Acetylcholinesterase
Encyclopedia
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Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme
that degrades (through its hydrolytic activity) the neurotransmitter acetylcholine
, producing choline
and an acetate
group. It is mainly found at neuromuscular junction
s and cholinergic
nervous system
, where its activity serves to terminate synaptic transmission. AChE has a very high catalytic activity — each molecule of AChE degrades about 25000 molecules of acetylcholine per second. The choline produced by the action of AChE is recycled — it is transported, through reuptake
, back into nerve terminals where it is used to synthesize new acetylcholine molecules.
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 oligomer
ic assembly and mode of attachment to the cell surface.
In humans acetylcholinesterase is encoded by the ACHE gene
.
s including at least some plants.
and post-translational associations of catalytic and structural subunits. There are three known forms: T (tail), R (read through), and H(hydrophobic).
ous, 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.
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.
, nerve gases(particularly the organophosphates (e.g. Sarin
) and insecticides (e.g. carbaryl
)). These agents — known as cholinesterase inhibitors — block the function of acetylcholinesterase and thus cause more acetylcholine to accumulate in the synaptic cleft.
Excess acetylcholine causes neuromuscular paralysis
(i.e. interminable muscle contraction
s) throughout the entire body, leading to death by asphyxiation.
Cholinesterase inhibitor may also be used in treatment of Lewy Body Dementia.
Cholinesterase inhibitors may be reversible inhibitors
or quasi-irreversible inhibitors
.
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.
It has been shown that the main active ingredient in cannabis, tetrahydrocannibinol, is a competitive inhibitor of acetylcholinesterase.
Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that degrades (through its hydrolytic activity) the neurotransmitter acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, producing choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
and an acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
group. It is mainly found at neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
s and cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, where its activity serves to terminate synaptic transmission. AChE has a very high catalytic activity — each molecule of AChE degrades about 25000 molecules of acetylcholine per second. The choline produced by the action of AChE is recycled — it is transported, through reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
, back into nerve terminals where it is used to synthesize new acetylcholine molecules.
Acetylcholinesterase is also found on the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
membranes, where it constitutes the Yt blood group antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
. Acetylcholinesterase exists in multiple molecular forms, which possess similar catalytic properties, but differ in their oligomer
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
ic assembly and mode of attachment to the cell surface.
In humans acetylcholinesterase is encoded by the ACHE gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Species distribution
Acetylcholine is widely expressed in eukaryoteEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s including at least some plants.
AChE gene
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 splicingAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
and post-translational associations of catalytic and structural subunits. There are three known forms: T (tail), R (read through), and H(hydrophobic).
AChET
The major form of acetylcholinesterase found in brain, muscle, and other tissues, known as is the hydrophilic species, which forms disulfide-linked oligomers with collagenCollagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
ous, or lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-containing structural subunits. In the neuromuscular junctions AChE expresses in asymmetric form which associates with ColQ
COLQ
Acetylcholinesterase collagenic tail peptide also known as AChE Q subunit, acetylcholinesterase-associated collagen, or ColQ is the collagen-tail subunit of acetylcholinesterase found in the neuromuscular junction...
or subunit. In the central nervous system it is associated with PRiMA
PRIMA1
Proline-rich membrane anchor 1, also known as PRiMA, is a protein that in humans is encoded by the PRIMA1 gene. PRiMA functions to organize acetylcholinesterase into tetramers, and to anchor AChE at neural cell membranes....
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
COLQ
Acetylcholinesterase collagenic tail peptide also known as AChE Q subunit, acetylcholinesterase-associated collagen, or ColQ is the collagen-tail subunit of acetylcholinesterase found in the neuromuscular junction...
for the neuromuscular junction and PRiMA for synapses.
AChEH
The other, alternatively-spliced form expressed primarily in the erythroidRed blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
tissues, differs at the C-terminus, and contains a cleavable hydrophobic peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
with a PI-anchor
Glycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
site. It associates with membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
through the phosphoinositide (PI) moieties added post-translationally.
AChER
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.AChE inhibitors
Acetylcholinesterase is the target of many Alzheimer's Dementia drugs and sage oilSage oil
Sage oil is the essential oil made from the culinary herb sage, Salvia officinalis. In addition to its valuable flavoring characteristics, sage oil can contain as much as 50% thujone by weight. The exact amount varies based on the time in the season and which part of the plant is tested...
, nerve gases(particularly the organophosphates (e.g. Sarin
Sarin
Sarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
) and insecticides (e.g. carbaryl
Carbaryl
Carbaryl is a chemical in the carbamate family used chiefly as an insecticide. It is a white crystalline solid commonly sold under the brand name Sevin, a trademark of the Bayer Company. Union Carbide discovered carbaryl and introduced it commercially in 1958...
)). These agents — known as cholinesterase inhibitors — block the function of acetylcholinesterase and thus cause more acetylcholine to accumulate in the synaptic cleft.
Excess acetylcholine causes neuromuscular paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
(i.e. interminable muscle contraction
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
s) throughout the entire body, leading to death by asphyxiation.
Cholinesterase inhibitor may also be used in treatment of Lewy Body Dementia.
Cholinesterase inhibitors may be reversible inhibitors
Reversible inhibitor
For acetylcholine esterase , reversible inhibitors are those that do not irreversibly bond to and decactivate AChE.Drugs that reversibly inhibit acetylcholine esterase are currently being explored as treatments for Alzheimer's disease and myasthenia gravis, among others. Examples include tacrine...
or quasi-irreversible inhibitors
Quasi-irreversible inhibitor
For acetylcholine esterase , quasi-irreversible inhibitors are those that rapidly phosphorylate AChE. A subsequent internal dealkylation reaction may then occur, which, according to X-ray crystallography data, is suggestive of covalent bond formation...
.
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.
It has been shown that the main active ingredient in cannabis, tetrahydrocannibinol, is a competitive inhibitor of acetylcholinesterase.
External links
- ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Insecticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services