The acetylcholinesterase (acetylcholine acetyl hydrolase, EC 3.1.1.7) is an enzyme found mainly in the central nervous system. Its task, as the name implies, is the hydrolytic processing of the neurotransmitter acetylcholine..
It is an enzyme associated with the cell membrane that works together with the acetylcholine receptor to mediate the excitation of postsynaptic cells and whose catalytic mechanism is surprisingly fast.
From the mechanical point of view, this enzyme can be seen as a serine hydrolase, and in the catalytic domain of its active site it contains the triad of amino acids characteristic of serine proteases: serine, histidine and an acidic residue. However, the acidic residue is a glutamate, while the serine proteases normally possess an aspartate..
One of the first observations that linked the catalytic activity of acetylcholinesterase with cholinergic nervous tissues and muscle tissues was made by Dale in 1914; later it has been determined that it is also present in non-cholinergic neurons and in hematopoietic, osteogenic and neoplastic cells.
Thanks to the study of various organisms, it is currently known that the enzyme is present in the membrane of different types of cells such as erythrocytes, nerve and muscle cells, electrical organs and others..
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Under natural conditions or "in vivo ", acetylcholinesterase is a polymorphic enzyme that is composed of several catalytic subunits of more or less 80 kDa, which assemble to form an oligomeric structure (of several subunits).
The quantity and complexity of these subunits depends on the cell type and the species considered..
Some of the more complex enzyme forms have catalytic subunits with globular (G) or asymmetric (A) forms linked by disulfide bridges. Disulfide bridges are covalent bonds formed between two sulfur molecules of the thiol groups (-SH) of two residues of the amino acid cysteine.
Each G subunit contains a single active site, while the A subunits are generally characterized by having three structural domains, namely: catalytic subunits, collagen-like tails rich in glycine, hydroxyproline and hydroxylysine residues, and others. non-collagenic glues (other than collagen).
The asymmetric forms of acetylcholinesterase are known as A12, A8, and A4, which have 12, 8, and 4 catalytic subunits, respectively..
Generally, the residues of the catalytic domain in the active site are found in a "deep" region of the subunits, which could be seen as contradictory with respect to the rapid rate of the reaction that catalyzes this enzyme and the apparent inaccessibility of the substrate to these sites..
Regardless of the polymorphism of the enzyme, both globular and asymmetric subunits have similar catalytic activities..
Certain cells other than nerve cells, such as erythrocytes, produce acetylcholinesterase enzymes that are predominantly globular, dimeric and mostly associated with the outer face of the plasma membrane..
The erythrocyte enzyme, although of less structural complexity, is also an amphipathic enzyme, whose active catalytic domain is found in the large hydrophilic region, while the hydrophobic domain, which contains the carboxyl terminal region, is responsible for sustaining it in the membrane.
Much of the current knowledge about the sequence of acetylcholinesterase emerged from the study of the enzyme Californica torpedo, a stingray fish that lives in the Pacific Ocean and has been traditionally used as a model organism for the study of different proteins of the nervous system.
Acetylcholinesterase subunits are synthesized as pro-proteins that are then processed to give rise to mature subunits. Each subunit consists of a polypeptide of about 575 amino acids and 65 kDa in molecular weight, which is increased by the addition of 7-8% carbohydrate residues (glycosylation)..
The catalytic activity of the active site of the subunits is determined by a serine residue at position 200, which is found in a "deep" region of the catalytic subunits..
Different variants or isoforms of the enzyme exist in organisms thanks to different sites for the “alternative splicing " of the pre-messenger RNAs at both ends (5 'and 3'). The carboxyl-terminal sequence of the isoform of each subunit is what determines the assembly of the oligomers with each other..
Acetylcholinesterase is an enzyme with multiple biological functions not necessarily related to each other. Fact attested by its differential expression during embryogenesis, embryonic neural extension, muscle development and synaptogenesis.
As highlighted above, it has an important role in the rapid hydrolysis of acetylcholine and therefore in the regulation of its effect in the neuromuscular synaptic space or in the cholinergic synaptic spaces of the central nervous system..
An example of its functions is the contraction of skeletal muscle, which occurs thanks to a type of chemical synapse known as a motor plate, located between a motor neuron and a muscle fiber..
In this synapse, hundreds of vesicles loaded with acetylcholine are obtained, which are released from the motor neuron for the propagation of an electrical impulse..
This neurotransmission process is quite complex, however, the participation of acetylcholinesterase is crucial for the termination of synaptic transmission that depends on the neurotransmitter acetylcholine, since it must be degraded and then must diffuse out of the synaptic cleft to culminate with the membrane excitation.
Thus, the enzyme acetylcholinesterase is responsible for regulating the concentration of this transmitter in the neuromotor synapse..
Other "non-classical" functions of the enzyme are related to neuritogenesis or growth of nerve cells; with the processes of cell adhesion, synaptogenesis, activation of neurons-dopamine in the substantia nigra of the midbrain, hematopoietic processes and poietic thrombus, among others.
Acetylcholinesterase inhibitors work by preventing it from hydrolyzing acetylcholine, thereby increasing the level and duration of action of this neurotransmitter. They can be classified, according to their mechanism of action, as reversible and irreversible.
They are those that irreversibly inhibit the hydrolytic activity of acetylcholinesterase by its covalent binding to the serine residue in the active site of the enzyme. This group is mainly composed of the organophosphates.
In general, these are active compounds found in many insecticides and are responsible for a large number of accidental poisoning deaths. They are esters or thiols derived from phosphoric, phosphonic, phosphinic or phosphoramidic acid.
Sarin, tabun, soman and cyclosarin are among the most toxic compounds synthesized by man since they can kill a human being by inducing respiratory and circulatory failure by blocking acetylcholinesterase in the peripheral nervous system..
Sarin, for example, is a “nerve gas” that has been used as a chemical weapon for terrorist use..
This order of classification groups competitive and non-competitive inhibitors that work by transient and reversible carbamylation of a serine residue in the active site and many have been synthesized and purified from plant or fungal sources..
Carbamates such as physostigmine and neostigmine are reversible inhibitors that are used as drugs for the treatment of diseases such as glaucoma and myasthenia gravis, respectively..
Other therapeutic agents in this group are also used for the treatment of Alzheimer's disease, Parkinson's disease, post-operative intestinal obstructions (postoperative ileus), bladder distention, and as antidotes for anticholinergic overdose..
An interesting natural mechanism against some acetylcholinesterase inhibitory substances has to do with the participation of a less specific enzyme known as butyrylcholinesterase.
This enzyme is also capable of hydrolyzing acetylcholine and at the same time it can act as a molecular decoy that reacts with these toxins before they exert their negative effect on acetylcholinesterase..
Acetylcholinesterase has been shown to form a stable complex with the components of the senile plaques characteristic of the pathology. In addition, some altered glycosylation patterns of this enzyme have been related to the presence and formation of amyloid plaques in the brain..
Many of the reversible acetylcholinesterase inhibitors, therefore, have been used as first-generation drugs for the treatment of this disease and other related neurodegenerative conditions. These include donepezil, rivastigmine, and galantamine..
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