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Acetylcholinesterase

Official Full Name
Acetylcholinesterase
Background
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.
Synonyms
true cholinesterase; choline esterase I; cholinesterase; acetylthiocholinesterase; acetylcholine hydrolase; acetyl; β-methylcholinesterase; AcCholE; EC 3.1.1.7; 9000-81-1; Acetylcholinesterase; AChE; acetylhydrolase

Catalog
ProductName
EC No.
CAS No.
Source
Price
CatalogEXWM-3497
EC No.EC 3.1.1.7
CAS No.9000-81-1
Source
CatalogNATE-0020
EC No.EC 3.1.1.7
CAS No.9000-81-1
SourceHEK 293 cells
CatalogNATE-0019
EC No.EC 3.1.1.7
CAS No.9000-81-1
SourceHuman erythrocy...
CatalogNATE-0018
EC No.EC 3.1.1.7
CAS No.9000-81-1
SourceElectrophorus e...
Related Products
CatalogCEI-0211
ProductName(-)-Huperzine A
EC No.
CAS No.102518-79-6
Source
Related Services
Related Protocols
cholinesterase-acetyl -Enzymatic Assay Protocol
Related Reading

Acetylcholinesterase (AChE) is a key enzyme in biological nerve conduction. In the cholinergic synapse, the enzyme degrades acetylcholine, stopping the neurotransmitter's excitatory effect on the postsynaptic membrane and ensuring the normal delivery of nerve signals in the organism. Cholinesterase is classified into acetylcholinesterase and butyrylcholinesterase (BuChE) according to its catalytic substrate properties. AChE is called true or specific cholinesterase and is a very important hydrolase for maintaining cholinergic nerve impulses in vivo. BuChE is called pseudo- or non-specific cholinesterase, and its physiological function is not yet clear.

Acetylcholinesterase

Distribution

Human AChE is mainly distributed in neural tissues, such as white matter and gray matter in brain, nerve cells and neuromuscular junctions in spinal cord and ganglions, and also distributed in non-neural tissues such as red blood cells, platelets, macrophages, and serum. AChE is a membrane-bound protein that is primarily localized to the cell membrane and presynaptic membrane, and some cells also have AChE in the subcellular structure. The activity of AChE bound by erythrocytes is related to the degree of erythrocyte maturation. The activity of AChE in erythroblasts is significantly higher than that of senescent erythrocytes. There was no significant difference in AChE activity between different ages and genders, and there was a trend of increased AChE in pregnant women. The individual differences in the contents of the two cholinesterases are large, and the coefficient of variation can reach 10% to 40%. In the same body, the two cholinesterases are relatively stable with a coefficient of variation of 10%.

Molecular Structure

AChE is a glycoprotein containing a small amount of glucosamine and galactosamine. AChE exists in many molecular forms and can be distinguished based on fluid dynamics and subunit attachment. The catalytic subunits can be linked to a lipid-linked subunit or to a collagen-like subunit to form different heterogeneous molecules. The molecules containing collagen-like structural units have four catalytic subunits, each of which is linked to a helix-like collagen-like subunit through a disulfide bond, in which the collagen-like collagen is similar to the procollagen in the basement membrane collagen. Collagen-like subunits have no collagen sequence at the amino- and carboxyl-terminus and bind to synaptic base components. Because of its filamentous collagen-like structure that leads to its structural asymmetry, it is named asymmetric or A-shaped. The lipid-linked subunit consisting of a tetramer (A4), two tetramers (A8) and three tetramers (A12) has a molecular weight of approximately 20 kD, covalently linked to fatty acids. The lipid-linked subunits are linked to the catalytic subunit tetramers through several disulfide bonds and connect the catalytic subunits to the outer surface of the cell. The enzyme positioned on the outer surface of the membrane creates hydrophobic properties by linking the phospholipids to the carboxyl end. According to its fluid dynamics, it can be attributed to a spherical or G-type. G-type can be further divided into hydrophilic G-type and hydrophobic G-type.

Catalytic Mechanism

The AChE active center consists of three major regions, including an esterification site, an anion site, and a hydrophobic region. The esterification site contains serine and histidine and can bind to the carbonyl carbon atom of ACh. The anion site contains at least one carbonyl group, probably from glutamic acid, which can electrostatically attract the quaternary ammonium cation group of ACh. The hydrophobic region is linked to an esterification or quaternary ammonium group binding site or is composed of an aromatic amino acid such as tryptophan or tyrosine, and plays an important role in the binding of the aromatic substrate. The three-dimensional structural analysis shows that the most prominent feature of AChE is a deep, narrow gorge in which the catalytically active group is located.

ACh binds to regions other than the AChE esterification site through electrostatic and hydrophobic reactions. The acyl group of ACh is reactive but not required for binding. The ACh containing the cationic head is captured at the peripheral binding site and reaches the active center of the enzyme by diffusion. The hydrophobicity of the two methylenes of ACh increases the affinity approximately 10-fold. The combination of ACh at the quaternary ammonium binding site and the hydrophobic region makes it linear and placed in a suitable position to facilitate the nucleophilic attack on the carbon on the ACh acyl group by the Ser hydroxyl oxygen in the active center. The active imidazole group accepts the signal and then releases the protons so that the AChE and the substrate first form a tetrahedral intermediate, which is converted into acetylase and releases the first hydrolysate choline. The carboxyl group of Glu at the active site attracts the proton of imidazolyls to promote the formation of a tetrahedral intermediate. In turn, His imidazole groups attract protons in water molecules to produce hydroxyl ions, attack acetylases to form another four-sided intermediate, and hydrolyze to acetic acid and free AChE.

Medical Applications

Acetylcholinesterase inhibitors can be used to treat various diseases such as Alzheimer's disease, myasthenia gravis and glaucoma. Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction. Its main pathological features are the presence of a large number of senile plaques between nerve cells and the presence of neurofibrillary tangles within nerve cells, seriously affecting the patient's cognitive, memory, language function and living ability. The decrease of cholinergic activity in the brain of AD patients is the main cause of cognitive and memory dysfunction. Increasing the level of acetylcholine in the brain can improve the symptoms of AD patients. The main drug for improving the symptoms of AD is to delay the hydrolysis of ACh by inhibiting AChE activity, thereby increasing the level of cholinergic synaptic cleft and achieving therapeutic goals. Myasthenia gravis is an autoimmune disease mediated by acetylcholine receptor antibodies, T-cell dependent, and complement-mediated neuro-muscular junction transmission disorders, which is currently treated based on anti-AChE drugs.


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