Acetylcholinesterase

Acetylcholinesterase

acetylcholinesterase
Acetylcholinesterase catalyzes this hydrolysis of acetylcholine to acetate and choline
Identifiers
EC number 3.1.1.7
CAS number 9000-81-1
Databases
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ExPASy NiceZyme view
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MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Acetylcholinesterase (Yt blood group)

PDB rendering based on 1b41.
.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; ACEE; ARACHE; N-ACHE; YT
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
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RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.

Contents

  • Enzyme structure and mechanism 1
  • Biological function 2
  • Disease relevance 3
  • Distribution 4
  • AChE gene 5
    • AChET 5.1
    • AChEH 5.2
    • AChER 5.3
  • See also 6
  • References 7
  • Further reading 8
  • External links 9

Enzyme structure and mechanism

AChe mechanism of action[1]

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]

Biological function

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]

Disease relevance

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]

Mechanism of Inhibitors of AChE

Irreversible inhibitors of AChE may lead to muscular

  • ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Insecticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services
  • Proteopedia Acetylcholinesterase
  • Proteopedia AChE_inhibitors_and_substrates
  • Proteopedia AChE_inhibitors_and_substrates_(Part_II)
  • Proteopedia AChE bivalent inhibitors AChE_bivalent_inhibitors AChE bivalent inhibitors
  • Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe

External links

  • Silman I, Futerman AH (1988). "Modes of attachment of acetylcholinesterase to the surface membrane". Eur. J. Biochem. 170 (1–2): 11–22.  
  • 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.  
  • Soreq H, Seidman S (2001). "Acetylcholinesterase--new roles for an old actor". Nature Reviews Neuroscience 2 (4): 294–302.  
  • Shen T, Tai K, Henchman RH, McCammon JA (2003). "Molecular dynamics of acetylcholinesterase". Acc. Chem. Res. 35 (6): 332–40.  
  • 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.  
  • Meshorer E, Soreq H (2006). "Virtues and woes of AChE alternative splicing in stress-related neuropathologies". Trends Neurosci. 29 (4): 216–24.  
  • Ehrlich G, Viegas-Pequignot E, Ginzberg D, et al. (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.  
  • Spring FA, Gardner B, Anstee DJ (1992). "Evidence that the antigens of the Yt blood group system are located on human erythrocyte acetylcholinesterase". Blood 80 (8): 2136–41.  
  • Shafferman A, Kronman C, Flashner Y, et al. (1992). "Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding". J. Biol. Chem. 267 (25): 17640–8.  
  • Getman DK, Eubanks JH, Camp S, et al. (1992). "The human gene encoding acetylcholinesterase is located on the long arm of chromosome 7". Am. J. Hum. Genet. 51 (1): 170–7.  
  • Li Y, Camp S, Rachinsky TL, et al. (1992). "Gene structure of mammalian acetylcholinesterase. Alternative exons dictate tissue-specific expression". J. Biol. Chem. 266 (34): 23083–90.  
  • Velan B, Grosfeld H, Kronman C, et al. (1992). "The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant". J. Biol. Chem. 266 (35): 23977–84.  
  • Soreq H, Ben-Aziz R, Prody CA, et al. (1991). "Molecular cloning and construction of the coding region for human acetylcholinesterase reveals a G + C-rich attenuating structure". Proceedings of the National Academy of Sciences of the United States of America 87 (24): 9688–92.  
  • Chhajlani V, Derr D, Earles B, et al. (1989). "Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase". FEBS Lett. 247 (2): 279–82.  
  • Lapidot-Lifson Y, Prody CA, Ginzberg D, et al. (1989). "Coamplification of human acetylcholinesterase and butyrylcholinesterase genes in blood cells: correlation with various leukemias and abnormal megakaryocytopoiesis". Proceedings of the National Academy of Sciences of the United States of America 86 (12): 4715–9.  
  • Bazelyansky M, Robey E, Kirsch JF (1986). "Fractional diffusion-limited component of reactions catalyzed by acetylcholinesterase". Biochemistry 25 (1): 125–30.  
  • Gaston SM, Marchase RB, Jakoi ER (1982). "Brain ligatin: a membrane lectin that binds acetylcholinesterase". J. Cell. Biochem. 18 (4): 447–59.  
  • Ordentlich A, Barak D, Kronman C, et al. (1995). "Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase". J. Biol. Chem. 270 (5): 2082–91.  
  • 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.  
  • 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.  
  • Massoulie J, Pezzementi L, Bon S, Krejci E, Valette F (1993). "Molecular and Cellular Biology of Cholinesterases". Prog. Brain Res. 41 (1): 31–91.  

Further reading

  1. ^ Katzung BG (2001). Basic and clinical pharmacology:Introduction to autonomic pharmacology (8 ed.). The McGraw Hill Companies. pp. 75–91.  
  2. ^ Quinn DM (1987). "Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states". Chemical Review 87 (5): 955–79.  
  3. ^ Taylor P, Z Radic (1994). "The cholinesterases: from genes to proteins". Annual Review of Pharmacology and Toxicology 34: 281–320.  
  4. ^ Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I (August 1991). "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein". Science 253 (5022): 872–9.  
  5. ^ Sussman JL, Harel M, Silman I (June 1993). "Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs". Chem. Biol. Interact. 87 (1–3): 187–97.  
  6. ^ Radić Z, Gibney G, Kawamoto S, MacPhee-Quigley K, Bongiorno C, Taylor P (October 1992). "Expression of recombinant acetylcholinesterase in a baculovirus system: kinetic properties of glutamate 199 mutants". Biochemistry 31 (40): 9760–7.  
  7. ^ Ordentlich A, Barak D, Kronman C, Ariel N, Segall Y, Velan B, Shafferman A (February 1995). "Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase". J. Biol. Chem. 270 (5): 2082–91.  
  8. ^ Ariel N, Ordentlich A, Barak D, Bino T, Velan B, Shafferman A (October 1998). "The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors". Biochem. J. 335 (1): 95–102.  
  9. ^ Ordentlich A, Barak D, Kronman C, Flashner Y, Leitner M, Segall Y, Ariel N, Cohen S, Velan B, Shafferman A (August 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". J. Biol. Chem. 268 (23): 17083–95.  
  10. ^ Tougu V (2001). "Acetylcholinesterase: Mechanism of Catalysis and Inhibition". Current Medicinal Chemistry Central Nervous System Agents 1 (2): 155–170.  
  11. ^ Harel, M; Schalk, I; Ehret-Sabatier, L; Bouet, F; Goeldner, M; Hirth, C; Axelsen, PH; Silman, I; Sussman first9 = JL (1993). "Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase". Proceedings of the National Academy of Sciences of the United States of America 90 (19): 9031–5.  
  12. ^ Tripathi A (October 2008). "Acetylcholinsterase: A Versatile Enzyme of Nervous System". Annals of Neuroscience 15 (4).  
  13. ^ Pauling L (1946). "Molecular Architecture and Biological Reactions". Chemical & Engineering News 24 (10): 1375.  
  14. ^ Fersht A (1985). Enzyme structure and mechanism. San Francisco: W.H. Freeman. p. 14.  
  15. ^ a b Pohanka (2011). "Cholinesterases, a target of pharmacology and toxicology". Biomedical Papers Olomouc 155 (3): 219–229.  
  16. ^ Pohanka M (2012). "Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology". Int J Mol Sci 13 (2): 2219–38.  
  17. ^ Whittaker V (1990). "The Contribution of Drugs and Toxins to Understanding of Cholinergic Function". Trends in Physiological Sciences 11 (1): 8–13.  
  18. ^ Purves D; George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, Leonard E. White (2008). Neuroscience 4th ed. Sinauer Associates. pp. 121–2.  
  19. ^ Pohanka M (2012). "Alpha7 Nicotinic Acetylcholine Receptor Is a Target in Pharmacology and Toxicology". International Journal of Molecular Sciences 13 (12): 2219–2238.  
  20. ^ [citation needed]
  21. ^ "National Pesticide Information Center-Diazinon Technical Fact Sheet". Retrieved 24 February 2012. 
  22. ^ "Clinical Application: Acetylcholine and Alzheimer's Disease". Retrieved 24 February 2012. 
  23. ^ Stoelting, R.K. (1999). Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice. Lippincott-Raven.  
  24. ^ Taylor, P; Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, Gilman, A.G.,eds (1996). "5: Autonomic Pharmacology: Cholinergic Drugs". The Pharmacologial Basis of Therapeutics. THe McGraw-Hill Companies. pp. 161–174.  
  25. ^ Blumenthal D, Brunton L, Goodman LS, Parker K, Gilman A, Lazo JS, Buxton I (1996). "5: Autonomic Pharmacology: Cholinergic Drugs". Goodman & Gilman's The pharmacological basis of therapeutics. New York: McGraw-Hill. p. 1634.  
  26. ^ Drachman, D.B.; Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. Kasper, D.L., eds (1998). Harrison's Principles of Internal Medicine (14 ed.). The McCraw-Hill Companies. pp. 2469–2472.  
  27. ^ Raffe, RB. Autonomic and Somatic Nervous Systems in Netter's Illustrated Pharmacology. Elsevier Health Science. p. 43.  
  28. ^ Pohanka M (2011). "Alzheimer´s disease and related neurodegenerative disorders: implication and counteracting of melatonin". Journal of Applied Biomedicine 9 (4): 185–196.  
  29. ^ 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.  
  30. ^ 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.  
  31. ^ Massoulie J, Pezzementi L, Bon S, Krejci E, Vallette FM (July 1993). "Molecular and cellular biology of cholinesterases". Progress in Neurobiology 41 (1): 31–91.  
  32. ^ Chacho LW, Cerf JA (1960). "Histochemical localization of cholinesterase in the amphibian spinal cord and alterations following ventral root section". Journal of Anatomy 94 (Pt 1): 74–81.  
  33. ^ Koelle GB (1954). "The histochemical localization of cholinesterases in the central nervous system of the rat". Journal of Comparative Anatomy 100 (1): 211–35.  
  34. ^ Bartels CF, Zelinski T, Lockridge O (May 1993). "Mutation at codon 322 in the human acetylcholinesterase (ACHE) gene accounts for YT blood group polymorphism". Am. J. Hum. Genet. 52 (5): 928–36.  
  35. ^ 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.  
  36. ^ "Entrez Gene: ACHE acetylcholinesterase (Yt blood group)". 
  37. ^ 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.  

References

See also

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]

AChER

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]

AChEH

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.

AChET

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]

AChE gene

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]

Distribution

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]