE in mice. A quantitative, linear correlation was demonstrated between blood-AChE levels and the protection afforded by exogenously administered AChE in mice when challenged with anti-ChE MEPQ. The results presented in this report demonstrate that such prophylactic measures are indeed sufficient to protect animals against poisoning by as high as an 8 x LD50 dose of organophosphate without the administration of any supportive drug. Despite the relatively large toxic dose, most of the mice that survived the challenge did not show any classical clinical signs of severe anti-ChE poisoning. MEPQ may be considered a suitable model compound for studying the quantitative aspects of the scavenger prophylactic approach described here.
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PMID:Acetylcholinesterase prophylaxis against organophosphate poisoning. Quantitative correlation between protection and blood-enzyme level in mice. 291 10

Fetal bovine serum acetylcholinesterase (FBS-AChE) protected mice from multiple LD50 doses of organophosphorus (OP) nerve agents. Mice were injected intraperitoneally (ip) with up to 3.3 mg (11,000 U) of FBS-AChE which exhibited a relatively long serum half-life and appeared well tolerated. The enzyme protected mice from the OP ethyl-S-2-diisopropylamino-ethylmethylphosphonothiolate (VX) with a stoichiometry equal to approximately 2 moles of enzyme active site per mole of VX. FBS-AChE, at a lower enzyme OP ratio, protected mice from 2 LD50s of the nerve agent methylphosphonofluoridic acid 1,2,2,-trimethylpropyl ester (soman) when used in conjunction with atropine and 2[(hydroxyimino)methyl]-1-methylpyridinium chloride. It is concluded that sequestration of highly toxic OPs by administration of AChE occurs in mice and suggests a new approach to treatment of OP intoxication.
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PMID:Acetylcholinesterase prophylaxis against organophosphate toxicity. 365 68

Both propidium and monoclonal antibody (mAb) 25B1 bind to the peripheral anionic site region of fetal bovine serum acetylcholinesterase (FBS AChE). Using electron paramagnetic resonance (EPR) with spin-labelled organophosphate specifically bound to the AChE active-site serine, we studied the effects of both ligands on the topography of the AChE active-site gorge. After incubation of FBS AChE with Fab fragments of mAb 25B1, freedom of motion of our spin label became more restricted, suggesting closing of the gorge. Stabilization against heat denaturation was also observed. No alterations in the freedom of motion or protection against heat denaturation could be detected after propidium binding. Our results demonstrate that two ligands binding to the peripheral anionic site region of AChE have different effects, suggesting a complex structure for this region of the molecule that allows various types of interactions with different ligands. We also demonstrate that EPR is a suitable tool for studying microtopographical alterations at the active sites of cholinesterases.
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PMID:Different effects of two peripheral anionic site-binding ligands on acetylcholinesterase active-site gorge topography revealed by electron paramagnetic resonance. 759 68

Pretreatment of rhesus monkeys with fetal bovine serum acetylcholinesterase (FBS AChE) provides complete protection against 5 LD50 of organophosphate (OP) without any signs of toxicity or performance decrements as measured by serial probe recognition tests or primate equilibrium platform performance (Maxwell et al., Toxicol Appl Pharmacol 115: 44-49, 1992; Wolfe et al., Toxicol Appl Pharmacol 117: 189-193, 1992). Although such use of enzyme as a single pretreatment drug for OP toxicity is sufficient to provide complete protection, a relatively large (stoichiometric) amount of enzyme was required in vivo to neutralize OP. To improve the efficacy of cholinesterases as pretreatment drugs, we have developed an approach in which the catalytic activity of OP-inhibited FBS AChE was rapidly and continuously restored, thus detoxifying the OP and minimizing enzyme aging by having sufficient amounts of appropriate oxime present. The efficacy of FBS AChE to detoxify several OPs was amplified by addition of bis-quaternary oximes, particularly 1-(2-hydroxyiminomethyl-1-pyridinium)-1-(4-carboxyaminopyridinium) -dimethyl ether hydrochloride (HI-6). When mice were pretreated with sufficient amounts of FBS AChE and HI-6 and challenged with repeated doses of O-isopropyl methylphosphonofluridate (sarin), the OP was continuously detoxified so long as the molar concentration of the sarin dose was less than the molar concentration of AChE in circulation. The in vitro experiments showed that the stoichiometry of sarin:FBS AChE was higher than 3200:1 and in vivo stoichiometry with mice was as high as 57:1. Addition of HI-6 to FBS AChE as a pretreatment drug amplified the efficacy of enzyme as a scavenger of nerve agents.
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PMID:Amplification of the effectiveness of acetylcholinesterase for detoxification of organophosphorus compounds by bis-quaternary oximes. 830 79

Carbamate, oxime and enzyme scavenger approaches to protection against the highly toxic organophosphorus compound, soman, were compared by using the most prominent example of each type of antidote. Pyridostigmine in combination with atropine, HI-6 [1-(2-(hydroxyimino)methyl))pyridinium-2-(4-(aminocarbonyl)p yridinium) dimethylether] in combination with atropine and fetal bovine serum acetylcholinesterase (FBS-AChE) without atropine were used as examples of oxime, carbamate and enzyme scavenger antidotes, respectively. Each antidotal regimen produced approximately equal maximal protection against the lethal effects of 952 to 1169 nmol/kg (LD50, 8-10) of soman in mice whose carboxylesterase had been inhibited with 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide. FBS-AChE was much better than either pyridostigmine-atropine or HI-6-atropine in reducing postexposure incapacitation from soman as measured by lacrimation, motor dysfunction, activity level and the inverted screen test. A lower dose of pyridostigmine (566 nmol/kg) or FBS-AChE (1150 nmol/kg) was required to protect against 968 nmol/kg (LD50, 8) of soman than was required for HI-6 (200,000 nmol/kg). Inasmuch as the in vivo biological half-life of FBS-AChE (1550 min) was much greater than the biological half-lives of pyridostigmine (48 min) or HI-6 (11 min), the ability of FBS-AChE to produce better protection against the postexposure incapacitation from soman suggests that it should be considered as an alternative to either pyridostigmine-atropine or HI-6-atropine antidotal regimens.
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PMID:Comparison of antidote protection against soman by pyridostigmine, HI-6 and acetylcholinesterase. 845 Apr 52


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