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Acetylcholinesterase, also known as AChE or acetylhydrolase, is a hydrolase that hydrolyzes the neurotransmitter acetylcholine. AChE is found at mainly neuromuscular junctions and cholinergic brain synapses, where its activity serves to terminate synaptic transmission. It belongs to carboxylesterase family of enzymes. It is the primary target of inhibition by organophosphorus compounds such as nerve agents and pesticides.
AChE has a very high catalytic activity - each molecule of AChE degrades about 25000 molecules of acetylcholine (ACh) per second, approaching the limit allowed by diffusion of the substrate.[2][3] The active site of AChE comprises 2 subsites - the anionic site and the esteratic subsite. The structure and mechanism of action of AChE have been elucidated from the crystal structure of the enzyme.[4][5]
The anionic subsite accommodates the positive quaternary angstroms long. The active site is located 4 angstroms from the bottom of the molecule.[11]
The esteratic subsite, where acetylcholine is hydrolyzed to acetate and choline, contains the catalytic triad of three amino acids: serine 200, histidine 440 and glutamate 327. 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.[12] 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.[13][14][15][16]
During neurotransmission, ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the post-synaptic membrane, relaying the signal from the nerve. AChE, also located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh. The liberated choline is taken up again by the pre-synaptic nerve and ACh is synthetized by combining with acetyl-CoA through the action of choline acetyltransferase.[17][18][19]
For a cholinergic neuron to receive another impulse, ACh must be released from the ACh receptor. This occurs only when the concentration of ACh in the synaptic cleft is very low. Inhibition of AChE leads to accumulation of ACh in the synaptic cleft and results in impeded neurotransmission.[20]
Irreversible inhibitors of AChE may lead to muscular
Note: Many of the AChE inhibitors listed above also act as BChE inhibitors.
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The third type has, so far, only been found in Torpedo sp. and mice although it is hypothesized in other species. It is thought to be involved in the stress response and, possibly, inflammation.[37]
The other, alternatively-spliced form expressed primarily in the erythroid tissues, differs at the C-terminus, and contains a cleavable hydrophobic peptide with a PI-anchor site. It associates with membranes through the phosphoinositide (PI) moieties added post-translationally.[36]
The major form of acetylcholinesterase found in brain, muscle, and other tissues, known as is the hydrophilic species, which forms disulfide-linked oligomers with collagenous, or lipid-containing structural subunits. In the neuromuscular junctions AChE expresses in asymmetric form which associates with ColQ or subunit. In the central nervous system it is associated with PRiMA which stands for Proline Rich Membrane anchor to form symmetric form. In either case, the ColQ or PRiMA anchor serves to maintain the enzyme in the intercellular junction, ColQ for the neuromuscular junction and PRiMA for synapses.
In mammals, acetylcholinesterase is encoded by a single AChE gene while some invertebrates have multiple acetylcholinesterase genes. Diversity in the transcribed products from the sole mammalian gene arises from alternative mRNA splicing and post-translational associations of catalytic and structural subunits. There are three known forms: T (tail), R (read through), and H(hydrophobic).[35]
Acetylcholinesterase is also found on the red blood cell membranes, where different forms constitute the Yt blood group antigens.[34] 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.
AChE is found in many types of conducting tissue: nerve and muscle, central and peripheral tissues, motor and sensory fibers, and cholinergic and noncholinergic fibers. The activity of AChE is higher in motor neurons than in sensory neurons.[31][32][33]
It has also been shown that the main active ingredient in cannabis, tetrahydrocannibinol, is a competitive inhibitor of acetylcholinesterase.[30]
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.[29]
[28][15] are inhibitors of acetylcholinesterase as well.rivastigmine, and galantamine, donepezil Alzheimer disease drugs [27][26][25][24][23][22].myasthenia gravis bromide is used to treat pyridostigmine, and Lewy body dementia is also used to treat Alzheimer's and Rivastigmine. Alzheimer's disease are FDA-approved to improve cognitive function in donepezil). 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 glaucoma for the treatment of physostigmine, esters of N-methyl carbamic acid, are AChE inhibitors that hydrolyze in hours and have been used for medical purposes (e.g., Carbamates). Soman and Sarin) and nerve gases for chemical warfare (e.g., malathion (e.g., insecticides bound. Irreversible AChE inhibitors have been used in covalently 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 [21]
Alzheimer's disease, Peripheral nervous system, Choline, Autonomic nervous system, Nicotine
Uniform resource locator, English language, Protein, Weizmann Institute of Science, Protein structure
Acetylcholine, Vitamin C, Medicine, Xenon, Nitrogen
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Acetylcholine, Xenon, Gene, Acetylcholinesterase, Cocaine
Acetylcholine, Glaucoma, Galantamine, Psychology, Rivastigmine
Xenon, Acetylcholine, Caffeine, Acetylcholinesterase, Choline
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