Acetylcholinesterase (HGNC symbolACHE; EC 3.1.1.7; systematic nameacetylcholine acetylhydrolase), also known asAChE, AChase oracetylhydrolase, is the primarycholinesterase in the body. It is anenzyme thatcatalyzes the breakdown ofacetylcholine and some othercholine esters that function asneurotransmitters:
AChE is ahydrolase thathydrolyzes choline esters. It has a very highcatalytic activity—each molecule of AChE degrades about 5,000 molecules ofacetylcholine (ACh) per second,[6] approaching the limit allowed bydiffusion of thesubstrate.[7][8] Theactive site of AChE comprises two 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.[9][10]
The anionic subsite accommodates the positive quaternaryamine of acetylcholine as well as other cationic substrates andinhibitors. The cationic substrates are not bound by a negatively charged amino acid in the anionic site, but by interaction of 14aromatic residues that line a gorge leading to the active site.[11][12][13] All 14 amino acids in the aromatic gorge are highly conserved across different species.[14] Among the aromatic amino acids,tryptophan 84 is critical and itssubstitution with alanine results in a 3000-fold decrease in reactivity.[15] The gorge is approximately 20angstroms deep and five angstroms wide.[16]
The esteratic subsite, where acetylcholine is hydrolyzed to acetate and choline, contains thecatalytic triad of three amino acids:serine 203,histidine 447 andglutamate 334. These three amino acids are similar to the triad in otherserine proteases except that the glutamate is the third member rather thanaspartate. Moreover, the triad is of opposite chirality to that of other proteases.[17] The hydrolysis reaction of the carboxyl ester leads to the formation of an acyl-enzyme and freecholine. Then, the acyl-enzyme undergoesnucleophilic attack by a water molecule, assisted by the histidine 440 group, liberatingacetic acid and regenerating the free enzyme.[18][19]
AChE is found in many biological species, including humans and other mammals, non-vertebrates, and plants.[20][21][22][23]
In humans, AChE is a cholinergic enzyme involved in the hydrolysis of the neurotransmitter acetylcholine (ACh) into its constituents, choline, and acetate.[20]Overall, in mammals, AChE is primarily involved in the termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine.[20] In non-vertebrates, 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.[22][23]
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 onSolanum 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.[20]
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.[23] The presence and role of AChE in bacteria is not well-documented.[23]
Duringneurotransmission, ACh is released from the presynaptic neuron into thesynaptic cleft and binds to ACh receptors on the post-synaptic membrane, relaying the signal from the nerve. AChE is concentrated in the synaptic cleft, where it terminates the signal transmission by hydrolyzing ACh.[6] The liberated choline is taken up again by the pre-synaptic neuron and ACh is synthesized by combining withacetyl-CoA through the action ofcholine acetyltransferase.[24][25]
Acholinomimetic drug disrupts this process by acting as a cholinergic neurotransmitter that is impervious to acetylcholinesterase's lysing action.[citation needed]
Irreversible inhibitors of AChE may lead to muscularparalysis, convulsions,bronchial constriction, and death byasphyxiation.Organophosphates (OP), esters of phosphoric acid, are a class of irreversible AChE inhibitors.[27] 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 becomecovalently bound. Irreversible AChE inhibitors have been used ininsecticides (e.g.,malathion) and nerve gases for chemical warfare (e.g.,Sarin andVX).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 ofglaucoma). 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) anddonepezil are FDA-approved to improve cognitive function inAlzheimer's disease.Rivastigmine is also used to treat Alzheimer's andLewy body dementia, andpyridostigmine bromide is used to treatmyasthenia gravis.[28][29][30][31][32][33]
An endogenous inhibitor of AChE in neurons isMir-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.[34]
It has also been shown that the main active ingredient in cannabis,tetrahydrocannabinol, is a competitive inhibitor of acetylcholinesterase.[35]
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.[36][37][38]
Acetylcholinesterase is also found on thered blood cell membranes, where different forms constitute theYt blood groupantigens.[39] Acetylcholinesterase exists in multiple molecular forms, which possess similar catalytic properties, but differ in theiroligomeric assembly and mode of attachment to the cell surface.[citation needed]
In mammals, acetylcholinesterase is encoded by a single AChE gene while some invertebrates have multiple acetylcholinesterase genes. Note higher vertebrates also encode a closely related paralog BCHE (butyrylcholinesterase) with 50% amino acid identity to ACHE.[40] Diversity in the transcribed products from the sole mammalian gene arises from alternativemRNA splicing andpost-translational associations of catalytic and structural subunits. There are three known forms: T (tail), R (read through), and H (hydrophobic).[41]
The major form of acetylcholinesterase found in brain, muscle, and other tissues, known as is the hydrophilic species, which forms disulfide-linked oligomers withcollagenous, orlipid-containing structural subunits. In the neuromuscular junctions AChE expresses in asymmetric form which associates withColQ or subunit. In the central nervous system it is associated withPRiMA 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.
The third type has, so far, only been found inTorpedo sp. and mice although it is hypothesized in other species. It is thought to be involved in the stress response and, possibly, inflammation.[43]
For acetylcholine esterase (AChE),reversible inhibitors are those that do not irreversibly bond to and deactivate AChE.[44] Drugs that reversibly inhibit acetylcholine esterase are being explored as treatments forAlzheimer's disease andmyasthenia gravis, among others. Examples includetacrine anddonepezil.[45]
Exposure to acetylcholinesterase inhibitors is one of several studied explanations for the chronic cognitive symptoms veterans displayed after returning from theGulf War. Soldiers were dosed with AChEIpyridostigmine bromide (PB) as protection from nerve agent weapons. Studying acetylcholine levels using microdialysis andHPLC-ECD, researchers at the University of South Carolina School of Medicine determined PB, when combined with a stress element can lead to cognitive responses.[46]
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