Acetylcholinesterase

Source: Wikipedia, the free encyclopedia.
"ACHE" redirects here. For other uses, see Ache.
Not to be confused with Cholinesterase or Choline acetyltransferase.

acetylcholinesterase
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
ACHE
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000087085

ENSMUSG00000023328

UniProt

P22303

P21836

RefSeq (mRNA)

NM_001290010
NM_009599

RefSeq (protein)

NP_001276939
NP_033729

Location (UCSC)Chr 7: 100.89 – 100.9 MbChr 5: 137.29 – 137.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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:

acetylcholine + H2O = choline + acetate

It is found at mainly

organophosphorus compounds such as nerve agents and pesticides
.

Enzyme structure and mechanism

AChe mechanism of action[5]

AChE is a

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

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

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.

Disease relevance

Main article: Acetylcholinesterase inhibitor

Drugs or toxins that inhibit AChE lead to persistence of high concentrations of ACh within synapses, leading to increased cholinergic signaling within the central nervous system, autonomic ganglia and neuromuscular junctions.[26]

Mechanism of Inhibitors of AChE

Irreversible inhibitors of AChE may lead to muscular

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

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.

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

ColQ
for the neuromuscular junction and PRiMA for synapses.

AChEH

The other, alternatively spliced form expressed primarily in the

phosphoinositide (PI) moieties added post-translationally.[42]

AChER

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]

Nomenclature

The nomenclatural variations of ACHE and of cholinesterases generally are discussed at Cholinesterase § Types and nomenclature.

Inhibitors

Main article: Acetylcholinesterase inhibitor

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

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]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000087085 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023328 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ISBN 978-0-07-160405-5
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  6. ^
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  7. doi:10.1021/cr00081a005
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  14. PMID 8349597. Open access icon
  15. doi:10.2174/1568015013358536. Closed access icon
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  17. doi:10.5214/ans.0972.7531.2008.150403
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  18. doi:10.1021/cen-v024n010.p1375
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  19. ISBN 0-7167-1614-3
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  20. ^
    S2CID 265016505
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  21. doi:10.5214/ans.0972.7531.2008.150403
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  22. ^
    S2CID 25702252
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  23. ^
    doi:10.1007/s42995-020-00065-9
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  24. PMID 2408211
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  25. ISBN 978-0-87893-697-7
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  26. ISBN 978-0-12-386525-0
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  27. ^ "National Pesticide Information Center-Diazinon Technical Fact Sheet" (PDF). Retrieved February 24, 2012.
  28. ^ "Clinical Application: Acetylcholine and Alzheimer's Disease". Retrieved February 24, 2012.
  29. ISBN 978-0-7817-5469-9. Archived from the original
    on March 3, 2016. Retrieved February 26, 2012.
  30. ISBN 978-0-07-146804-6. Archived from the original
    on March 4, 2016. Retrieved February 26, 2012.
  31. ISBN 978-0-07-146804-6
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  32. ISBN 978-0-07-020291-7
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  33. ISBN 978-1-929007-60-8
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  34. PMID 20005135
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  35. PMID 17140265
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  36. S2CID 21601586
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  37. PMID 13808985
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  38. S2CID 23021010
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  39. PMID 8488842
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  40. S2CID 39348660
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  41. PMID 18541228
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  42. ^ "Entrez Gene: ACHE acetylcholinesterase (Yt blood group)".
  43. PMID 17379257
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  44. S2CID 11744952
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  45. ISBN 978-1-4292-0679-2
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  46. PMID 30953774
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  47. PMID 35702400
    .

Further reading

External links
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