The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of

choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...

-based

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

s: : an acylcholine + H₂O = choline + a carboxylate Several of these serve as neurotransmitters. Thus, it is either of two

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s that

catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolys ...

of these

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...

neurotransmitters, such as breaking acetylcholine into

and acetic acid. These reactions are necessary to allow a cholinergic

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

to return to its resting state after activation. For example, in

muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...

, acetylcholine at a neuromuscular junction triggers a contraction; but for the muscle to relax afterward, rather than remaining locked in a tense state, the acetylcholine must be broken down by a choline esterase. The main type for that purpose is acetylcholinesterase (also called choline esterase I or erythrocyte cholinesterase); it is found mainly in

chemical synapse Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

s and

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

membranes. The other type is

butyrylcholinesterase Butyrylcholinesterase ( HGNC symbol BCHE; EC 3.1.1.8), also known as BChE, BuChE, BuChase, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it ...

(also called choline esterase II or plasma cholinesterase); it is found mainly in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

Types and nomenclature

The two types of cholinesterase are acetylcholinesterase (ACHE) and

(BCHE). The difference between the two types has to do with their respective preferences for substrates: the former hydrolyses acetylcholine more quickly; the latter hydrolyses

butyrylcholine Butyrylcholine is a choline-based ester that can function as a neurotransmitter. It is similar to acetylcholine, with activation of some of the same receptors as acetylcholine. Butyrylcholine is a synthetic compound and does not occur in the body ...

more quickly. The term ''cholinesterase'' is sometimes used to refer specifically to butyrylcholinesterase, but this

usage The usage of a language is the ways in which its written and spoken variations are routinely employed by its speakers; that is, it refers to "the collective habits of a language's native speakers", as opposed to idealized models of how a language ...

produces the oddity that ''cholinesterase'' and ''false cholinesterase'' (''pseudocholinesterase'') under that scheme mean the same thing (confusingly), and acetylcholinesterase is then called ''true cholinesterase'' in contrast, producing the second oddity that ''cholinesterase'' and ''true cholinesterase'' then do not mean the same thing. But such usage is now outdated; the current, unambiguous

HGNC The HUGO Gene Nomenclature Committee (HGNC) is a committee of the Human Genome Organisation (HUGO) that sets the standards for human gene nomenclature. The HGNC approves a ''unique'' and ''meaningful'' name for every known human gene, based on a q ...

names and symbols are acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE). Acetylcholinesterase () (ACHE), also known as AChE, choline esterase I, RBC cholinesterase, or erythrocyte cholinesterase, true cholinesterase, choline esterase I, or (most formally) acetylcholine acetylhydrolase, is found primarily in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

membranes, in neuromuscular junctions, and in other neural synapses. Acetylcholinesterase exists in multiple molecular forms. In the mammalian brain the majority of AChE occurs as a tetrameric, G4 form (10) with much smaller amounts of a monomeric G1 (4S) form. Butyrylcholinesterase () (BCHE), also known as cholinesterase, choline esterase II, BChE, BuChE, pseudocholinesterase (PCE), plasma cholinesterase (PChE), serum cholinesterase (SChE), butylcholinesterase, or (most formally) acylcholine acylhydrolase, is produced in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

and found primarily in

. The

butyl In organic chemistry, butyl is a four- carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, gi ...

and butyryl syllables both refer to butane with one of its terminal

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...

s substituted. The half-life of BCHE is approximately 10 to 14 days. BCHE levels may be reduced in patients with advanced

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...

. The decrease must be greater than 75% before significant prolongation of neuromuscular blockade occurs with

succinylcholine Suxamethonium chloride, also known as suxamethonium or succinylcholine, or simply sux by medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. This is done to help with tracheal intubation or ele ...

Discovery

In 1968, Walo Leuzinger ''et al.'' successfully purified and crystallized acetylcholinesterase from

electric eel The electric eels are a genus, ''Electrophorus'', of neotropical freshwater fish from South America in the family Gymnotidae. They are known for their ability to stun their prey by generating electricity, delivering shocks at up to 860 volt ...

s at Columbia University, New York. The 3D structure of acetylcholinesterase was first determined in 1991 by Joel Sussman ''et al.'' using protein from the

Pacific electric ray ''Tetronarce californica'' also known as the Pacific electric ray is a species of electric ray in the family Torpedinidae, endemic to the coastal waters of the northeastern Pacific Ocean from Baja California to British Columbia. It generally inh ...

. Clinically useful quantities of butyrylcholinesterase were synthesized in 2007 by PharmAthene, through the use of genetically modified goats. *

Clinical significance

An absence or mutation of the BCHE enzyme leads to a medical condition known as

pseudocholinesterase deficiency Pseudocholinesterase deficiency is an autosomal recessive inherited blood plasma enzyme abnormality in which the body's production of butyrylcholinesterase (BCHE; pseudocholinesterase aka PCE) is impaired. People who have this abnormality may be ...

. This is a silent condition that manifests itself only when people that have the deficiency receive the muscle relaxants

or mivacurium during a surgery. Pseudocholinesterase deficiency may also affect local anaesthetic selection in dental procedures. The enzyme plays an important role in the metabolism of ester-based local anaesthetics, a deficiency lowers the margin of safety and increases the risk of systemic effects with this type of anaesthetic. The selection of an amide-based solution is recommended in such patients. Elevation of plasma BCHE levels was observed in 90.5% of cases of acute

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

. The presence of ACHE in the amniotic fluid may be tested in early pregnancy. A sample of amniotic fluid is removed by

amniocentesis Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is n ...

, and presence of ACHE can confirm several common types of birth defect, including abdominal wall defects and

neural tube defects Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...

. BCHE can be used as a

prophylactic Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...

agent against

nerve gas Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that ...

and other organophosphate poisoning. Some early research points to genetic butylcholinesterase deficiency as a possible candidate component in

sudden infant death syndrome Sudden infant death syndrome (SIDS) is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and detailed death scene investigation. SIDS usuall ...

Inhibitors

A cholinesterase inhibitor (or "anticholinesterase") suppresses the action of the enzyme. Because of its essential function, chemicals that interfere with the action of cholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death (examples are some snake venoms, and the nerve gases sarin and VX). One counteracting medication is

pralidoxime Pralidoxime (2-pyridine aldoxime methyl chloride) or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to treat organophosph ...

. The so-called nerve gases and many substances used in insecticides have been shown to act by combining with a residue of serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. The enzyme acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the

. The structural requirements are a

phosphorus Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...

atom bearing two

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

groups, a leaving group (such as a halide or

thiocyanate Thiocyanate (also known as rhodanide) is the anion . It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Mercury(II) thiocyanate was formerly used in pyr ...

), and a

terminal Terminal may refer to: Computing Hardware * Terminal (electronics), a device for joining electrical circuits together * Terminal (telecommunication), a device communicating over a line * Computer terminal, a set of primary input and output dev ...

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

. The entry on

Lawesson's reagent Lawesson's reagent (LR) is a chemical compound used in organic synthesis as a thiation agent. Lawesson's reagent was first made popular by Sven-Olov Lawesson, who did not, however, invent it. Lawesson's reagent was first made in 1956 during a s ...

has some details on one sub-class of the phosphorus-based compounds. Some benzodiazepines, e.g.

temazepam Temazepam (sold under the brand names Restoril among others) is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hyp ...

have an inhibitory effect on cholinesterase. Cholinesterase levels can be used as an indirect marker of arsenic exposure. Outside of biochemical warfare, anticholinesterases are also used for reversing medication induced paralysis during anesthesia; as well as in the treatment of myasthenia gravis,

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

, and Alzheimer's disease. Such compounds are used for killing

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

in a range of products including

sheep dip Sheep dip is a liquid formulation of insecticide and fungicide which shepherds and farmers use to protect their sheep from infestation against external parasites such as itch mite (''Psoroptes ovis''), blow-fly, ticks and lice. History Sheep ...

, organophosphate pesticides, and carbamate pesticides. In addition to acute poisoning as described above, a semi-acute poisoning characterized by strong mental disturbances can occur. Also, prolonged exposure can cause

birth defects A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

Additional images

Image:Acetylcholine.svg, Acetylcholine Image:Choline-skeletal.svg,

Choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...

Image:Acetic-acid-2D-skeletal.svg, Acetic acid Image:Butyrylcholine.png,

Butyrylcholine Butyrylcholine is a choline-based ester that can function as a neurotransmitter. It is similar to acetylcholine, with activation of some of the same receptors as acetylcholine. Butyrylcholine is a synthetic compound and does not occur in the body ...

References

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 The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is ...

Movies at weizmann.ac.il
showing the structure of acetylcholinesterase and interactions with various inhibitors. * * * * {{Portal bar, Biology, border=no Acetylcholine Peripheral membrane proteins EC 3.1.1