Acetylcholinesterase AChE

Several structures of small molecule complexes with acetylcholinesterase have been solved. They reveal a binding site next to the catalytic serine preferrentially occupied by a positively charged moiety next to a hydrophobic portion. The positively charged functional groups almost superimpose in front of a trj tophan residue at the bottom of the gorge [25-27]. 

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Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

Arthun DA, Chakraborti TK, Chapman JL, et al. 1991. Comparison of in vivo acetylcholinesterase (AChE) inhibition in neonatal and adult rats by three organophosphoms insecticides. Neurotoxicology 12 143. 

Cholinesterases are another group of B-esterases. The two main types are acetylcholinesterase (EC 3.1.1.7) and unspecific or butyrylcholinesterase (EC 3.1.1.8). Acetylcholinesterase (AChE) is found in the postsynaptic membrane of cholinergic... 

Figure 3. Plot of V against total enzyme [ET] showing the irreversible inhibition of el tric eel acetylcholinesterase (AChE) by ANTX-A(S). The enzymes were incubated with 0.32 fig/mL ANTX-A(S) for 1.0 min and acetylthiocholine (final concentrations 2.5, 4.7, 6.3, and 7.8 X 10 M) was added. V was determined from the double reciprocal plots (not shown). Key (o) control ( ) ANTX-A(S). (Reproduced with permission from Ref. 42. Copyright 1987 Pergamon Press)...

Greenfield, SA (1991) A noncholinergic action of acetylcholinesterase (AchE) in the brain. From neuronal secretion to the generation of movement. Cell. Mol. Neurohiol. 11 55-77. 

Biosensors may provide the basis for in-field analyses and real-time process analysis. However, biosensors are generally limited to the determination of a limited range of analytes in defined matrices. Enzyme-based biosensors, principally acetylcholinesterase (AChE) inhibition, have been successfully used in environmental analysis for residues of dichlorvos and paraoxon, " carbaryl " and carbofuran. " Immunochemically based biosensors may be the basis for the determination of pesticide residues in liquid samples, principally water and environmental samples, but also fruit juices. The sensors can be linked to transducers, for example based on a piezo-... 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

Acetylcholine is formed from acetyl CoA (produced as a byproduct of the citric acid and glycolytic pathways) and choline (component of membrane lipids) by the enzyme choline acetyltransferase (ChAT). Following release it is degraded in the extracellular space by the enzyme acetylcholinesterase (AChE) to acetate and choline. The formation of acetylcholine is limited by the intracellular concentration of choline, which is determined by the (re)uptake of choline into the nerve ending (Taylor Brown, 1994). 

Griffiths, G. and Pritchard, D.I. (1994) Purification and biochemical characterisation of acetylcholinesterase (AChE) from the excretory/secretory products of Trichostrongylus colubriformis. Parasitology 108, 579-586. 

Acetylcholinesterase (AChE) isolated from various organisms has been used in the majority of pesticide biosensors. In the early 1950s potentiometric detection was adopted for pesticide detection. In the middle of the 1980s it was used for the construction of the first integrated biosensors for detection of pesticides based on inhibition of AChE. Later rapid changes in science and technology introduced novel genetically... 

The postsynaptic membrane opposite release sites is also highly specialized, consisting of folds of plasma membrane containing a high density of nicotinic ACh receptors (nAChRs). Basal lamina matrix proteins are important for the formation and maintenance of the NMJ and are concentrated in the cleft. Acetylcholinesterase (AChE), an enzyme that hydrolyzes ACh to acetate and choline to inactivate the neurotransmitter, is associated with the basal lamina (see Ch. 11). 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues. Based largely on substrate specificity, the cholinesterases are subdivided into the acetylcholinesterases (AChEs) (EC... 

Diazinon exerts its toxic effects by binding to the neuronal enzyme acetylcholinesterase (AChE) for long periods after exposure. Diazinon, in turn, is converted to diazoxon, which has a higher affinity for AChE (and thus greater toxicity) than the parent compound. There is a latent period in... 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Exposure to nerve agents is not restricted to the battlefield. Possible terrorist use of these weapons and the destruction of the chemical weapon depots certainly will increase the risk of exposure. Since treatment for intoxication with at least some of these organophosphorus (OP) acetylcholinesterase (AChE) inhibitors is still far from ideal, research efforts are devoted towards finding an effective treatment. 

Acetylcholinesterase (AChE) This enzyme is found in the troughs of the junctional folds of the muscle membrane and is responsible for metabolizing ACh within the synaptic cleft. 

Compound 10 was evaluated for anti-bacterial activity and acetylchohnesterase (AChE) inhibitory activities. This compound was foimd to be inactive in antibacterial assay and exhibited AChE inhibitory activity with an ICj, value of 67 pM. Acetylcholine serves as a neurotransmitter in the central and peripheral nervous system. Acetylcholinesterase (AChE) stops the function of acetylcholine by its... 

Microbial natural product chemistiy has generated a number of bioactive natural products. For instance cyclosporine A FK506 and rapamycin are used as immunosuppressants [16]. Other examples of microbial metabolites, having potential biomedical application include antihyperlipidemics, lovastatin and guggulsterone [17, 18]. The crude extracts of Mucor plumbeus exhibited acetylcholinesterase (AChE) enzyme inhibition activity. Our detailed chromatographic work on this crude extract resulted in the isolation of mucoralactone A (11), a novel steroid containing a lactone moeity incorporated in its structure. 

Table 10.4 Pharmacological properties of selected acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer s disease... 

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