Disease relevance of ACHE

• Our findings suggest that inherited interactive weakness of AChE and PON1 expression increases the insecticide-induced occurrence of Parkinson's disease [1].
• Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic) [2].
• Surgical pieces of non-small lung carcinomas (NSLC) and their adjacent non-cancerous tissues (ANCT) were analysed for AChE and BChE activities [3].
• The probable involvement of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in cancer and the relevance of cholinergic responses for lung cancer growth prompted us to study whether cholinesterase activity of human lung is altered by malignancy [3].
• To minimize toxicity, however, a cholinesterase inhibitor selective for only AChE would be an ideal treatment [4].

Psychiatry related information on ACHE

• However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines [5].
• CSF AChE activity was not related to dementia severity and did not change significantly over an 18-month period [6].
• AChE decreased in Huntington's chorea (degeneration of striatal cholinergic interneurons) but also in multiple sclerosis (not known to affect cholinergic systems) [7].
• In contrast, erythrocyte AChE activity was higher in patients with vascular dementia (p = 0.004) [8].
• This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon) [9].

High impact information on ACHE

• Under all experimental conditions, any change in the rate of AChE secretion was accompanied by an identical change in the rate of ACh receptor incorporation into the plasma membrane [10].
• Moreover, atypical BuChE demonstrated 1/200th the affinity for tacrine of normal BuChE or the related enzyme acetylcholinesterase (AChE) [11].
• Synapses form when cultures are grown in the presence of acetylcholine receptor antagonists, but AChE does not accumulate at these synapses [12].
• The appearance of acetylcholinesterase (AChE) at newly formed nerve-muscle synapses depends on synaptic transmission [12].
• Treatment with dibutyryl cyclic GMP mimics muscle activity, directly inducing synaptic AChE appearance [12].

Chemical compound and disease context of ACHE

• A significant fraction of the amphiphilic AChE species was converted into hydrophilic components by incubation of the soluble enzyme with phosphatidylinositol-specific phospholipase C (PIPLC) from Bacillus thuringiensis, this fraction being increased by a double treatment with PIPLC and alkaline hydroxylamine [13].
• Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD) [14].
• OBJECTIVE: This preliminary open-label study aims to investigate the effects of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in 20 patients diagnosed with frontotemporal dementia (FTD) [15].
• Inhibition of RBC AChE activity is consistently exhibited at lower dosages of chlorpyrifos than those required to result in clinical symptoms of OP toxicity, or alterations in cognitive functional responses [16].
• Exposure to organophosphate (OP) chemical warfare agents (CWAs), pesticides, anesthetics, and a variety of drugs such as cocaine, as well as some neurodegenerative and liver disease states, selectively reduces AChE or BChE activity [17].

Biological context of ACHE

• To delineate the protein domains that are responsible for this phenomenon, we mutated residues within the rim of the active site gorge, the region parallel to the peripheral site in the homologous enzyme acetylcholinesterase [AChE (acetylcholine acetyl hydrolase); EC 3.1.1.7], the oxyanion hole, and the choline-binding site [18].
• Transcripts encoding ColQ increased during myogenic differentiation of C2C12 cells; the increase was in parallel with AChE catalytic subunit [19].
• These phenotypes showed a relative risk (RR) of 8.8 of erythrocyte AChE inhibition when compared to the usual phenotype [20].
• 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 [21].
• 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) [21].

Anatomical context of ACHE

• The picture was reversed in the putamen, where BuChE immunoreactivity (340 ng/g) was far outweighed by that of AChE (6,100 ng/g) [22].
• There was intense staining for BuChE or AChE throughout the thalamus, with some nuclei primarily expressing one or the other cholinesterase [23].
• Neuronal staining in the subthalamic nucleus and hypothalamus was predominantly positive for AChE activity [23].
• Furthermore, BuChE activity, like AChE activity, is found in certain thalamic nuclei related to cognitive and behavioral functions [23].
• The presence of a collagenous protein (ColQ) characterizes the collagen-tailed forms of acetylcholinesterase (AChE) and butyrylcholinesterase at vertebrate neuromuscular junctions, which is tethered in the synaptic basal lamina [19].

Associations of ACHE with chemical compounds

• AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group [24].
• At the micromolar range concentration, sertraline (60-120 microM) and amitriptyline (60-180 microM) inhibited human erythrocyte AChE [25].
• Positron emission tomography scans in AD patients (n = 15) and control subjects (n = 12) measured both BuChE (using [(11)C]BMP) and AChE activity (using N-[(11)C] methylpiperidin-4-yl propionate, an established method) [26].
• Another type of substitution, that of Asp-74 by Gly or Asn, generated an active enzyme with increased resistance to succinylcholine and dibucaine; thus mimicking in an AChE molecule the phenotype of the atypical butyrylcholinesterase natural variant (D70G mutation) [27].
• OBJECTIVE: To study the long-term dual inhibitory effects of rivastigmine on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in patients with AD [28].

Physical interactions of ACHE

• Rabbit polyclonal antibodies prepared against the purified clone-produced BuChE polypeptides interacted in immunoblots with denatured serum BuChE as well as with purified and denatured erythrocyte AChE [29].
• An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition [30].
• We have shown that AChE interacts with the amyloid beta-peptide (Abeta) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme [31].
• Interestingly, treatment with Abeta-AChE complexes decreases the cytoplasmic beta-catenin level, a key component of Wnt signaling [32].

Regulatory relationships of ACHE

• 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) [33].
• We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQ mutant with ACHE(T) in COS cells [34].
• In order to identify the structural domains of the amyloid-beta-peptide (Abeta) involved in the aggregation induced by AChE, we have studied the effect of this cholinergic enzyme on Abeta peptide fragments of different sizes [35].
• AChE was able to promote the aggregation of these fragments in a very specific way and both mutant peptides were able to form amyloid fibrils, as revealed by negative staining under the electron microscope [35].
• A remarkable inhibition of MSA was obtained with propidium iodide, suggesting that AChE triggers PrP 106-126 and Abeta aggregation through a similar mechanism [36].

Other interactions of ACHE

• Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures [37].
• AChE was predominantly expressed in neurons of the anterodorsal, midline, ventral, intralaminar, and reticular nuclei [23].
• The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ [2].
• When all biomarkers of individual susceptibility to pesticides were considered at the same time, the GSTT1 null allele determined higher ALA-D and AChE activities at the period of high exposure to pesticides [38].

Analytical, diagnostic and therapeutic context of ACHE

• Enzyme-linked immunosorbent assays for acetylcholinesterase (AChE) and for butyrylcholinesterase (BuChE) were markedly more specific than conventional assays using selective enzyme inhibitors [22].
• Validation of the putative positron emission tomography method included regional distribution, positive correlation with age, and attenuation by the nonselective cholinesterase inhibitor physostigmine, but no attenuation by the AChE-selective inhibitor donepezil [26].
• Attempts to convert the AChE triad into a Cys-His-Glu or Ser-His-Asp configuration by site-directed mutagenesis did not yield effective AChE activity [27].
• In contrast, native BuChE tetramers from human serum, but not AChE dimers from erythrocytes, interacted with these antibodies in solution to produce antibody-enzyme complexes that could be precipitated by second antibodies and that sedimented faster than the native enzyme in sucrose gradient centrifugation [29].
• The distribution of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) molecular forms and their solubility characteristics were examined, using density gradient centrifugation, in various regions of the postmortem human CNS [39].

References