Acetylcholine AChE catalyzed hydrolysis

In the presence of acetylcholine, AChE catalyzes the hydrolysis reaction of acetylcholine to acetate and thiocholine. The thiocholine, in turn, donates electrons... 

Comparison with AChE-Catalyzed Hydrolysis of Acetylcholine. 143... 

Carbachol (see structure above), the carbamate analogue of acetylcholine, shows no selectivity for muscarinic or nicotinic receptors. Because it is a carbamate ester, carbachol is more resistant toward acid-, base-, or enzyme (AChE)-catalyzed hydrolysis than acetylcholine. It also is reported to exhibit weak anticholinesterase activity. Both of these actions work to prolong the duration of action of carbachol. Because of erratic absorption and its actions at nicotinic receptors, use of carbachol has been limited to the treatment of glaucoma and for the induction of miosis in ocular surgery. Carbachol is available as an intraocular solution and an ophthalmic solution. 

Extensive studies of AChE have resulted in the purification and amino acid sequencing of the enzyme from several sources as well as the description of its quaternary structure from x-ray crystallographic and molecular modeling studies (38). To understand the mode of action of AChEls, it is necessary to examine the mechanism by which AChE catalyzes hydrolysis of acetylcholine. This enzymatically controlled hydrolysis parallels the two chemical mechanisms for hydrolysis of esters. The first mechanism is acid-catalyzed hydrolysis, in which the initial step involves protonation of the carbonyl oxygen. The transition state is formed by the attack of a molecule of water at the electrophilic carbonyl carbon atom. Collapse of the transition state affords the carboxylic acid and the alcohol (Fig. 12.11). The second mechanism, base-catalyzed hydrolysis, involves the nucleophilic attack ... 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

To avoid repetitive excitation of the receiving cell caused by the presence of acetylcholine, excessive acetylcholine has to be removed by the enzyme acetylcholinesterase (AChE), which catalyzes hydrolysis of the ester bond as follows ... 

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... 

The synapses using acetylcholine (ACh) as the transmitter substance are the target for a wide variety of pesticides and therefore need a more detailed description. Acetylcholine is used as a transmitter substance in nearly all animal phyla, but at different parts of the nervous system. It is also present in single-cell animals and even in plants. Enzymes that catalyze the hydrolysis of acetylcholine, the cholinesterases, are also present in various organisms not having a nervous system. In insects and other arthropods, ACh is the transmitter of messages from sensory neurons to the central nervous system (CNS) and within the CNS, but not from motor neurons to skeletal muscles, where the transmitter is glutamate. In annelids, the excitatory transmitter for the body wall muscles is acetylcholine, as at the neuromuscular junctions in vertebrates. 

Figure 8.10 Acetylcholine Esterase, (a) Hydrolysis reaction catalyzed by acetyl choline esterase (AChE) (b) ribbon display structure of AChE Torpedo californica) (pdb lamn) illustrating crystallographic water molecules (oxygen red hydrogen white) plus sulphate ion and substrate analogue bound in catalytic site. Both these are rendered as CPK structures (red oxygen yellow sulphur grey carbon blue nitrogen).

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... 

The enzyme acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylcholine to acetate and choline to terminate nerve impulse transmission at cholinergic synapses. This enzyme binds nerve agents such as VX and sarin. Inhibition of AChE by these compounds and the closely related organophosphate pesticides results in constant... 

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

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... 

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 ... 

Butyrylcholinesterase (BChE), also known as serum cholinesterase, catalyzes the hydrolysis of butyrylcholine at rates similar to those of acetylcholine hydrolysis by AChE. Though the function of BChE is poorly understood, it shows 73% similarity and 53% amino acid sequence identity with AChE from electric eel. There is some evidence that BChE is responsible for the activation or inactivation of compounds such as heroine and cocaine and that it is involved in defense against cholinesterase inhibitors... 

New experimental results suggest berberine may have a potential for inhibition and prevention of AD due to the multiple activities that berberine possesses including antioxidant activity, AChE and BChE inhibitory activity, MAO inhibitory activity, and its abilities to reduce Ap peptide level and to lower cholesterol. Many studies have proved AChE-inhibiting property of berberine [83-85]. AChE is mainly present in the central nervous system and its major role is to catalyze the hydrolysis of the neurotransmitter acetylcholine to choline. This process can return an activated cholinergic neuron to its resting state. The pathogenesis of AD is linked to acetylcholine deficiency in the brain. 

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