Acetylcholinesterase organic phosphates

Organic phosphates can cause moderate to severe acute poisoning. These substances inhibit the function of the enzyme, acetylcholinesterase by phospho-rylating or binding the enzyme at its esteratic site. The symptoms of acute toxicity... 

Specific Metabolic Inhibitors. The organic phosphates and carbamates interfere with the synaptic chemistry through inhibition of acetylcholinesterase. 

These organic phosphates inhibit acetylcholinesterase by reacting with the active-site serine residue to form a stable phosphorylated derivative. They cause respiratory paralysis by blocking synaptic transmission at cholinergic synapses. 

Metrifonate, which was originally introduced as an organic phosphate insecticide, is a pro-drug for dichlorovos,10 a potent acetylcholinesterase inhibitor (Chapter 8) to which it is nonenzymatically metabolized spontaneously in vitro even at neutral pH (Eq. 7.11). The drug s clinical application is exclusively against S. hematobium infections. Although some effectiveness against other schistosomes exists, this is not achieved at safe doses. 

Many simpler carbamates, as well as organic phosphates, which have this property of blocking acetylcholinesterase, are used in treating glaucoma, also as anthelmintics and insecticides (see Section 13.3). 

By these standards, organic phosphates, and also urethanes, have been shown to exert their biological effects by inhibiting acetylcholinesterase and... 

Apart from inhibition by organic phosphates and other acylating agents (Section 13.3), acetylcholinesterase can also be reversibly blocked by simple quaternary ammonium compounds. As the size of the alkyl-groups in these was increased, the increased affinity (measured as —AF) contributed by each... 

Beginning with the fiat worms, and proceeding at once to the flukes, we come to the most devastating worm diseases of all, those caused by flukes in the blood, particularly schistosomiasis, whose natural history is sketched in Section i.i (p. ii). Depending on the species, the remedy of first choice is either niridazole (6,24) or an organic antimonial (see Table 4.4, p. 132 also Section 12.0). Also an organic phosphate, metriphonate (12.24) (dimethyl 2,2,2-trichloro-i-hydroxyethylphosphonate), which selectively inhibits the worm s acetylcholinesterase, provides a useful supplement to the treatment. The greatest need is to find an efficient and safe prophylactic. 

The action of naturally secreted acetylcholine can be reinforced by drugs which acylate, and hence block, the enzyme acetylcholinesterase (see Section 12.3). The organic phosphates and carbamates do this. Of the carbamates, the alkaloid physostigmine (7.25), also known as eserine, has long been used for therapeutic results which can now be defined as giving the patient a much enhanced effect from his own acetylcholine . Even at a dilution of io" m, it strongly inhibits this enzyme, and is pharma-... 

Many enzymes, however, do not show temperature compensation in their activities (Eckberg, 1962 Precht, 1964 Vellas, 1965 Hebb etal., 1969 Hazel and Prosser, 1970 Shkorbatov et al., 1972 Hochachka and Somero, 1973 Penny and Goldspink, 1981). Among these are catalase, peroxidase, acid phosphatase, D-amino acid oxidase, choline acetyltransferase, acetylcholinesterase and glucose-6-phosphate dehydrogenase. What is more, the same enzyme can show opposing temperature dependencies when examined in different organs and tissues of fish (Romanenko etal., 1991). 

Organophosphate IA class of toxic organic molecules containing phosphate, and often fluoride, that are used as insecticides and nerve gases (such as sarin) many of these molecules block the action of an enzyme (acetylcholinesterase) that recycles an important brain chemical called acetylcholine. 

Acetylcholinesterase is inhibited by organic fluorophosphates through the formation of covalent phosphate esters with the serine residue at the active site of the enzyme. The reactivation of the enzyme can be achieved by treatment with hydroxylamine which acts as a transesterification and not an aminolysis agent (119). The transition state symbiosis may be the determinant for the specificity. 

The mechanism of the action of acetylcholinesterase purified from the electric organs of Electrophorus electricus involves the attraction of the positively charged nitrogen of acetylcholine to an anionic site on the enzyme and cleavage of the substrate at an esteratic site of a nucleophilic character. The irreversible inhibition by the alkyl phosphates, tetraethyl pyrophosphate (TEPP) and diisopropyl-fluorophosphate (DFP) may be due to phosphorylation of the nucleophilic esteratic site. The phosphorylation by DFP of the phenolic hydroxyl group of free tyrosine has been demonstrated by Ashbolt and Rydon. Chymotrypsin and citrus fruit acetylesterase are also inhibited by DFP and TEPP. ... 

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