Cholinesterases hydrolysis

Bethanechol incorporates the stabilizing structural features of both methacholine and carbachol. Thus it is like carbachol in that no appreciable cholinesterase hydrolysis takes place, and like methacholine it does not stimulate ganglia or skeletal muscle. This dmg appears to show some specificity of action in the gastrointestinal and urinary tracts. Thus, it has clinical applications in postoperative distention of the abdomen and bladder in the latter case it relieves the urinary retention that results following surgery. The drug is even orally effective. 

Pharmacogenetics the responses to dmgs may be significantiy different according to heritable factors that can modulate pharmacodynamic or pharmacogenetic factors (118). Atypical cholinesterase occurs in about 1 in 2000 Caucasians and is associated with a markedly reduced sensitivity to hydrolysis of the muscle-relaxant cholinesterase. Similarly, the reduced sensitivity to the anticoagulant warfarin is associated with a reduced receptor affinity. 

The Structure of the Active Surface of Cholinesterases and the Mechanism of Their Catalytic Action in lister Hydrolysis... 

Michaelis-Menten kinetics. Consider the hydrolysis of phenyl acetate catalyzed by acetyl cholinesterase,... 

Similarly to quantitative determination of high surfactant concentrations, many alternative methods have been proposed for the quantitative determination of low surfactant concentrations. Tsuji et al. [270] developed a potentio-metric method for the microdetermination of anionic surfactants that was applied to the analysis of 5-100 ppm of sodium dodecyl sulfate and 1-10 ppm of sodium dodecyl ether (2.9 EO) sulfate. This method is based on the inhibitory effect of anionic surfactants on the enzyme system cholinesterase-butyryl-thiocholine iodide. A constant current is applied across two platinum plate electrodes immersed in a solution containing butyrylthiocholine and surfactant. Since cholinesterase produces enzymatic hydrolysis of the substrate, the decrease in the initial velocity of the hydrolysis caused by the surfactant corresponds to its concentration. Amounts up to 60 pg of alcohol sulfate can be spectrometrically determined with acridine orange by extraction of the ion pair with a mixture 3 1 (v/v) of benzene/methyl isobutyl ketone [271]. 

There is a second type of cholinesterase called butyrylcholinesterase, pseudocholinesterase, or cholinesterase. This enzyme is present in some nonneural cells in the central and peripheral nervous systems as well as in plasma and serum, the liver, and other organs. Its physiologic function is not known, but is hypothesized to be the hydrolysis of esters ingested from plants (Lefkowitz et al. 1996). Plasma cholinesterases are also inhibited by organophosphate compounds through irreversible binding this binding can act as a detoxification mechanism as it affords some protection to acetylcholinesterase in the nervous system (Parkinson 1996 Taylor 1996). 

Released ACh is broken down by membrane-bound acetylcholinesterase, often called the true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo-or non-specific plasma cholinesterase. It is an extremely efficient enzyme with one molecule capable of dealing with something like 10000 molecules of ACh each second, which means a short life and rapid turnover (100 ps) for each molecule of ACh. It seems that about 50% of the choline freed by the hydrolysis of ACh is taken back into the nerve. There is a wide range of anticholinesterases which can be used to prolong and potentiate the action of ACh. Some of these, such as physostigmine, which can cross the blood-brain barrier to produce central effects and neostigmine, which does not readily... 

Brief notes are added on phosphorofluoridates even though their destruction by microbial activity— though clearly possible—is limited by their toxicity to the requisite microorganisms. One of the motivations for their inclusion is the fact that the hydrolytic enzyme(s) responsible for defluorination—organophosphorus acid anhydrase (OPA)—is widespread, and is found in a number of bacteria (Landis and DeFrank 1990). The microbial hydrolysis of organophosphorus pesticides and cholinesterase inhibitors is accomplished by several distinct enzymes, which are collectively termed organophosphorus acid anhydrases (OPAs). These have been reviewed (DeFrank 1991), so that only a few additional comments are necessary. 

However, there are some data on interactions of phosphate esters with other compounds. Cocaine undergoes metabolism by three major routes one of these routes involves hydrolysis by liver and plasma cholinesterases to form ecgonine methyl ester. It has been suggested that cocaine users with serious complications tend to have lower plasma cholinesterase levels. Thus, it is possible that individuals with decreased plasma cholinesterase levels (such as resulting from organophosphate ester exposure) may be highly sensitive to cocaine (Cregler and Mark 1986 Hoffman et al. 1992). However, there are no experimental data to support this hypothesis. 

Observations The reaction lasts 1 h. The results are expressed in pM s 1kg" 1 of fresh mass. As shown in our experiments, the rates of hydrolysis of acetylthiocholine of studied plant cells varied from 0.4 0.05 pM s 1kg 1 of fresh mass for pollen of knights star up to 0.105 0.01 pM s 1kg 1 of fresh mass for horsetail vegetative microspores. Table 1 shows I50 for inhibition of cholinesterase from microspores by used inhibitors. 

Observations The preliminary treatment of the cholinesterase-containing material with allelochemical (or other compound, e.g. active oxygen species, ozone free radicals and peroxides, formed in allelopathic relations) is for 30 min, then a substrate acetylcholinesterase is added to the reaction medium and final reaction of hydrolysis is for 1 h. 

Organophosphate and carbamate pesticides are potent inhibitors of the enzyme cholinesterase. The inhibition of cholinesterase activity by the pesticide leads to the formation of stable covalent intermediates such as phosphoryl-enzyme complexes, which makes the hydrolysis of the substrate very slow. Both organophosphorus and carbamate pesticides can react with AChE in the same manner because the acetylation of the serine residue at the catalytic center is analogous to phosphorylation and carbamylation. Carbamated enzyme can restore its catalytic activity more rapidly than phosphorylated enzyme [17,42], Kok and Hasirci [43] reported that the total anti-cholinesterase activity of binary pesticide mixtures was lower than the sum of the individual inhibition values. 

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],... 

Cholinesterase (ChE) An enzyme that catalyzes the hydrolysis of acetocholine to choline (a vitamin) and acetic acid. 

Darvesh S, McDonald RS, Darvesh KV, et al. On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases. Bioorg Med Chem 2006 14(13) 4586 1599. 

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,... 

Whereas the above evidence clearly points to a catalytic activity of serum albumin, it does not exclude an activity toward less-reactive substrates due to contamination of some HSA preparations. Indeed, the hypothesis of a contamination by plasma cholinesterase (EC 3.1.1.8) has been raised [126][127]. The efficient hydrolysis of nicotinate esters by HSA (see Chapt. 8) [128][129] could be due to contamination by cholinesterase in samples of a commercially available, essentially fatty acid free albumin. Support for this hypothesis was obtained when HSA contaminated with cholinesterase was resolved into two peaks by affinity chromatography, and the esterase activity toward nicotinate esters was found exclusively in the cholinesterase fraction [130],... 

Enol esters are distinct from other esters not because of a particular stability or lability toward hydrolases, but due to their hydrolysis releasing a ghost alcohol (an enol), which may immediately tautomerize to the corresponding aldehyde or ketone. A well-studied example is that of vinyl acetate (CH3-C0-0-CH=CH2), a xenobiotic of great industrial importance that, upon hydrolysis, liberates acetic acid (CH3-CO-OH) and acetaldehyde (CH3-CHO), the stable tautomer of vinyl alcohol [25], The results of two studies are compiled in Table 7.1, and demonstrate that vinyl acetate is a very good substrate of carboxylesterase (EC 3.1.1.1) but not of acetylcholinesterase (EC 3.1.1.7) or cholinesterase (EC 3.1.1.8). The presence of carboxylesterase in rat plasma but not in human plasma explains the difference between these two preparations, although the different experimental conditions in the two studies make further interpretation difficult. 

A variety of hydrolases catalyze the hydrolysis of acetylsalicylic acid. In humans, high activities have been seen with membrane-bound and cytosolic carboxylesterases (EC 3.1.1.1), plasma cholinesterase (EC 3.1.1.8), and red blood cell arylesterases (EC 3.1.1.2), whereas nonenzymatic hydrolysis appears to contribute to a small percentage of the total salicylic acid formed [76a] [82], A solution of serum albumin also displayed weak hydrolytic activity toward the drug, but, under the conditions of the study, binding to serum albumin decreased chemical hydrolysis at 37° and pH 7.4 from tm 12 1 h when unbound to 27 3 h for the fully bound drug [83], In contrast, binding to serum albumin increased by >50% the rate of carboxylesterase-catalyzed hydrolysis, as seen in buffers containing the hydrolase with or without albumin. It has been postulated that either bound acetylsalicylic acid is more susceptible to enzyme hydrolysis, or the protein directly activates the enzyme. 

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