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)

We have previously reported that the 10s molecular form (G4) of acetylcholinesterase (AChE) is selectively lost from several cortical areas of Alzheimer's disease (AD) brain. In the current follow-up study, we microdissected several areas of nondemented and AD brain, including the hippocampus, amygdala, and cingulate gyrus. Tissue homogenates were separated on sucrose density gradients and the resulting fractions were analyzed for AChE activity in order to define the ratios of the predominant AChE molecular forms (G4/G1). Both the hippocampus and amygdala exhibited distinct patterns of alterations in the G4/G1 ratio which correlate with the known distribution of histopathological changes in AD brain. In order to further define the major pool of AChE that is depleted in AD, we separated fractionated tissue homogenates into salt-soluble and detergent-soluble fractions. The G4/G1 ratios were only altered in the detergent-soluble fractions, indicating that the loss of the G4 AChE molecular form involves a selective depletion of the membrane pool. Available evidence would suggest that this form is the AChE molecular form physiologically relevant at the cholinergic synapse.
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PMID:Molecular forms of acetylcholinesterase in subcortical areas of normal and Alzheimer disease brain. 232 17

Chicken muscle and retina, and rat muscle asymmetric acetylcholinesterase (AChE) species were bound to immobilized heparin at 0.4 M NaCl. Binding efficiency was between 50 and 80% for crude fraction I A-forms (AI; muscle), and nearly 100% for fraction II A-forms (AII; muscle and retina). Antibody-affinity-purified AI-forms (chicken) were, however, quantitatively bound to heparin-agarose gels, whereas diisopropylfluorophosphate-inactivated high-salt extracts partially prevented the binding of both AI and AII AChE forms, thus suggesting the presence in crude AI extracts of heparin-like molecules interfering with the tail-heparin interaction. All bound A-forms were progressively displaced from the heparin-agarose columns by increasing salt concentrations, with maximal release at about 0.6 M. They were also efficiently eluted by heparin solutions (1 mg/ml), other glycosaminoglycans being much less effective. Chicken globular AChE forms (G-forms, both low-salt-soluble and detergent-soluble) also bound to immobilized heparin in the absence of salt. Stepwise elution with increasing NaCl concentrations showed maximal release of G-forms at 0.15 M, all globular forms being totally displaced from the column at 0.4 M NaCl. Heparin (1 mg/ml) had the same eluting capacity as 0.4 M NaCl, whereas other glycosaminoglycans were only marginally effective. We conclude that the molecular forms of AChE in these vertebrate species interact with heparin, at salt concentrations that are characteristic for asymmetric and globular forms. Within the A and G molecular form groups, no differences were found in the behavior of the different fractions or subtypes, provided that the enzyme samples were free of interfering molecules.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of asymmetric and globular acetylcholinesterase species with glycosaminoglycans. 232 46

The influence of KCl on the second-order rate constant kII = k2/Ks of acetylcholinesterase-catalyzed hydrolysis of butyl acetate is quantitatively described by the linear equation log kII = log k0II + delta kappa c, where c is the salt concentration and delta kappa = kappa E - kappa X* + kappa s is the difference between the salting-out coefficients of the initial reagents (E and S) and of the transition state (X*). The salting-out parameter delta kappa increases with increasing pH (pH range 4.8-6.0) up to the constant value at pH 6.0-8.0, where delta kappa = kappa s. The pH-dependent delta kappa is discussed as an indication of the change in the volume and/or solvation of the enzyme upon the formation of the transition state. The data show that while the pKa1 = 5.6 +/- 0.1 and pKa2 = 8.0 +/- 0.1 of kII are independent of the KCl concentration, the apparent pKa shift can be observed at high salt concentrations due to a pH-dependent salt effect.
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PMID:pH-dependent salting-out effect in enzyme-catalyzed reaction kinetics. 235 97

Freshly dissected chick neural retina and pigmented epithelium do not apparently contain asymmetric molecular forms (A-forms) of acetylcholinesterase (AChE). The neighboring choroid, and the ciliary muscles and iris, are however rich in type II A-forms (high salt/EDTA-extractable). Most if not all the asymmetric AChE activity detected in chick 'whole retina' preparations could then be explained in terms of contamination by non-retinal eye tissues.
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PMID:Asymmetric acetylcholinesterase is absent from chick retina, but present in choroid, ciliary muscles and iris. 235 30

Several chemical delivery systems (CDS) were synthesized for the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroacridine (THA). The derivatives prepared were substituted with a 1,4-dihydropyridine in equilibrium pyridinium salt redox system at the amino functionality. These compounds were synthesized by acylation of the 9 amino group of THA with nicotinic anhydride under forced conditions, followed by a selective N-alkylation of the pyridine ring and regioselective reduction of the resulting quaternary salts. Lipophilicity parameters indicated increased lipophilic indices for various CDS's compared to the THA. Oxidation studies showed that dihydronicotinamides readily converted to the quaternary salt, both chemically and enzymatically. The transport forms of THA were also shown not to interact with acetylcholinesterase in vivo. In vivo distribution studies in the rat indicated that high and sustained levels of the pyridinium quaternary ion derivative were present in the central nervous system (CNS). In addition, THA was produced in the CNS from the quaternary salt precursor in low concentrations, indicating a slow but sustained release. The CDS for THA were found to be less acutely toxic than THA.
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PMID:Application of a brain-targeting chemical delivery system to 9-amino-1,2,3,4-tetrahydroacridine. 236 35

Contractile force of isolated atria from most mammalian species increases with the rate of electrical stimulation, resulting in an ascending staircase. In contrast, in the rat, contractile force decreases with increasing rate of stimulation (descending staircase). The bradycardic and antianginal drug alinidine (5.7-91.2 mumol/l) reversed the descending staircase to ascending by a positive inotropic effect at higher stimulation rates. Maximal positive inotropy was obtained with 45.6 mumol/l, a concentration which also caused maximal bradycardia in spontaneously beating atria. Concentrations of 1 mumol/l of the antimuscarinic compounds atropine as well as the quaternary salt ipratropium bromide also reversed the descending staircase of rat atria. Addition of alinidine did not cause any further increase in force of contraction under these conditions. Addition of 1 mumol/l physostigmine to isolated left atria from guinea pigs for blockade of acetylcholinesterase decreased contractility at all stimulation rates, but did not change the ascending character of the staircase. Alinidine antagonized the negative inotropic effect of physostigmine. The known antimuscarinic action of alinidine was quantified in electrically driven (0.25 Hz) left rat atria by antagonism of the negative inotropic effect of oxotremorine (0.01-10 mumol/l). Alinidine acted as a strictly competitive antagonist with a pA2 of 5.82. In isolated papillary muscle from guinea pigs, pretreated with reserpine for depletion of catecholamines, carbachol (0.1-3000 mumol/l) exerted positive inotropic effects. Alinidine antagonized also this effect in a competitive fashion with a pA2 value of 5.58.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alinidine reverses the descending staircase of isolated rat atria by an antimuscarinic action. 252 72

Subcellular distribution and some extraction properties of acetylcholinesterase (AchE) (EC 3.1.1.7) and nonspecific cholinesterase (ChE) (EC 3.1.1.8) were studied in rat liver employing subcellular fractionation techniques. All purified subcellular fractions were enriched in total cholinesterase activity over the homogenate. Plasma membrane and Golgi fractions showed a significant enrichment in AchE activity, while ChE activity was enriched in both rough and smooth endoplasmic reticulum. Subcellular fractions were subjected to conditions that selectively release proteins having varying degrees of association to membranes. High-pH treatment (known to release peripheral and soluble proteins) extracted ChE activity, but more than 90% of AchE activity remained associated to the pellet. Solubility properties and molecular forms of AchE and ChE in this tissue were studied by extraction in high-salt medium with and without Triton X-100, followed by velocity sedimentation centrifugation. Most of AchE activity (88%) (41% G4 and 59% G2 + G1) was detergent soluble; 42% of ChE activity (detected only as G2 + G1) was high-salt soluble, whereas remaining ChE activity was detergent soluble. These results indicate not only a different subcellular location for both enzymes, but also point to a differential association to membranes. AchE behaves as an integral membrane protein and ChE behaves as a peripheral or a luminal soluble protein.
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PMID:Acetylcholinesterase and nonspecific cholinesterase activities in rat liver: subcellular localization, molecular forms, and some extraction properties. 261 91

Choline acetyltransferase (ChAT) activity, the sedimentation and solubility forms of acetylcholinesterase (AChE) as well as total (3H-quinuclidinyl benzilate, QNB) and M1 (3H-pirenzepine, PZ) muscarinic binding were investigated in the temporal cortex (TC) and nucleus caudatus (NC) of both non-demented and demented parkinsonian patients and controls. ChAT activity and low-salt-soluble and detergent-soluble AChE were lower in the TC of demented patients with Parkinson's disease than in controls. ChAT activity and the solubility forms of AChE in the NC did not differ between controls and parkinsonian patients. In the TC, the activity of the intermediate form of AChE was lower in parkinsonian patients, but the activity of the light form of AChE did not differ between controls and parkinsonian patients. In the TC of patients with Parkinson's disease the Bmax of 3H-QNB binding was slightly higher than in controls, but the Bmax of 3H-PZ binding did not differ between controls and parkinsonian patients. In the NC the Bmax of 3H-QNB binding was unchanged compared to that of the controls. The concomitant decrease of ChAT with soluble as well as membrane-bound tetrameric AChE suggests a close relationship between ChAT and tetrameric form of AChE. M1 receptors (3H-PZ binding sites) are not affected in the TC, but are decreased in the NC of demented parkinsonian patients. This decrease may be secondary to the loss of dopaminergic neurons projecting from the substantia nigra to the striatum.
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PMID:Different forms of brain acetylcholinesterase and muscarinic binding in Parkinson's disease. 272 71

Cholinesterases represent a ubiquitous, polymorphic family of acetylcholine hydrolyzing enzymes. The multileveled tissue-specific heterogeneity which characterizes these enzymes makes the cholinesterases an appropriate model for studying the mechanisms involved in regulating divergent pathways in protein biogenesis. For this purpose, a cDNA coding for human butyrylcholine esterase (BuChE) was subcloned into the SP 6 transcription vector. Synthetic mRNA transcribed from this construct was microninjected into Xenopus laevis oocytes alone, and in conjunction with poly(A)+ RNAs extracted from human brain or muscle. Injected BuChE-mRNA induced the biosynthesis of a protein exhibiting the catalytic activity, substrate specificity, and sensitivity to selective inhibitors characteristic of native human serum BuChE, and clearly distinct from the related enzyme acetylcholinesterase (AChE). The nascent BuChE was reproducibly distributed into low salt-soluble and detergent-extractable pools. Sucrose gradient analysis demonstrated that the nascent human enzyme was capable of limited subunit assembly, appearing as functional dimeric molecules in both of these fractions. Co-injection with brain or muscle-derived mRNAs facilitated higher order oligomeric assembly. Co-injected brain mRNA induced the appearance of tetramers while co-injected muscle mRNA induced the appearance of an array of heavy molecular forms, including a heavy 16 S form. These results indicate that the molecular determinants which distinguish BuChE from AChE are inherent to its primary amino acid sequence and that additional, tissue-specific protein(s) are involved in the modulation of subunit assembly within particular biological milieues.
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PMID:Expression and tissue-specific assembly of human butyrylcholine esterase in microinjected Xenopus laevis oocytes. 273 42

Two classes of collagen-tailed, asymmetric forms (A-forms) of acetylcholinesterase (AChE) have been described in skeletal muscles of vertebrates. They are distinguished by their different solubilization requirements: class I A-forms are solubilized in the presence of high salt, whereas class II A-forms require in addition a chelating agent for solubilization. We report here that class II A-forms are less sensitive to nerve section than are class I A-forms. The latter form decreases faster and to a lower level of activity after denervation. The decay of both AChE classes is more rapidly in short-stump nerves than in long ones. The effect of nerve section on class II A-forms appears to be dependent on the particular muscle group being studied. Both classes of A-forms reappear after muscle reinnervation, but the class I A-forms recovered earlier. More interestingly, both classes of A-forms increase in normally innervated skeletal muscles after contralateral nerve injury. In this case, however, the class II A-forms change first. Muscular disuse induced by contralateral tenotomy is also followed by a rise in class II A-forms. Our results, showing differences in response and flexibility in the changes of the two classes of A-forms in several experimental conditions, represent a relevant contribution to the understanding of the regulation and functional role of the asymmetric forms of AChE in vertebrate skeletal muscles.
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PMID:Nerve regulation of class I and class II-asymmetric forms of acetylcholinesterase in rat skeletal muscles. 276 Sep 43


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