Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.
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PMID:Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. 1060 46

It has been reported that the ACTH-(4-9) analog H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuronal tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early postnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. the sensitivity of cholinergic neurons against excitotoxic damage. Wistar rat pups received injections of ORG 2766 or saline on postnatal days 1, 3 and 5 and were then left undisturbed until adulthood. At the age of 6 months, the animals were subjected to unilateral lesion of magnocellular basal nucleus by infusion of high dose of N-methyl-D-aspartate (NMDA). The effects of the excitotoxic insult were studied 28 hours and 12 days after the lesion by measuring both the acute cholinergic and glial responses, and the final outcome of the degeneration process. Twenty eight hours after NMDA infusion, postnatally ACTH-(4-9)-treated animals showed stronger suppression of choline-acetyltransferase immunoreactivity and increased reaction of glial fibrillary acidic protein -immunopositive astrocytes in the lesioned nucleus compared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholinesterase -positive fibre projections in the cortex, were less in ACTH-(4-9) animals. Our data indicate that the early developmental effects of ACTH-(4-9) influence intrinsic neuroprotective mechanisms and reactivity of neuronal and glial cells, thereby resulting in a facilitated rescuing mechanism following excitotoxic injury.
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PMID:Postnatal treatment with ACTH-(4-9) analog ORG 2766 attenuates N-methyl-D-aspartate-induced excitotoxicity in rat nucleus basalis in adulthood. 1103 12

The role of active-site residues in the dealkylation reaction in the P(S)C(S) diastereomer of 2-(3,3-dimethylbutyl)methylphosphonofluoridate (soman)-inhibited Torpedo californica acetylcholinesterase (AChE) was investigated by full-scale molecular dynamics simulations using CHARMM: >400 ps equilibration was followed by 150-200 ps production runs with the fully solvated tetracoordinate phosphonate adduct of the wild-type, Trp84Ala and Gly199Gln mutants of AChE. Parallel simulations were carried out with the tetrahedral intermediate formed between serine-200 Ogamma of AChE and acetylcholine. We found that the NepsilonH in histidine H(+)-440 is positioned to protonate the oxygen in choline and thus promote its departure. In contrast, NepsilonH in histidine H(+)-440 is not aligned for a favourable proton transfer to the pinacolyl O to promote dealkylation, but electrostatic stabilization by histidine H(+)-440 of the developing anion on the phosphonate monoester occurs. Destabilizing interactions between residues and the alkyl fragment of the inhibitor enforce methyl migration from Cbeta to Calpha concerted with C-O bond breaking in soman-inhibited AChE. Tryptophan-84, phenyalanine-331 and glutamic acid-199 are within 3.7-3.9 A (1 A=10(-10) m) from a methyl group in Cbeta, 4.5-5.1 A from Cbeta and 4.8-5.8 A from Calpha, and can better stabilize the developing carbenium ion on Cbeta than on Calpha. The Trp84Ala mutation eliminates interactions between the incipient carbenium ion and the indole ring, but also reduces its interactions with phenylalanine-331 and aspartic acid-72. Tyrosine-130 promotes dealkylation by interacting with the indole ring of tryptophan-84. Glutamic acid-443 can influence the orientation of active-site residues through tyrosine-421, tyrosine-442 and histidine-440 in soman-inhibited AChE, and thus facilitate dealkylation.
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PMID:Molecular dynamics study of active-site interactions with tetracoordinate transients in acetylcholinesterase and its mutants. 1117 Oct 62

The effect of different L-phenylalanine (Phe) concentrations (0.12-1.8 mM) on acetylcholinesterase (AChE), (Na(+), K(+))-ATPase and Mg(2+)-ATPase activities was investigated in homogenates of adult and aged rat whole brain at 37 degrees C. Adult and aged rat experiments were necessary in relation to phenylketonuria (PKU) since phenylketonuric patients usually discontinue their therapeutic special diet when they reach adulthood. Diet discontinuation results in the pathological increase of Phe concentration in plasma and consequently in brain. AChE activity in adult brain homogenates showed a decrease up to 18% (P<0.01) with 0.48--1.8 mM Phe preincubated for 1 h. Adult brain Na(+), K(+)-ATPase was stimulated by 30--35% (P<0.01) in the presence of 0.48--1.8 mM Phe. However, high Phe concentrations were not able to affect the activities of AChE and Na(+), K(+)-ATPase, when preincubated with aged brain homogenate for 3 h. Moreover, high Phe concentrations appeared unable to affect the activity of eel E. electricus pure AChE inhibited about 30% (P<0.001) by the free radical system H(2)O(2)/Fe(2+). Also, the antagonists of alpha- and beta-adrenergic receptors (phenoxybenzamine and propranolol, respectively) inhibited adult rat brain Na(+), K(+)-ATPase activity about 30--40% (P<0.01) and Phe was unable to change this action. It is suggested that: (a) The inhibitory effect of Phe on brain AChE and its stimulatory effect on brain Na(+), K(+)-ATPase are decreased with age; (b) These effects may be influenced by aging factors, such as free radical action and/or reduced density of alpha- and beta-adrenergic receptors in the tissue.
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PMID:Effects of L-phenylalanine on acetylcholinesterase and Na(+), K(+)-ATPase activities in adult and aged rat brain. 1129 14

The effect of different L-phenylalanine (Phe) concentrations (0.12-12.1 mM) on acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+-ATPase activities was investigated in homogenates of adult rat whole brain and frontal cortex at 37 degrees C. AChE, (Na+,K+)-ATPase and Mg2+-ATPase activities were determined after preincubation with Phe. AChE activity in both tissues showed a decrease up to 18% (p<0.01) with Phe. Whole brain Na+,K+-ATPase was stimulated by 30-35% (p<0.01) with high Phe concentrations, while frontal cortex Na+,K+-ATPase was stimulated by 50-55% (p<0.001). Mg2+-ATPase activity was increased only in frontal cortex with high Phe concentrations. It is suggested that: a) The inhibitory effect of Phe on brain AChE is not influenced by developmental factors, while the stimulation of Phe on brain Na+,K+-ATPase is indeed affected; b) The stimulatory effect of Phe on rat whole brain Na+,K+-ATPase is decreased with age; c) Na+,K+-ATPase is selectively more stimulated by high Phe concentrations in frontal cortex than in whole brain homogenate; d) High (toxic) Phe concentrations can affect Mg2+-ATPase activity in frontal cortex, but not in whole brain, thus modulating the amount of intracellular Mg2+.
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PMID:Effects of L-phenylalanine on acetylcholinesterase, (Na+,K+)-ATPase and Mg2+-ATPase activities in adult rat whole brain and frontal cortex. 1130 3

Thyroglobulin (Tg) binds to cell surfaces through various binding sites of high, moderate and low affinity. We have previously shown that binding with low to moderate affinity is pH dependent, selective, but not tissue specific. To identify the regions of Tg involved in this cell surface binding, we studied the binding of (125)I-labeled cyanogen bromide peptides from human Tg to cell surfaces of thyroid cells (inside-out follicles) and of CHO cells. Electrophoretic analysis of cell homogenates after binding of native or of reduced and alkylated (125)I-labeled peptides showed that three peptides, P1, P2 and P3, were always associated with the cells. Sequence analysis allowed the identification of P1 (Ser-2445 to Met-2596 or Met-2610) and P2 (Phe-2156 to Met-2306). P3 proved to be a mixture of several peptides among which two were identified: P3-1 (Cys-1306 to Met-1640) and P3-2 (Cys-2035 to Met-2413) which includes P2. P1, P2 and P3-2 are entirely (P1) or partly (P2 and P3-2) located in the C-terminal domain of Tg homologous with acetylcholinesterase. The smallest peptides, P1 and P2, were purified by preparative electrophoresis. They both displayed strong binding properties towards cell surfaces. Inhibition experiments of (125)I-labeled Tg binding by P1 or P2 indicated that they were involved in Tg binding to cell surfaces. All the other peptides tested for their binding abilities were either not or only poorly involved in Tg binding to cell surfaces, which suggested that P1 and P2 are major Tg sites of binding to cell surfaces. These two peptides are not involved in the binding of Tg to the known Tg 'receptors' described in the literature, to which recycling, transcytosis and regulation functions have been ascribed. Thus they are potential tools to identify cell surface components involved in the process of Tg endocytosis leading to lysosomal degradation.
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PMID:Identification of thyroglobulin domain(s) involved in cell-surface binding and endocytosis. 1143 Nov 54

The effect of different L-phenylalanine (Phe) concentrations (0.12-12.1 mM) on acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+-ATPase activities was evaluated in homogenates of suckling rat frontal cortex, hippocampus and hypothalamus. Phe, at high concentrations, reduced AChE activity in frontal cortex and hippocampus by 18%-20%. On the contrary, the enzyme activity was unaltered in the hypothalamus. Na+,K+-ATPase was stimulated by high levels of the amino acid, both in the frontal cortex and the hypothalamus by 60%, whereas it was inhibited in the hippocampus by 40%. Mg2+-ATPase was not influenced by Phe. It is suggested that: a) In the frontal cortex, the improper acetylcholine (ACh) release, due to AChE inhibition by Phe, combined with the stimulation of Na+,K+-ATPase, possibly explain tremor and the hyperkinetic behaviour in patients with classical phenylketonuria (PKU). b) In the hippocampus, inhibition of AChE by Phe could lead to problems in memory, while Na+,K+-ATPase inhibition by Phe may induce metabolic disorders and electrical instability of the synaptosomal membrane. c) In the hypothalamus, the behavioral problems in PKU "off diet" may be related to noradrenaline (NA) levels, which are probably correlated with the modulated Na+,K+-ATPase by Phe.
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PMID:Effects of L-phenylalanine on acetylcholinesterase and Na+,K+-ATPase activities in suckling rat frontal cortex, hippocampus and hypothalamus. 1192 33

The aim of this work was to evaluate, in vitro, the effect of L-alanine (Ala) on suckling rat brain acetylcholinesterase (AChE) and on eel Electrophorus electricus pure AChE inhibited by L-phenylalanine (Phe) as well as to investigate whether Phe or Ala is a competitive inhibitor or an effector of the enzyme. AChE activity was determined in brain homogenates and in the pure enzyme after 1 h preincubation with 1.2 mM of Phe or Ala as well as with Phe plus Ala. The activity of the pure AChE was also determined using as a substrate different amounts of acetylthiocholine. Ala reversed completely the inhibited AChE by Phe (18-20% in 500-600 microM substrate, p<0.01). Lineweaver-Burk plots showed that Vmax remained unchanged. However, Km was found increased with Phe (150%, p<0.001), decreased with Ala alone (50%, p<0.001) and unaltered with Phe plus Ala. It is suggested that: a) Phe presents a competitive inhibitory action with the substrate whereas Ala a competitive activation; b) Ala competition with Phe might unbind the latter from AChE molecule inducing the enzyme stimulation; c) Ala might reverse the inhibitory effect of Phe on brain AChE in phenylketonuric patients, if these results are extended into the in vivo reality.
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PMID:Alanine reverses the inhibitory effect of phenylalanine on acetylcholinesterase activity. 1213 93

A series of eight double and triple mutants of mouse acetylcholinesterase (AChE; EC 3.1.1.7), with substitutions corresponding to residues found largely within the butyrylcholinesterase (BChE; EC 3.1.1.8) active-centre gorge, was analysed to compare steady-state kinetic constants for substrate turnover and inhibition parameters for enantiomeric methylphosphonate esters. The mutations combined substitutions in the acyl pocket (Phe(295)-->Leu and Phe(297)-->Ile) with the choline-binding site (Tyr(337)-->Ala and Phe(338)-->Ala) and with a side chain (Glu(202)--> Gln) N-terminal to the active-site serine, Ser(203). The mutations affected catalysis by increasing K (m) and decreasing k (cat), but these constants were typically affected by an order of magnitude or less, a relatively small change compared with the catalytic potential of AChE. To analyse the constraints on stereoselective phosphonylation, the mutant enzymes were reacted with a congeneric series of S (P)- and R (P)-methylphosphonates of known absolute stereochemistry. Where possible, the overall reaction rates were deconstructed into the primary constants for formation of the reversible complex and intrinsic phosphonylation. The multiple mutations greatly reduced the reaction rates of the more reactive S (P)-methylphosphonates, whereas the rates of reaction with the R (P)-methylphosphonates were markedly enhanced. With the phosphonates of larger steric bulk, the enhancement of rates for the R (P) enantiomers, coupled with the reduction of the S (P) enantiomers, was sufficient to invert markedly the enantiomeric preference. The sequence of mutations to enlarge the size of the AChE active-centre gorge, resembling in part the more spacious gorge of BChE, did not show an ordered conversion into BChE reactivity as anticipated for a rigid template. Rather, the individual aromatic residues may mutually interact to confer a distinctive stereospecificity pattern towards organophosphates.
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PMID:Acetylcholinesterase active centre and gorge conformations analysed by combinatorial mutations and enantiomeric phosphonates. 1266 27

Alzheimer's disease (AD) is initially and primarily associated with the degeneration and alteration in the metabolism of cholinesterases (ChEs). The use of ChEs inhibitors to treat Alzheimer's condition, on the basis of the cholinergic hypothesis of the disease, is, therefore, without grounds. Most disturbing is the fact that the currently available anti-ChEs are designed to inhibit normal ChEs in the brain and throughout the body, but not the abnormal ones. Based on the acetylcholinesterase (AChE) deficiency theory, treatment should be designed to protect the cranial ChEs system from alteration and/or to help that system fight against degeneration through restoring its homeostatic action for brain structure and function instead. The overlap in the clinical, biochemical, molecular-cellular, and pathological alterations seen in patients with AD and individuals with many other brain disorders, which has bewildered many investigators, may now be explained by the shared underlying mismetabolism of brain ChEs. The abnormal metabolism of ChEs existing in asymptomatic subjects may indicate that the system is "at risk" and deserves serious attention. Future perspectives of ChEs research in vivo and in vitro in connection with AD and clinical diagnosis, prevention and treatment are proposed. Several potentially useful therapeutic and preventive means and pharmacological agents in this regard are identified and discussed, such as physical and intellectual stimulation, and a class of drugs including vitamin E, R-(-)-deprenyl (deprenyl, selegiline), acetyl L-carnitine, cytidine diphosphocholine (CDP-choline), centrophenoxine, L-phenylalanine, naloxone, galactose, and lithium, that have been proven to be able to stimulate AChE activity. Their working mechanisms may be through directly changing the configuration of AChE molecules and/or correcting micro- and overall environmental biological conditions for ChEs.
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PMID:Brain cholinesterases: III. Future perspectives of AD research and clinical practice. 1523 94


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