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Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalysis the breakdown of acetylcholine and some other choline esters that function as :
It is found at mainly neuromuscular junctions and in of the cholinergic type, where its activity serves to terminate cholinergic synaptic transmission. It belongs to the carboxylesterase family of enzymes. It is the primary target of inhibition by organophosphorus compounds such as and .
The anionic subsite accommodates the positive quaternary amine of acetylcholine as well as other cationic substrates and Enzyme inhibitor. The cationic substrates are not bound by a negatively charged amino acid in the anionic site, but by interaction of 14 aromatic residues that line a gorge leading to the active site. All 14 amino acids in the aromatic gorge are highly conserved across different species. Among the aromatic amino acids, tryptophan 84 is critical and its Alanine scanning results in a 3000-fold decrease in reactivity. The gorge is approximately 20 deep and five angstroms wide.
The esteratic subsite, where acetylcholine is hydrolyzed to acetate and choline, contains the catalytic triad of three amino acids: serine 203, histidine 447 and glutamate 334. These three amino acids are similar to the triad in other serine proteases except that the glutamate is the third member rather than aspartate. Moreover, the triad is of opposite chirality to that of other proteases. The hydrolysis reaction of the carboxyl ester leads to the formation of an acyl-enzyme and free choline. Then, the acyl-enzyme undergoes nucleophilic attack by a water molecule, assisted by the histidine 440 group, liberating acetic acid and regenerating the free enzyme. (1985). 9780716716143, W.H. Freeman. ISBN 9780716716143
In humans, AChE is a cholinergic enzyme involved in the hydrolysis of the neurotransmitter acetylcholine (ACh) into its constituents, choline, and acetate. Overall, in mammals, AChE is primarily involved in the termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine. In invertebrates, AChE plays a similar role in nerve conduction processes at the neuromuscular junction. It is usually located in the membranes of these animals and controls ionic currents in excitable membranes.
In plants, the biological functions of AChE are less clear, and its existence has been recognized by indirect evidence of its activity. For instance, a study on Solanum lycopersicum (tomato) identified 87 SlAChE genes containing GDSL lipase/acylhydrolase domain. The study also showed up-and down-regulation of SlAChE genes under salinity stress condition.
Some marine fungi have been found to produce compounds that inhibit AChE. However, the specific role and mechanisms of AChE in fungi are not as well-studied as in mammals. The presence and role of AChE in bacteria is not well-documented.
A cholinomimetic drug disrupts this process by acting as a cholinergic neurotransmitter that is impervious to acetylcholinesterase's lysing action.
Irreversible inhibitors of AChE may lead to muscular paralysis, convulsions, bronchial constriction, and death by asphyxiation. Organophosphates (OP), esters of phosphoric acid, are a class of irreversible AChE inhibitors. Cleavage of OP by AChE leaves a phosphoryl group in the esteratic site, which is slow to be hydrolyzed (on the order of days) and can become covalently bound. Irreversible AChE inhibitors have been used in insecticides (e.g., malathion) and nerve gases for chemical warfare (e.g., Sarin and VX). Carbamates, esters of N-methyl carbamic acid, are AChE inhibitors that hydrolyze in hours and have been used for medical purposes (e.g., physostigmine for the treatment of glaucoma). Reversible inhibitors occupy the esteratic site for short periods of time (seconds to minutes) and are used to treat of a range of central nervous system diseases. Tetrahydroaminoacridine (THA) and donepezil are FDA-approved to improve cognitive function in Alzheimer's disease. Rivastigmine is also used to treat Alzheimer's and Lewy body dementia, and pyridostigmine bromide is used to treat myasthenia gravis. (1996). 9780071468046, THe McGraw-Hill Companies. ISBN 9780071468046 (1996). 9780071468046, McGraw-Hill. ISBN 9780071468046 (2025). 9781929007608, Elsevier Health Science. ISBN 9781929007608
An endogenous inhibitor of AChE in neurons is Mir-132 microRNA, which may limit inflammation in the brain by silencing the expression of this protein and allowing ACh to act in an anti-inflammatory capacity.
It has also been shown that the main active ingredient in cannabis, tetrahydrocannabinol, is a competitive inhibitor of acetylcholinesterase.
Acetylcholinesterase is also found on the red blood cell membranes, where different forms constitute the Yt blood group . Acetylcholinesterase exists in multiple molecular forms, which possess similar catalytic properties, but differ in their oligomeric assembly and mode of attachment to the cell surface.
Exposure to acetylcholinesterase inhibitors is one of several studied explanations for the chronic cognitive symptoms veterans displayed after returning from the Gulf War. Soldiers were dosed with AChEI pyridostigmine bromide (PB) as protection from nerve agent weapons. Studying acetylcholine levels using microdialysis and HPLC-ECD, researchers at the University of South Carolina School of Medicine determined PB, when combined with a stress element can lead to cognitive responses.
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