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
catalyzes the breakdown of
acetylcholine and some other
choline esters that function as
neurotransmitters:
AChE is a
hydrolase that
hydrolyzes choline esters. It has a very high
catalytic activity—each molecule of AChE degrades about 5,000 molecules of
acetylcholine (ACh) per second,[6] approaching the limit allowed by
diffusion of the
substrate.[7][8] The
active 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 quaternary
amine of acetylcholine as well as other cationic substrates and
inhibitors. 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.[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 its
substitution with alanine results in a 3000-fold decrease in reactivity.[15] The gorge is approximately 20
angstroms deep and five angstroms wide.[16]
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.[17] 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.[18][19]
Species
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 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.[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]
Biological function
During
neurotransmission, ACh is released from the presynaptic neuron into the
synaptic 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 with
acetyl-CoA through the action of
choline acetyltransferase.[24][25]
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.[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 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.[28][29][30][31][32][33]
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.[34]
It has also been shown that the main active ingredient in cannabis,
tetrahydrocannabinol, is a competitive inhibitor of acetylcholinesterase.[35]
Distribution
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 the
red blood cell membranes, where different forms constitute the
Yt blood groupantigens.[39] 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 gene
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 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).[41]
AChET
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.
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.[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 for
Alzheimer's disease and
myasthenia gravis, among others. Examples include
tacrine and
donepezil.[45]
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.[46]
^Tripathi A (October 2008). "Acetylcholinsterase: A Versatile Enzyme of Nervous System". Annals of Neurosciences. 15 (4): 106–111.
doi:
10.5214/ans.0972.7531.2008.150403.
^Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JO, White LE (2008). Neuroscience (4th ed.). Sinauer Associates. pp. 121–2.
ISBN978-0-87893-697-7.
^Koelle GB (1954). "The histochemical localization of cholinesterases in the central nervous system of the rat". Journal of Comparative Neurology. 100 (1): 211–35.
doi:
10.1002/cne.901000108.
PMID13130712.
S2CID23021010.
^Johnson G, Moore SW (2012). "Why has butyrylcholinesterase been retained? Structural and functional diversification in a duplicated gene. 2012". Neurochem. Int. 16 (5): 783–797.
doi:
10.1016/j.neuint.2012.06.016.
PMID22750491.
S2CID39348660.
^Dori A, Ifergane G, Saar-Levy T, Bersudsky M, Mor I, Soreq H, Wirguin I (2007). "Readthrough acetylcholinesterase in inflammation-associated neuropathies". Life Sci. 80 (24–25): 2369–74.
doi:
10.1016/j.lfs.2007.02.011.
PMID17379257.
^Millard CB, Kryger G, Ordentlich A, Greenblatt HM, Harel M, Raves ML, Segall Y, Barak D, Shafferman A, Silman I, Sussman JL (June 1999). "Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level". Biochemistry. 38 (22): 7032–9.
doi:
10.1021/bi982678l.
PMID10353814.
S2CID11744952.
Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I (1991). "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein". Science. 253 (5022): 872–9.
Bibcode:
1991Sci...253..872S.
doi:
10.1126/science.1678899.
PMID1678899.
S2CID28833513.
Soreq H, Seidman S (2001). "Acetylcholinesterase--new roles for an old actor". Nature Reviews Neuroscience. 2 (4): 294–302.
doi:
10.1038/35067589.
PMID11283752.
S2CID5947744.
Shen T, Tai K, Henchman RH, McCammon JA (2003). "Molecular dynamics of acetylcholinesterase". Acc. Chem. Res. 35 (6): 332–40.
doi:
10.1021/ar010025i.
PMID12069617.
Pakaski M, Kasa P (2003). "Role of acetylcholinesterase inhibitors in the metabolism of amyloid precursor protein". Current Drug Targets. CNS and Neurological Disorders. 2 (3): 163–71.
doi:
10.2174/1568007033482869.
PMID12769797.
Ehrlich G, Viegas-Pequignot E, Ginzberg D, Sindel L, Soreq H, Zakut H (1992). "Mapping the human acetylcholinesterase gene to chromosome 7q22 by fluorescent in situ hybridization coupled with selective PCR amplification from a somatic hybrid cell panel and chromosome-sorted DNA libraries". Genomics. 13 (4): 1192–7.
doi:
10.1016/0888-7543(92)90037-S.
PMID1380483.
Chhajlani V, Derr D, Earles B, Schmell E, August T (1989). "Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase". FEBS Lett. 247 (2): 279–82.
doi:
10.1016/0014-5793(89)81352-3.
PMID2714437.
S2CID41843002.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Ben Aziz-Aloya R, Sternfeld M, Soreq H (1994). "Promoter elements and alternative splicing in the human ACHE gene". Prog. Brain Res. 98: 147–53.
doi:
10.1016/s0079-6123(08)62392-4.
PMID8248502.