Acetylcholinesterase

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Acetylcholinesterase
Acetylcholinesterase
Ribbon model of the human AChE monomer in complex with fasciculin (a snake toxin ), according to PDB  1B41

Existing structural data : 1b41 , 1f8u , 1vzj , 1PUV , 1PUW , 2CLJ , 2X8B , 3LII 4BDT , 4EY4 , 4EY5 , 4EY6 , 4EY7 , 4EY8 , 4M0E , 4M0F , 4PQE

Properties of human protein
Mass / length primary structure 58.4 to 67.4 kilodaltons / 526 to 617 amino acids (depending on isoform)
Secondary to quaternary structure Homotetramer
Isoforms 4th
Identifier
Gene names AChE  ; ARAChE; N-AChE; YT
External IDs
Enzyme classification
EC, category 3.1.1.7 esterase
Response type hydrolysis
Substrate Acetylcholine + H 2 O
Products Choline + acetate
Occurrence
Homology family Carboxylesterase
Parent taxon Chordates
Orthologue
human House mouse
Entrez 43 11423
Ensemble ENSG00000087085 ENSMUSG00000023328
UniProt P22303 P21836
Refseq (mRNA) NM_000665 NM_001290010
Refseq (protein) NP_000656 NP_001276939
Gene locus Chr 7: 100.89 - 100.9 Mb Chr 5: 137.29 - 137.29 Mb
PubMed search 43 11423

Ribbon model of the AChE from Torpedo californica in a complex with Huperzine, according to 1EA5

The acetylcholinesterase ( AChE ) is an enzyme from the group of cholinesterases which specifically the neurotransmitter acetylcholine (ACh) in acetic acid and choline hydrolyzed .

effect

AChE acts primarily in the central nervous system (CNS), at neuromuscular synapses (such as the motor endplate ) and in the vegetative nervous system , since ACh is used here as a neurotransmitter for exocytosis . Acetylcholinesterase is one of the fastest enzymes ever (diffusion-controlled, see enzyme kinetics and diffusion ). The high speed is necessary in order to keep the time interval between the excitations transmitted by the neurons as short as possible by immediately breaking down the neurotransmitter.

Structure of the active center of the enzyme

The active center is located in a 20 Ångström (2 nanometer) deep pocket in the enzyme (also known as gorge ) and consists of a catalytic triad (part of the esteratic site ES), consisting of the amino acids serine , histidine and Glutamic acid , on which the acetylcholine is cleaved, and on the opposite side (at a distance of slightly more than 4 angstroms (0.4 nm)), an anionic site (AS), to which the nitrogen atom of the acetylcholine attaches. In the vicinity of the ES there are other binding sites, such as a pocket for the acyl group of acetylcholine. The names originate from the time before the precise three-dimensional structure determination of the enzyme: ES (esteratic site) with the active center, anionic site AS (anionic site) and outside the deep pocket on its outer edge the peripheral anionic site (PAS), the is important for the binding of a number of AChE inhibitors (such as the snake venom fasciculin ) and for allosteric modulation of enzyme function.

Cholinesterase inhibitors

Acetylcholinesterase is inhibited , among other things, by organophosphoric acid esters through phosphorylation of serine . These include both insecticides such as parathion (E 605) or malathion , as well as chemical warfare agents such as sarin , tabun and soman . The enzyme becomes ineffective, i.e. it can no longer hydrolyze the ACh, and ACh accumulates in the synaptic cleft in a higher concentration . The increase in the parasympathetic tone leads to motor and sensitive overstimulation of internal organs, in particular to spasms of the gastrointestinal tract, and can result in death from respiratory paralysis . Various carbamates used as insecticides act analogously, transferring their carbamate group to the serine and thus deactivating the enzyme. Other AChE inhibitors are e.g. B. diisopropyl (DIFP), 4-chloromercuribenzoic , physostigmine , huperzine A or neostigmine , also known as curare - antagonist effect. It breaks through the action of curare, which prevents ACh binding to subsynaptic receptors . In contrast to neostigmine, physostigmine is common in the CNS .

A number of nerve agents of the organic phosphoric acid ester type such as sarin , VX and Novitschok act as particularly efficient AChE inhibitors, in which the molecules fit into the deep pocket of the enzyme by mimicking the binding of acetylcholine to ES and AS themselves. The amino group of VX and Novitschok binds to the AS, the phosphoric acid ester group to the ES. The warfare agents phosphorylate the serine in the active center and form a covalent bond with it. In a manner specific to the respective nerve agent, a process called aging follows, which begins more or less rapidly and leads to an irreversible loss of function of the enzyme. The complex with a conformational change that forms during aging through dealkylation on the phosphorus group is then resistant to spontaneous hydrolysis and the strong nucleophiles ( oximes ) administered as an antidote .

Other AChE inhibitors are donepezil , rivastigmine , tacrine and galantamine , all of which are approved for the symptomatic treatment of Alzheimer's disease . According to a Swedish study, donepezil, rivastigmine and galantamine also have cardioprotective effects. Patients who took these drugs for their Alzheimer's disease were one-third less likely to have heart attacks . Mortality was also lower in this group. The active ingredient pyridostigmine is used in the form of the non-CNS-common salt pyridostigminium bromide for myasthenia gravis .

In addition, some components of Harpagophytum procumbens (devil's claw) may inhibit cholinesterases, including acetylcholinesterase.

Other uses

Acetylcholinesterase is also used in devices for checking drinking water or for examining samples for insecticides or other acetylcholinesterase-inhibiting toxins.

See also

literature

  • Hay Dvir, Israel Silman, Michal Harel, Terrone Rosenberry, Joel Sussman: Acetylcholinesterase: From 3D Structure to Function . In: Chem. Biol. Interact. , Volume 187, 2010, pp. 10–22, PMC 2894301 (free full text)

Web links

Individual evidence

  1. Hay Dvir, Israel Silman, Michal Harel, Terrone Rosenberry, Joel Sussman: Acetylcholinesterase: From 3D Structure to Function . In: Chem. Biol. Interact. , Volume 187, 2010, pp. 10-22, Figure 7,8, PMC 2894301 (free full text).
  2. See Figure 2 in Dvir u. a .: acetylcholinesterase . In: Chem. Biol. Interact. , Volume 187, 2010
  3. Helen Rice: Toxicology of Organophosphorus Nerve Agents . In: Franz Worek, John Jenner, Horst Thiermann (eds.): Chemical Warfare Toxicology . Royal Society of Chemistry, 2016, p. 88
  4. P. Nordstrom, D. Religa, A. Wimo, B. Winblad, M. Eriksdotter: The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease. In: European Heart Journal . 34, 2013, pp. 2585-2591. doi: 10.1093 / eurheartj / eht182
  5. MI Georgiev, K. Alipieva, IE Orhan: Cholinesterases inhibitory and antioxidant activities of Harpagophytum procumbens from in vitro systems . In: Phytother. Res. February 2012, p. 313-316 , doi : 10.1002 / ptr.3555 , PMID 21721061 .