Inhibitors serine esterases

A potent irreversible inhibitor (abbreviated DFP) of many serine proteinases and serine esterases (especially acetylcholinesterase). This substance is EXTREMELY POISONOUS, but the vapor state can be minimized by using dry, water-miscible solvents such as 2-propanoL. Aqueous solutions become inactivated by hydrolysis, but solutions made with dry 2-propanol are stable at -20°C for many months. 

SERINE DEHYDRATASE SERINE DEHYDRATASE SERINE DEHYDROGENASE Serine esterase inhibitor, irreversible, PHENYLMETHYLSULFONYL FLUORIDE SERINE HYDROXYMETHYLTRANSFERASE SERINE PALMITOYLTRANSFERASE Serine protease inhibitor, irreversible, PHENYLMETHYLSULFONYL FLUORIDE Serine proteinase inhibitor,... 

Trifluoromethyl /1-thioalkyls and /1-amino alcohols are often good reversible inhibitors of esterases and proteases, respectively. Depending on the enzymes (serine or aspartyl enzymes), fluorinated alcohols are often less efficient inhibitors than the corresponding ketones, which act as analogues of the transition state (vide infra). Nevertheless, fluoroalcohols inhibit hydrolytic enzymes with high inhibition constants (Figure 7.25)." ... 

Like pancreatic lipase, this enzyme is clearly dependent on a lipid/water interface for maximal activity, where it also may reach a very high catalytic rale, Abo like pancreatic lipase, it is not inhibited by serine esterase inhibitors like DFP orPMSF. 

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... 

Enzyme inhibitors are often poisonous. For example, diisopropyl-fluorophosphate is a nerve poison because the enzyme acetylcholinesterase has a reactive site serine. Chymotrypsin and acetylcholinesterase are both members of the class of enzymes known as serine esterases, which are all inhibited by diisopropylfluorophosphate. 

Several protease inhibitors from plasma, tissue, and plant sources did not inhibit the esterase and C3 convertase activity (Cooper, 1975b). Recently, Medicus et al. (1976a) proposed that C2a is a serine esterase. 

In this connection, it is noteworthy that some cellular proteins, including hoimones and other secretory polypeptides, are produced by limited cleavage of precursors. The proteases involved are not fully characterized, but seem to be located on membrane-bound structures (1J, 27, 28), have optimiim activities at neutral to slightly alkaline pH, and are sensitive to phosphofluoridate or other serine esterase inhibitors (12, 27, 29). 

They are susceptible to DFP or PMSF, which is a serine esterase inhibitor. 

Analytical procedures applied to diagnosis and retrospective verification of exposure to OP include (Worek et al., 2005) (i) biochemical determination of ChE activity (ii) identification of imbound OP (iii) identification of decomposition products (iv) fluoride-induced reactivation of inhibited ChE, followed by analysis of the inhibitor and (v) analysis of phosphyl-protein-adducts after tryptic digestion of the protein. The last procedure is regarded to be the most specific and sensitive, but it has the drawback of being strongly dependent on the analysis of butyrylcholinesterase (BChE), the most abim-dant plasma serine esterase with a half-life of about 16 days. 

Makhaeva, G.R, Radchenko, E.V., Baskin, I.L, et al., 2012. Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer s disease. SAR QSAR Environ. Res. 23, 627-647. 

The reaction between esterase and phosphorus inhibitor (109) is bimolecular, of the weU-known S 2 type, and represents the attack of a nucleophilic serine hydroxyl with a neighboring imida2ole ring of a histidine residue at the active site, on the electrophilic phosphorus atom, and mimics the normal three-step reaction that takes place between enzyme and substrate (reaction ). 

The ester of the phosphorous acid or organophos-phorsus inhibitors of the acetylcholine esterase phos-phorylate serine in the active center of the enzyme. The phosphorylated enzyme is extremely stable, resulting in an irreversible inhibition. The duration of action of this compounds is determined by the rate of enzyme synthesis de novo. 

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