Esterase other

The mechanism of action of anticholinesterases is to form a stable covalent complex with the Achase enzyme. Achase is one of several enzymes known as serine esterases. Other examples include the intestinal enzymes trypsin and chymotrypsin as well as the blood clotting agent thrombin. During the course of the catalysis the alcohol -OH of a serine side chain in the active site of the enzyme forms an ester complex, called the acyl-enzyme, with the substrate. So, acetylcholine will go through similar chemical reactions with Achase. 

Various esterases exist in mammalian tissues, hydrolyzing different types of esters. They have been classified as type A, B, or C on the basis of activity toward phosphate triesters. A-esterases, which include arylesterases, are not inhibited by phosphotriesters and will metabolize them by hydrolysis. Paraoxonase is a type A esterase (an organophosphatase). B-esterases are inhibited by paraoxon and have a serine group in the active site (see chap. 7). Within this group are carboxylesterases, cholinesterases, and arylamidases. C-esterases are also not inhibited by paraoxon, and the preferred substrates are acetyl esters, hence these are acetylesterases. Carboxythioesters are also hydrolyzed by esterases. Other enzymes such as trypsin and chymotrypsin may also hydrolyze certain carboxyl esters. 

Kinetic resolution with racemisation Enzymes versus whole organisms Desymmetrisation with lipases Immobilised enzymes in desymmetrisation Polymer-supported reagents and enzymes Effects of amines on lipases and esterases Other acylating enzymes Enzymatic Oxidation... 

Clinically, the most important effects of OP nerve agents are anticholinesterase actions. However, it should not be forgotten that OPs bind to a variety of enzymes, including esterases other than acetylcholinesterase, e.g. carboxylesterase, (long-chain fatty acid hydrolase), serine... 

Milatovic. D., Moretto, A., Osman, K. A and Lotti, M, (1997), Phenyl valerate esterases other than neuropathy target c.sterase aod the promotion of organophosphate polyneuropathy, Cheit , Res. Toxicol. 10, 1045-1048. 

The relative levels of hCE-1 protein were measured in human microsomes by immunoblotting to determine if variation in hydrolytic metabolism was related to the abundance of hCE-1 in the microsomes. Human CE-1 levels did not correlate (r = 0.294) well with F ,ax values for the hydrolysis of Irans-permethrin. Esterases other than hCE-1 are believed to be responsible for the different values. CDMB (1,2-ethanedione, l-(2-chlorophenyl)-2-(3,4-dimethoxyphenyl)-(CAS no. 56159-70-7)) was used to inhibit the activity of hCE-2 (Wadkins et al. 2005). 

Hydrolases. Enzymes catalysing the hydrolytic cleavage ofC —O, C —N and C —C bonds. The systematic name always includes hydrolase but the recommended name is often formed by the addition of ase to the substrate. Examples are esterases, glucosidases, peptidases, proteinases, phospholipases. Other bonds may be cleaved besides those cited, e.g. during the action of sulphatases and phosphatases. 

One approach called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers Some of the most commonly used ones are lipases and esterases enzymes that catalyze the hydrol ysis of esters In a typical procedure one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed m the presence of an esterase from hog liver... 

Elestolol sulfate is a nonselective, ultrashort acting P-adrenoceptor blocker. It has no ISA and produces weak inhibition of the fast sodium channel. The dmg is under clinical investigation for supraventricular tachyarrhythmias, unstable angina, and acute MI. In humans, flestolol has hemodynamics and electrophysiologic effects similar to those of other P-adrenoceptor blockers. The pharmacokinetics of flestolol are similar to those of esmolol. It is 50 times more potent than esmolol and the elimination half-life is 7.2 min. Recovery from P-adrenoceptor blockade is 30—45 min after stopping iv infusions. The dmg is hydrolyzed by tissue esterases and no active metabohtes of flestolol have been identified (41). 

Specificity is not always perfect. Sometimes an enzyme will work with any member of a class of compounds. For example, some esterases (enzymes that catalyze the reaction of esters with water) will work with numerous esters of similar, but different, structures. Usually, in cases of this kind, one of the members of the substrate class will react faster than the others, so the rates will vary from one substrate to another. 

When esterase models are designed, several important and fundamental problems have to be solved. Systematic studies on other interactions, such as hydrogen-bonding and charge-transfer type forces have not been fully performed. Furthermore, various cooperative actions between different kinds of interactions, e. g. the correlation between the attraction of substrate and repulsion of a product by a polyelectrolyte catalyst, has not yet been carried. 

ChEs possess the a/ 3-fold structure, which is shared with other esterases and non-catalytic proteins such as thyroglobulin, glutactin, neurotactin, gliotactin and neuroligins, all of these include a single ChE domain. Both ChEs are ellipsoidal molecules of 45-60-65 A3. Their structure consists of a central, highly twisted, 8-12-stranded (3-sheet, in which most strands are parallel, flanked on both sides by a-helices. Studies have indicated three major domains within the protein ... 

Sometimes called lysophospholipase to distinguish it from other esterases of this kind... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

The organophosphorons insecticides dimethoate and diazinon are mnch more toxic to insects (e.g., housefly) than they are to the rat or other mammals. A major factor responsible for this is rapid detoxication of the active oxon forms of these insecticides by A-esterases of mammals. Insects in general appear to have no A-esterase activity or, at best, low A-esterase activity (some earlier stndies confnsed A-esterase activity with B-esterase activity) (Walker 1994b). Diazinon also shows marked selectivity between birds and mammals, which has been explained on the gronnds of rapid detoxication by A-esterase in mammals, an activity that is absent from the blood of most species of birds (see Section 23.23). The related OP insecticides pirimiphos methyl and pirimiphos ethyl show similar selectivity between birds and mammals. Pyrethroid insecticides are highly selective between insects and mammals, and this has been attributed to faster metabolic detoxication by mammals and greater sensitivity of target (Na+ channel) in insects. 

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