Acetylcholine cholinesterase hydrolysis

Two structurally and functionally very similar, yet di.stinct enzymes form the family of cholinesterases (ChHs). Acetylcholinesterase (AChE EC 3.1.1,7) and butyryl-cholinestcrase (BuChE EC 3.1.1.8) both catalyze acetylcholine (ACh) hydrolysis with similarly high efficiency and only differ in efficiency to catalyze the hydrolysis of carboxylic acid e.sters of larger acyl group size, such as butyrylchoHnc or benzoylcholinc. Larger substrates are hydrolyzed much better by BuChE due to small but significant differences in their structure that al.so allows BuChE to... 

There are at least two cholinesterases acetylcholinestarase (AChE), a specific cholinesterase hydrolyzing predominantly the choline esters and occurring in high concentrations in brain, nerve and red blood cells and the other, butyrylcholinesterase (BChE), a nonspecific ( pseudo ) cholinesterase, hydrolyzing other esters as well, and found in the blood, serum, pancreas and liver. These enzymes manifest maximum catalytic activity around neutral pH and at the low levels of acetylcholine. The hydrolysis reaction of acetylcholine catalyzed by AChE is shown below ... 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

There is some confusion in the literature regarding the substances designated as anti-choline-esterases (usually shortened to anticholinesterases). The term cholinesterase was first used1 in connexion with an enzyme present in the blood serum of the horse which catalysed the hydrolysis of acetylcholine and of butyrylcholine, but exhibited little activity towards methyl butyrate,... 

Thus a distinction was provided between simple esterases, such as fiver esterase, which catalysed the hydrolysis of simple aliphatic esters but were ineffective towards choline esters. The term 1 cholinesterase was extended to other enzymes, present in blood sera and erythrocytes of other animals, including man, and in nervous tissue, which catalysed the hydrolysis of acetylcholine. It was assumed that only one enzyme was involved until Alles and Hawes2 found that the enzyme present in human erythrocytes readily catalysed the hydrolysis of acetylcholine, but was inactive towards butyrylcholine. Human-serum enzyme, on the other hand, hydrolyses butyrylcholine more rapidly than acetylcholine. The erythrocyte enzyme is sometimes called true cholinesterase, whereas the serum enzyme is sometimes called pseudo-cholinesterase. Stedman,3 however, prefers the names a-cholinesterase for the enzyme more active towards acetylcholine, and / -cholinesterase for the one preferentially hydrolysing butyrylcholine. Enzymes of the first type play a fundamental part in acetylcholine metabolism in vivo. The function of the second type in vivo is obscure. Not everyone agrees with the designation suggested by Stedman. It must also be stressed that enzymes of one type from different species are not always identical in every respect.4 Furthermore,... 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

This enzyme [EC 3.1.1.7], also known as true cholinesterase, choline esterase I, and cholinesterase, catalyzes the hydrolysis of acetylcholine to produce choline and acetate. The enzyme will also act on a number of acetate esters as well as catalyze some transacetylations. 

Unlike acetylcholine and methacholine, carbachol contains a carbamino functional group instead of an acetyl group, which is not responsive to hydrolysis by cholinesterase. In vitro studies have shown that the rate of hydrolysis is at least twice as slow as that of acetylcholine. 

Reversible cholinesterase inhibitors form a transition state complex with the enzyme, just as acetylcholine does. These compounds are in competition with acetylcholine in binding with the active sites of the enzyme. The chemical stracture of classic, reversible inhibitors physostigmine and neostigmine shows their similarity to acetylcholine. Edrophonium is also a reversible inhibitor. These compounds have a high affinity with the enzyme, and their inhibitory action is reversible. These inhibitors differ from acetylcholine in that they are not easily broken down by enzymes. Enzymes are reactivated much slower than it takes for subsequent hydrolysis of acetylcholine to happen. Therefore, the pharmacological effect caused by these compounds is reversible. 

Mechanism of Action A cholinesterase inhibitor that enhances and prolongs cholinergic function by increasing the concentration of acetylcholine through inhibition of f he hydrolysis of acefylcholine. Therapeutic Effect Increases muscle strength in myasthenia gravis. 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

There are two types of esterases found in animal tissues. True cholinesterase which is found in neural structures, RBC and placenta and is concerned with destruction of acetylcholine released at the nerve endings. The second type is pseudocholinesterase (non-specific cholinesterase) is found in blood serum, intestines, liver and skin and is responsible for the hydrolysis of benzoylcholine and does not hydrolyse methacholine. Cholinesterase hydrolyses acetylcholine into choline and acetic acid. 

Choline esters are poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase in the body. Acetylcholine is very rapidly hydrolyzed (see Chapter 6 Introduction to Autonomic Pharmacology) large amounts must be infused intravenously to achieve concentrations high enough to produce detectable effects. A large intravenous bolus injection has a brief effect, typically... 

One of the most important hydrolases is acetylcholine esterase (cholinesterase). Acetylcholine is a potent neurotransmitter for voluntary muscle. Nerve impulses travel along neurons to the synaptic cleft, where acetylcholine stored in vesicles is released, carrying the impulse across the synapse to the postsynaptic neuron and propagating the nerve impulse. After the nerve impulse moves on, the action of the neurotransmitter molecules must be stopped by cholinesterase, which hydrolyzes acetylcholine to choline and acetic acid. Some dangerous toxins such as the exotoxin of Clostridium botulinum and saxitoxin interfere with cholinesterase, and many nerve agents such as tabun and sarin act by blocking the hydrolytic action of cholinesterase, see also Enzymes Hydrolysis. 

Cholinesterases, e.g., acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholi-nesterase (BChE, EC 3.1.1.8), are serine hydrolases that break down the neurotransmitter acetylcholine and other choline esters [5]. In the neurotransmission processes at the neuromuscular junction, the cationic neurotransmitter acetylcholine (ACh) is released from the presynaptic nerve, diffuses across the synapse and binds to the ACh receptor in the postsynaptic nerve (Fig. 1). Acetylcholinesterase is located between the synaptic nerves and functions as the terminator of impulse transmissions by hydrolysis of acetylcholine to acetic acid and choline as shown in Scheme 4. The process is very efficient, and the hydrolysis rate is close to diffusion controlled [6, 7]. 

The wide use of cholinesterase inhibitors in various spheres of human activities and the risk of acute and chronic intoxications associated with this process prompted investigation of the role of acetylcholinesterase (AChE) and nonspecific esterases in the immunotropic effects of these chemicals. They irreversibly bind to AChE that normally catalyzes the hydrolysis of acetylcholine (ACh) at the... 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

Acyl Cholinesterases. Acetylcholinesterase (AChE EC 3.1.1.7 CAS 9000-81-1) is the serine esterase which catalyzes the hydrolysis of acetylcholine and possesses an esteratic site, and which is responsible for unspecific hydrolyses of several substrates. Also, butyrylcholinesterase (EC 3.1.1.8 CAS 9001-08-5) has been sometimes used for asymmetric hydrolysis of esters. Acetylcholinesterase has been used for... 

Various other reactions. Some other enzymatic reactions, such as the catalysis of the oxidation of aldehydes and of xanthine [181], and oxidation of catechol and hydroquinone catalyzed by tyrosinose [182] have been described in the book [3]. The activity of cholinesterase is proportional to the increase of the anodic wave of thiocholine, which is produced by the hydrolysis of acetylcholine [183]. 

Suxamethonium consists of two acetylcholine molecules linked together. Initially, it acts like acetylcholine by depolarizing the motor end-plate. However, unlike acetylcholine, which on dissociation from the receptor is immediately destroyed by acetylcholinesterase present in the neuromuscular junction, suxamethonium is hydrolysed by a (pseudo)cholinesterase present in the plasma but not at the neuromuscular junction. Most of an injected dose of suxamethonium is normally destroyed before it reaches the neuromuscular junction. If the activity of plasma cholinesterase in a particular patient is reduced, more of the suxamethonium reaches the neuromuscular junction and its action is proportionately prolonged. The molecules of suxamethonium that reach the acetylcholine receptor sites interact repeatedly with them, producing prolonged depolarization of the motor end-plate, which becomes surrounded by an electrically inactive zone. The end-result is flaccid paralysis. The action of suxamethonium is terminated by diffusion away from the neuromuscular junction. Hydrolysis results in choline and succinylmonocholine, which has a very weak competitive blocking action and is further slowly hydrolysed by plasma cholinesterase to choline and succinic acid. 

Acetylcholinesterase (AChE) (also termed true cholinesterase ) is found in the synaptic cleft of cholinergic synapses, and is of undoubted importance in regulation of neurotransmission by rapid hydrolysis of released endogenous acetylcholine (ACh). AChE is also found in erythrocytes and in the CSF, and can be present in soluble form in cholinergic nerve terminals, but its function at these sites is not clear, AChE is specific for substrates that include acetylcholine and the agents methacholine and acetylthiocholine. but it has little activity with other esters. It has a maximum turnover rate at very low concentrations of AChE (and is inhibited by high concentrations). 

Compounds that inhibit or inactivate the body s normal hydrolysis of acetylcholine by acetylcholinesterase in nervous tissue and/or by butyrylcholinesterase (pseudocholinesterase, cholinesterase) in the plasma are called anticholinesterases. The gross observable pharmacological effects of both types of compounds are quite similar. More recently, compounds have been found that enhance the release of acetylcholine from cholinergic nerve terminals, thus (like the anticholinesterases) producing cholinergic effects by an indirect mechanism. 

Replacement of one or more of the hydrogen atoms of the ethylene bridge with alkyl groups produces marked changes in potency and activity. Acetyl /3-methylcholine (31) is equipotent to acetylcholine as a muscarinic agonist, but it has a much weaker nicotinic action (74). A factor in the observed potency of acetyl ]8-methylcholine is its slower rate of hydrolysis by acetylcholinesterase because of poor affinity of the compound for the enzyme s catalytic site (81) and its extremely high resistance to hydrolysis by nonspecific serum cholinesterases. 

Two related enzymes have the ability to hydrolyze acetylcholine. One is acetylcholinesterase (EC 3.1.1.7, acetylcholine acetyUiydrolase), which is called true cholinesterase or choline esterase I. True cholinesterase is found in erythrocytes, the lungs and spleen, nerve endings, and the gray matter of the brain. It is responsible for the prompt hydrolysis of acetylcholine released at the nerve endings to mediate transmission of the neural impulse across the synapse. The degradation of acetylcholine is required for the depolarization of the nerve so that it is repolarized in the next conduction event. 

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