Wikipedia

User:Sbolmer/sandbox

For other uses, see Ache.
acetylcholinesterase
Identifiers
EC no.3.1.1.7
CAS no.9000-81-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
AChe mechanism of action [1]
Mechanism of Inhibitors of AChe

Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is a serine protease that hydrolyzes the neurotransmitter acetylcholine. AChE is found at mainly neuromuscular junctions and cholinergic brain synapses, where its activity serves to terminate synaptic transmission.

Enzyme Structure and Mechanism edit

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 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 the gorge leading to the active site. [6][7][8] All 14 amino acids in the aromatic gorge are highly conserved across different species. [9] Among the aromatic amino acids, tryptophan 84 is critical and its substitution with alanine results in a 3000-fold decrease in reactivity. [10] The gorge penetrates half way through the enzyme and is approximately 20 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 asparate. Moreover, the triad is of opposite handedness 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]

Biological Function edit

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. [15] [16]

Disease Relevance edit

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.

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. [17] 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., Sorin snd Soman). 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. Tetrohydroaminoacridine (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. [18] [19] [20] [21] [22] [23]

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 an in anti-inflammatory capacity.[24]

It has also been shown that the main active ingredient in cannabis, tetrahydrocannibinol, is a competitive inhibitor of acetylcholinesterase.[25]

Distribution edit

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. [26] [27] [28]

Acetylcholinesterase is also found on the red blood cell membranes, where it constitutes the Yt blood group antigen. 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 edit

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).[29]

AChET edit

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.

AChEH edit

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.[30]

AChER edit

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.[31]


See also edit

References edit

  1. ^ Katzung, BG (2001). Basic and clinical pharmacology:Introduction to autonomic pharmacology (8 ed.). The McGraw Hill Companies. pp. 75–91. ISBN 978-0071604055.
  2. ^ Quinn, D.M. (1987). "Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states". Chemical Review. 87 (5): 955–79. doi:10.1021/cr00081a005.
  3. ^ Taylor, P.; Radić, Z. (1994). "The cholinesterases: from genes to proteins". Annual Review of Pharmacology and Toxicology. 34: 281–320. doi:10.1146/annurev.pa.34.040194.001433. PMID 8042853.{{cite journal}}: CS1 maint: date and year (link)
  4. ^ Sussman, Joel L.; Harel, Michal; Frolow, Felix; Oefner, Christian; Goldman, Adrian; Toker, Lilly; Silman, Israel (1991). "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein". Science. 253 (5022): 872–9. doi:10.1126/science.1678899. PMID 1678899 PMID 1678899. {{cite journal}}: Check |pmid= value (help)CS1 maint: date and year (link)
  5. ^ Sussman, J.L. (1992). "Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs In Multidisciplinary Approaches to Cholinesterase Function". Chemico-biological Interactions. 87 (1–3): 95–108. doi:10.1016/0009-2797(93)90042-W. PMID 8343975. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Radić, Z.; Gibney, G.; Kawamoto, S.; Macphee-Quigley, K.; Bongiorno, C.; Taylor, P. (1992). "Expression of recombinant acetylcholinesterase in a baculovirus system: kinetic properties of glutamate 199 mutants". Biochemistry. 31 (40): 9760–7. doi:10.1021/bi00155a032. PMID 1356436.{{cite journal}}: CS1 maint: date and year (link)
  7. ^ Ordentlich, A.; Barak, D.; Kronman, C.; Ariel, N.; Segall, Y.; Velan, B.; Shafferman, A. (1995). "Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase". Journal of Biological Chemistry. 270 (5): 2082–91. doi:10.1074/jbc.270.5.2082. PMID 7836436.{{cite journal}}: CS1 maint: date and year (link)
  8. ^ Ariel, N.; Ordentlich, A.; Barak, D.; Bino, T.; Velan, B.; Shafferman, A. (1998). "The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors". Biochemistry Jerounal. 335 (1): 95–102. doi:10.1042/bj3350095. PMC 1219756. PMID 9742217.{{cite journal}}: CS1 maint: date and year (link)
  9. ^ Ordentlich, A.; Barak, D.; Kronman, C.; Flashner, Y.; Leitner, M.; Segall, Y.; Ariel, N.; Cohen, S.; Velan, B.; Shafferman, A. (1993). "Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket". Journal of Biological Chemistry. 268 (23): 17083–95. doi:10.1016/S0021-9258(19)85305-X. PMID 8349597.{{cite journal}}: CS1 maint: date and year (link)
  10. ^ Tougu, V (2001). "Acetylcholinesterase: Mechanism of Catalysis and Inhibition". Current Medicinal Chemistry Central Nervous System Agents. 1 (2): 155–170. doi:10.2174/1568015013358536.
  11. ^ Harel, M.; Schalk, I.; Ehret-Sabatier, L.; Bouet, F.; Goeldner, M.; Hirth, C.; Axelsen, P. H.; Silman, I.; Sussman, J. L. (1993). "Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase". Proceedings of the National Academy of Science of the United States of America. 90 (19): 9031–5. doi:10.1073/pnas.90.19.9031. PMC 47495. PMID 8415649.{{cite journal}}: CS1 maint: date and year (link)
  12. ^ Tripathi, Anurag (October 2008). "Acetylcholinsterase: A Versatile Enzyme of Nervous System". Annals of Neuroscience. 15 (4): 106–111. doi:10.5214/ans.0972.7531.2008.150403.{{cite journal}}: CS1 maint: date and year (link)
  13. ^ Pauling, Lynus (1946). "Molecular Architecture and Biological Reactions" (PDF). Chemical Engineering News. 24 (10): 1375–1377. doi:10.1021/cen-v024n010.p1375.
  14. ^ Fersht, Alan (1985). Enzyme structure and mechanism. San Francisco: W.H. Freeman. p. 14. ISBN ISBN 0-7167-1614-3. {{cite book}}: Check |isbn= value: invalid character (help)
  15. ^ Whittaker, V (1990). "The Contribution of Drugs and Toxins to Understanding of Cholinergic Function". Trends in Physiological Sciences. 11 (1): 8–13. doi:10.1016/0165-6147(90)90034-6. PMID 2408211.
  16. ^ Purves, Dale (2008). Neuroscience 4th ed. Sinauer Associates. pp. 121–2. ISBN 978-0-87893-697-7. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ "National Pesticide Information Center-Diazinon Technical Fact Sheet" (PDF). Retrieved 24 February 2012.
  18. ^ "Clinical Application: Acetylcholine and Alzheimer's Disease". Retrieved 24 February 2012.
  19. ^ Stoelting, R.K. (1999). Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice. Lippincott-Raven. ISBN 9780781754699.
  20. ^ Taylor, P (1996). "5: Autonomic Pharmacology: Cholinergic Drugs". The Pharmacologial Basis of Therapeutics. THe McGraw-Hill Companies. pp. 161–174. ISBN 9780071468046. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ Moroi, SE (1996). "5: Autonomic Pharmacology: Cholinergic Drugs". The Pharmacologial Basis of Therapeutics. THe McGraw-Hill Companies. p. 1634. ISBN 9780071468046. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ Drachman, D.B. (1998). Harrison's Principles of Internal Medicine (14 ed.). The McCraw-Hill Companies. pp. 2469–2472. ISBN 9780070202917. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  23. ^ Raffe, RB (2004). Autonomic and Somatic Nervous Systems in Netter's Illustrated Pharmacology. Elsevier Health Science. p. 43. ISBN 978-1-929007-60-8.
  24. ^ Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H (2009). "MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase". Immunity. 31 (6): 965–73. doi:10.1016/j.immuni.2009.09.019. PMID 20005135.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Eubanks LM, Rogers CJ, Beuscher AE 4th, Koob GF, Olson AJ, Dickerson TJ, Janda KD. (2006). "A molecular link between the active component of marijuana and Alzheimer's disease pathology". Mol Pharm. 3 (6): 773–7. doi:10.1021/mp060066m. PMC 2562334. PMID 17140265.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  26. ^ Massoulié, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette, F. M. (1993). "Molecular and cellular biology of cholinesterases". Progress in Neurobiology. 41 (1): 31–91. doi:10.1016/0301-0082(93)90040-y. PMID 8321908. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  27. ^ Chacho, LW (1960). "Histochemical localization of cholinesterase in the amphibian spinal cord and alterations following ventral root section". Journal of Anatomy. 94: 74–81. PMID PMC1244416. {{cite journal}}: Check |pmid= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ Koelle, GB (1954). "The histochemical localization of cholinesterases in the central nervous system of the rat". Journal of Comparative Anatomy. 100 (1): 211–35. doi:10.1002/cne.901000108. PMID 13130712.
  29. ^ Massoulié J, Perrier N, Noureddine H, Liang D, Bon S (2008). "Old and new questions about cholinesterases". Chem Biol Interact. 175 (1–3): 30–44. doi:10.1016/j.cbi.2008.04.039. PMID 18541228.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ "Entrez Gene: ACHE acetylcholinesterase (Yt blood group)".
  31. ^ 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. PMID 17379257.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Sbolmer/sandbox&oldid=1168312400"