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)

The distribution of acetylcholinesterase activity in human Meibomian glands was evaluated using enzyme-histochemical methods. The butyrylcholinesterase (BuChE) inhibitor, tetraisopropyl pyrophosphoramide (iso-OMPA), was used to localize acetylcholinesterase (AChE) activity, the AChE inhibitor, 1,5-bis (4-allyldimethylammoniumphenyl) pentan-3-one dibromide (BW284c51), was used to localize BuChE activity, and eserine was used to inhibit all cholinesterase activity in control incubations; the appropriate specific inhibitors for competing enzymic activities were added to the incubation medium. At the light microscopic level, acetylcholinesterase reaction product appeared as cytoplasmic brown deposits, often crystalline. A very dense accumulation of AChE-positive nerve fibers was seen in the form of a network around the acinar and the ductal tissue of the glands. No discrete nerve endings were observed, whereas a strong reaction was elicited in some fibers in close association with blood vessels. These observations suggest that the cholinergic system is involved in the regulation of the Meibomian glands secretory function.
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PMID:Histochemical demonstration of acetylcholinesterase activity in human Meibomian glands. 874 Oct 98

1. Human isolated pulmonary vessels were treated with cholinesterase (ChE) inhibitors to determine the role of these enzymes in regulating vascular muscle tone. In addition, kinetic parameters were determined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in human pulmonary vessel homogenates. 2. Carbachol (CCh) and acetylcholine (ACh) were equipotent contractile agonists in human pulmonary arteries (pD2 values, 5.28 +/- 0.05 and 5.65 +/- 0.16; Emax, 0.91 +/- 0.26 and 0.98 +/- 0.30 g wt. for CCh and ACh, respectively; n = 7). In venous preparations, ACh was ineffective and CCh induced small contractions (Emax, 0.08 +/- 0.04 g wt; n = 13). 3. In human pulmonary arteries following pretreatment with tetraisopropylpyrophosphoramide (iso-OMPA, 100 microM), an increased sensitivity to the contractile agonist ACh was observed (pD2 values, 5.80 +/- 0.13 and 6.37 +/- 0.19 for control and treated preparations, respectively; n = 5). This pretreatment had no effect on the CCh concentration response curve. In contrast, human pulmonary veins pretreated with iso-OMPA failed to elicit a contractile response to ACh. 4. Neither Iso-OMPA nor neostigmine elicited concentration-dependent contractions in human isolated pulmonary arteries or veins. These results suggest the absence of sufficient spontaneous release of ACh to modulate human pulmonary vessel basal tone. 5. CCh was less potent than ACh in relaxing precontracted human isolated pulmonary arteries (pD2 value, CCh: 6.55 +/- 0.15 and ACh: 7.16 +/- 0.13, n = 4) and veins (pD2 value, CCh: 4.95 +/- 0.13; n = 5 and ACh: 5.56 +/- 0.17; n = 6). Pretreatment of vessels with either iso-OMPA or neostigmine did not modify ACh relaxant responses in either type of preparation. 6. In human pulmonary veins, the ChE activity was two fold greater than in arteries (n = 6). Vmax for AChE was 1.73 +/- 0.24 and 3.36 +/- 0.26 miu mg-1 protein in arteries and veins, respectively, whereas Vss for BChE was 1.83 +/- 0.22 and 4.71 +/- 0.17 miu mg-1 protein, in these respectively. 7. In human pulmonary arteries, BChE activity may play a role in the smooth muscle contraction but not on the smooth muscle endothelium-dependent relaxation induced by ACh. A role for ChE activity in the control of venous tone is presently difficult to observe, even though this tissue contains a greater amount of enzyme than the artery.
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PMID:Cholinesterase activity in human pulmonary arteries and veins. 922 57

Asp-70 is the defining amino acid in the peripheral anionic site of human butyrylcholinesterase (BuChE), whereas acetylcholinesterase has several additional amino acids, the most important one being Trp-277 (Trp-279 in Torpedo AChE). We studied mutants D70G, D70K and A277W to evaluate the role of Asp-70 and Trp-277 in reactions with organophosphates. We found that Asp-70 was important for binding positively charged echothiophate, but not neutral paraoxon and iso-OMPA. Asp-70 was also important for binding of positively charged pralidoxime (2-PAM) and for activation of re-activation by excess 2-PAM. Excess 2-PAM had an effect similar to substrate activation, suggesting the binding of 2 mol of 2-PAM to wild-type but not to the D70G mutant. A surprising result was that Asp-70 was important for irreversible aging, the D70G mutant having a 3- and 8-fold lower rate of aging for paraoxon-inhibited and di-isopropyl fluorophosphate-inhibited BuChE. Mutants of Asp-70 had the same rate constants for phosphorylation and re-activation by 2-PAM as wild-type. The A277W mutant behaved like wild-type in all assays. Our results predict that people with the atypical (D70G) variant of BuChE will be more sensitive to the toxic effects of echothiophate, but will be equally sensitive to paraoxon and di-isopropyl fluorophosphate. People with the D70G mutation will be resistant to re-activation of their inhibited BuChE by 2-PAM, but this will be offset by the lower rate of irreversible aging of inhibited BuChE, allowing some regeneration by spontaneous hydrolysis.
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PMID:Importance of aspartate-70 in organophosphate inhibition, oxime re-activation and aging of human butyrylcholinesterase. 922 29

Physostigmine, a powerful cholinesterase inhibitor, has recently been labelled with 11C in view of its potential application for in vivo imaging of cerebral acetylcholinesterase (AChE) using positron emission tomography. Here we carried out autoradiography of the rat brain using [11C]physostigmine in order to characterize the cerebral targets of this ligand. Autoradiograms were obtained using phosphor storage plates which, compared to autoradiographic films, greatly improved the quality of 11C images. Following autoradiography, brain sections were stained for AChE activity, allowing a direct comparison of autoradiographic and histoenzymatic localizations. The distributions of 11C label and of AChE activity were found to be essentially super-imposable, both after in vivo injection of and after in vitro incubation with [11C]physostigmine. Densitometric analysis showed that radioactivity and enzymatic activity distributions were regionally correlated. The fixation of [11C]physostigmine to cerebral tissue was abolished after incubation of the rat brain sections with BW 284C51, a specific AChE inhibitor, but not after incubation with iso-OMPA, a specific inhibitor of butyrylcholinesterase. Unilateral excitotoxic lesions of the striatum that eliminated local AChE expression concomitantly reduced the binding of the ligand in the lesioned area. These results indicate that autoradiographic images of the rat brain obtained with [11C]physostigmine reflect AChE distribution, thus supporting the use of this radioligand to trace cerebral AChE activity in humans with positron emission tomography.
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PMID:Rat brain acetylcholinesterase visualized with [11C]physostigmine. 934 68

In the annelid polychaete Spirographis spallanzanii two acetylcholinesterases, named DS and HSDS, were detected. They differ in relative amount, membrane anchoring and pharmacological properties. Studies with inhibitors evidenced complete inhibition of both acetylcholinesterases by 10(-3) M eserine and different sensitivities for edrophonium or procainamide. Both enzymes, sensitive to BW284c51, were unaffected by iso-OMPA; at variance, only the HSDS form underwent excess-substrate inhibition. DS and HSDS enzymes were solubilized by homogenization in a low-salt or high-salt-Triton X-100 buffer and then purified by affinity chromatography on edrophonium- or procainamide-Sepharose column respectively. According to gel-filtration chromatography, sedimentation analysis and SDS-PAGE, the least represented (30%) DS form is a G2 amphiphilic globular dimer (124-130 kDa, 6.0-7.0S) with S-S linked monomers (66 kDa). Phosphatidylinositol anchors give cell membrane insertion, self-aggregation and detergent (Triton X-100, Brij 97) interaction. The prevailing (70%) HSDS acetylcholinesterase is once again a G2 form similar to DS enzyme in its molecular size (117-125 kDa), sedimentation coefficient (6.0S) of the native form and presence of S-S linked subunits (66 kDa). However, it is likely attached to the cell membrane by involvement of strong electrostatic interactions. DS acetylcholinesterase displays moderate active site specificity with differently sized substrates. The HSDS form is inactive on butyrylthiocholine. DS and HSDS forms show a comparable catalytic efficiency (kcat/K(m)) approaching that of other invertebrate enzymes. The results suggest that DS and HSDS enzymes, likely encoded by distinct genes, are both functional in cholinergic synapses.
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PMID:Acetylcholinesterase in Spirographis spallanzanii (Polychaeta: Sedentaria): presence of two dimeric membrane-bound forms. 935 89

The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA.
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PMID:Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease. 963 11

The contribution of carboxylesterase (CarbE) to the development of tolerance to the organophosphorus anticholinesterase (OP-ANTIChE) paraoxon (diethyl p-nitrophenyl phosphate) was investigated in rats. Daily injections (20 days) of paraoxon (0.09 mg/kg) led to a cumulative dose that was 9.0-fold higher than the acute ED50 of 0.20 mg/kg, s.c. During this period, the rats did not demonstrate visible signs of cholinergic hyperactivity nor did they die, despite the persistence of critically reduced brain acetylcholinesterase (AChE) activity (20-30% of control). In addition, none of these rats died following the administration of a dose of carbachol (3.1 mg/kg, i.p.) that was an LD90 in untreated rats. Daily treatment with the CarbE inhibitors CBDP [2-(o-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide] (2 mg/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (3 mg/kg, i.p.) followed by paraoxon (0.09 mg/kg, s.c.) 60 min later prevented the development of tolerance to paraoxon, since signs of cholinergic hyperactivity were observed and rats died on day 4 of the combined treatment. In tolerant rats, one-time CBDP or iso-OMPA pretreatment increased toxicity to paraoxon, causing the death of all rats within 60 min. The increase in paraoxon toxicity was correlated with inhibition of a plasma CarbE, with high affinity toward alpha-naphthyl acetate (alpha-NA) and to the inhibitors CBDP, iso-OMPA, and paraoxon. Inhibition of a plasma CarbE with high affinity toward p-nitrophenyl acetate (p-NPA) and low affinity to the above inhibitors did not potentiate paraoxon toxicity significantly. Neither the liver CarbEs, which showed high affinity to iso-OMPA, nor the inhibition of butyrylcholinesterase (BuChE) by iso-OMPA in plasma and liver potentiated paraoxon toxicity. By eliminating plasma CarbE (alpha-NA) as potential binding sites for paraoxon with either CBDP or iso-OMPA, paraoxon can exert its toxicity to a greater extent at its specific target site, the functionally important AChE at cholinergic synapses. It is concluded that plasma CarbE (alpha-NA) provided a significant protection against paraoxon intoxication and that the inhibition of this enzyme prevented the tolerance development seen with repeated paraoxon treatments.
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PMID:Prevention of tolerance to the organophosphorus anticholinesterase paraoxon with carboxylesterase inhibitors. 1007 34

In peripheral nerves, the function of acetylcholinesterase (AChE) is not related to hydrolysis of acetylcholine. To test for a trophic role, AChE or its inhibitors were administered locally to normal and regenerating nerves of rats. In the normal nerve, neither AChE nor serum albumin affected the cytological pattern of the nerve. BW284c51, a specific inhibitor of AChE, resulted in demyelination, proliferation of Schwann cells and sprouting of axons after 5-7 days. Edrophonium or propidium, other specific inhibitors of AChE, did so to a much lesser extent. Vehicle, and iso-OMPA (inhibitor of pseudocholinesterases) did not affect the cytology of the nerve. Elongation of regenerating axons was evaluated at day 3 post-crush. Native AChE applied distal to the crush reduced the elongation of regenerating axons (- 36%), while serum albumin, heated AChE and filtered AChE did not. BW284c51, edrophonium or propidium enhanced the axonal elongation (33%) when they were administered for 2 days before, but not after, the crush. Iso-OMPA or vehicle administered before or after the crush were not effective. Thus, AChE reduces elongation of regenerating axons, while inhibition of AChE enhances elongation and affects the cytology of the normal nerve as well. We propose that AChE has a trophic role in mammalian peripheral nerves.
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PMID:Acetylcholinesterase and inhibitors: effects upon normal and regenerating nerves of the rat. 1010 97

An inhibitor-free assay for the simultaneous determination of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the cerebrospinal fluid (CSF) is described. It is based on our finding that the individual activity ratios of BChE on both its substrates acetylthiocholine (ACh) and butyrylthiocholine (BCh) in the CSF and in the parallel serum are identical under conditions of at least 5 mmol/l substrate concentration (Q(BChE)SE = Q(BChe)CSF). Considering that AChE only reacts with ACh as substrate and occurs with negligible activities in the serum, the measured individual activity ratio of BChE in the serum (Q(BChE)SE) and the total hydrolysis rate of ACh and BCh in the CSF do allow a precise calculation of the AChE activity in the cerebrospinal fluid. The derivation of the corresponding formula is demonstrated in detail. The inhibitor-free assay was compared with procedures using cholinesterase inhibitors (BW284c51 for AChE and/or iso-OMPA for BChE). Achieving widely identical results in particular between the procedure using the AChE inhibitor and the inhibitor-free test, the latter has decisive advantages: (1) it avoids the use of highly toxic inhibitors, (2) it minimizes the test volume needed, (3) it characterizes additionally the status of the blood-CSF barrier by means of the BChE activity ratio in the CSF and in the parallel serum.
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PMID:An inhibitor-free assay of acetylcholinesterase and butyrylcholinesterase in the cerebrospinal fluid. 1034 Apr 41

1. In human blood, heroin is rapidly hydrolysed by sequential deacylation of two ester bonds to yield first 6-monoacetylmorphine (6-MAM), then morphine. 2. Serum butyrylcholinesterase (BuChE) hydrolyses heroin to 6-MAM with a catalytic efficiency of 4.5/min per mumol/L, but does not proceed to produce morphine. 3. In vitro, human erythrocyte acetylcholinesterase (AChE) hydrolyses heroin to 6-MAM, with a catalytic efficiency of 0.5/min per mumol/L under first-order kinetics. Moreover, erythrocyte AChE, but not BuChE is capable of further hydrolysing 6-MAM to morphine, albeit at a considerably slower rate. 4. Both hydrolysis steps by erythrocyte AChE were totally blocked by the selective AChE inhibitor BW284c51 but were not blocked by the BuChE-specific inhibitor, iso-OMPA (tetraisopropylpyrophosphoramide). 5. The brain synaptic form of AChE, which differs from the erythrocyte enzyme in its C-terminus, was incapable of hydrolysing heroin. 6. Heroin suppressed substrate hydrolysis by antibody-immobilized erythrocyte but not by brain AChE. 7. These findings reveal a new metabolic role for erythrocyte AChE, the biological function of which is as yet unexplained, and demonstrate distinct biochemical properties for the two AChE variants, which were previously considered catalytically indistinguishable.
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PMID:Human erythrocyte but not brain acetylcholinesterase hydrolyses heroin to morphine. 1047 72


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