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Serine hydrolase inhibition

Acetylcholinesterase (AchE) hydrolyses the neurotransmitter acetylcholine and yields acetic acid and choline. AchE is a serine hydrolase inhibited by organophosphorus poisons, as well as by carbamates and sulfonyl halides which form a covalent bond to a serine residue in the active site. AchE inhibitors are used in the treatment of various disorders. ... [Pg.63]

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... [Pg.357]

Mutagenesis of known enzyme towards a desired activity will be the fastest developing direction. The use of mutants of simple serine-hydrolases, which exhibit the phosphotriesterase activity (in contrast to the native enzymes, which are irreversibly inhibited under such conditions), clearly shows that practically any kind of substrates can be enzymatically transformed. The... [Pg.198]

The power of the pooled GST fusion protein approach will increase as new biochemical reagents and assays become available. The development of chemical probes for biological processes, termed chemical biology, is a rapidly advancing field. For example, the chemical synthesis of an active site directed probe for identification of members of the serine hydrolase enzyme family has recently been described (Liu et al., 1999). The activity of the probe is based on the potent and irreversible inhibition of serine hydrolases by fluorophosphate (FP) derivatives such as diisopropyl fluorophosphate. The probe consists of a biotinylated long-chain fluorophosphonate, called FP-biotin (Liu et al., 1999). The FP-biotin was tested on crude tissue extracts from various organs of the rat. These experiments showed that the reagent can react with numerous serine hydrolases in crude extracts and can detect enzymes at subnanomolar... [Pg.95]

Most poly(HA) depolymerases are inhibited by reducing agents, e.g., dithio-erythritol (DTT), which indicates the presence of essential disulfide bonds, and by serine hydrolase inhibitors such as diisopropyl-fluoryl phosphate (DFP) or acylsulfonyl derivates. The latter compounds covalently bind to the active site serine of serine hydrolases and irreversibly inhibit enzyme activity [48]. [Pg.293]

Other serine hydrolases such as cholinesterases, carboxylesterases, lipases, and fl-lactamases of classes A, C, and D have a hydrolytic mechanism similar to that of serine peptidases [25-27], The catalytic mechanism also involves an acylation and a deacylation step at a serine residue in the active center (see Fig. 3.3). All serine hydrolases have in common that they are inhibited by covalent attachment of diisopropyl phosphorofluoridate (3.2) to the catalytic serine residue. The catalytic site of esterases and lipases has been less extensively investigated than that of serine peptidases, but much evidence has accumulated that they also contain a catalytic triad composed of serine, histidine, and aspartate or glutamate (Table 3.1). [Pg.74]

Aeylpeptide hydrolase is a member of the serine hydrolase family. It deaeetylates the acetylated N-terminus of polypeptides. Rat brain aeylpeptide hydrolase was inhibited 93% at a dose of diehlorvos (4mg/kg, i.p.) which inhibited aeetyleholinesterase only 47%. The in vitro sensitivity of aeylpeptide hydrolase to chlorpyrifosmethyl oxon, diehlorvos, and diisopropyl fluorophosphate (IC50) was 6-10 times greater than that of acetylcholinesterase (Riehards et al, 2000). Aeylpeptide hydrolase is also found in human erythroeytes where it could potentially serve as a biomarker for low dose exposure to OP in humans, though human eases of OP exposure have not yet been tested for OP-modified acylpeptide hydrolase. [Pg.852]

The inhibitory and postinhibitory steps in the interaction of an OP compound with a serine hydrolase (E-OH) sueh as NTE or AChE are illustrated in Figure 57.6. The mathe-matieal relationships deseribing the kineties of irreversible inhibition of serine esterases by OP eompounds and post-inhibitory reaetions of the enzyme-inhibitor adduet (eonjugate) summarized here were elegantly set forth in the elassie work by Aldridge and Reiner (1972), and synopses are available in other sourees (Clothier et al, 1981 Main, 1980 Riehardson, 1992). The equations featured below... [Pg.863]

The inhibition of hLAL by boronic acids and diethyl p-nitrophenyl phosphate (Sando and Rosenbaum, 1985 G. N. Sando and H. L. Brockman, unpublished, cited by Anderson and Sando, 1991) indicates that hLAL is a serine hydrolase. Two lipase/esterase consensus pentapep-tides, G-X-S-X-G, are found, but only one of them appears to be consistent with the packing requirements of the )8-eSer-a nucleophilic motif (see above). Susceptibility of the enzyme to sulfhydryl reagents, and the requirement of thiols for the stability of purified hLAL, prompted Anderson and Sando (1991) to propose that a cysteine residue, or rather a Cys/Ser couple, may be involved in an internal transacylation reaction. It must be pointed out, however, that hLAL has all three cysteines of the gastric enzyme (as well as six additional ones), and so the inhibitory Cys is also there. The same argument proposed herein with respect to hGL, i.e., that a free cysteine is topologically close to the active site, also holds for hLAL. [Pg.44]

Both AChE and BChE are of the serine hydrolase class, which includes proteases such as trypsin (see PROTEASE inhibitors). Characteristically, such enzymes can be inhibited through covalent linkage of constituent parts of irreversible anticholinesterases such as dyflos (DFP, diisopropylfluorophosphonate). The active site of the enzyme contains a catalytic triad with a glutamate residue, a serine residue and a histidine imidazole ring. The mechanism of the catalysis of break down of AChE has been characterized, and the reaction progresses at a very fast rate. [Pg.25]

Since MGL is a serine hydrolase, its sensitivity to many of the available serine hydrolase inhibitors has been explored (Table 3). The results support the hypothesis that MGL can be inhibited by compounds that interact with its reactive serine. On the other hand, the potencies of the inhibitors are quite variable in some cases, this likely reflects differences in assay methodology (i.e., substrate concentration, pH, form of the enzyme). However, in a few cases, the same assay conditions revealed very different inhibitory potencies (e.g., compare the platelet and macrophage membrane studies by Di Marzo et al. 1999). In any event, studies of these compounds are not likely to yield selective inhibitors of MGL. All of these compounds are inhibitors of FAAH (see above) and many are also inhibitors of PLA2, diacylglycerol lipase, and acetylcholine esterase, among other hydrolases. By analogy to the development of the URB series of FAAH inhibitors (Kathuria et al. 2003), it is likely that selective inhibitors of MGL will come from other synthetic avenues. [Pg.198]

Kovach, I.M. 2004. Stereochemistry and secondary reactions in the irreversible inhibition of serine hydrolases by organophosphorus compounds. Journal of Physical Organic Chemistry, 17 602-614. [Pg.46]

Since OPs inhibit serine hydrolases such as AChE by phosphorylating them, it follows that OPs are potential inhibitors of all other serine hydrolases. This means that OPs can be used as synergists, notably for the pyrethroids that are detoxified by ester hydrolysis, and OP-containing mixture have proven successful in several cases (34.) The usefulness of these mixtures can be prolonged by using them in rotations with other mixtures and/or insecticides. [Pg.49]

Fig. 7.3-4 Fluorophosphonate labeling of serine hydrolase (SH) active sites. As a result of a shared catalytic mechanism, nearly all SHs are potently and irreversibly inhibited by fluorophosphonates (FPs). Fig. 7.3-4 Fluorophosphonate labeling of serine hydrolase (SH) active sites. As a result of a shared catalytic mechanism, nearly all SHs are potently and irreversibly inhibited by fluorophosphonates (FPs).

See other pages where Serine hydrolase inhibition is mentioned: [Pg.23]    [Pg.23]    [Pg.357]    [Pg.217]    [Pg.373]    [Pg.184]    [Pg.23]    [Pg.426]    [Pg.59]    [Pg.192]    [Pg.150]    [Pg.357]    [Pg.143]    [Pg.763]    [Pg.863]    [Pg.863]    [Pg.867]    [Pg.868]    [Pg.316]    [Pg.284]    [Pg.643]    [Pg.668]    [Pg.216]    [Pg.194]    [Pg.192]    [Pg.98]    [Pg.805]    [Pg.114]    [Pg.224]    [Pg.409]   
See also in sourсe #XX -- [ Pg.863 , Pg.864 ]




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