Inhibition esterases

It was suggested,1 on the basis of kinetic measurements, that the phosphorofluoridates inhibit esterases by virtue of a highly specific affinity for the active centres of this group of enzymes. Preliminary experiments by Boursnell and Webb2 with diisopropyl phosphorofluoridate containing 32P gave results which were in accordance with this view. 

Although ajmaline also influences Na+ channels, its activity is to block these channels. This influences the refraction phase of the heart beat and also decreases heart rate. Ajmaline may be used to correct arrhythmic defects. Sanguinarine also influences Na+ ions and particularly inhibits esterase activity. This alkaloid has several other activities in the body and specifically in tissues. Possible applications are linked to the promotion discharge of mucus from the respiratory tract. 

B. Botulinum toxin has no ability to inhibit esterase (A) or inhibit enzymes involved in the acetylcholine synthetic pathways (C), nor does it possess muscarinic receptor blocking properties (D). 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

The inhibited esterase can also undergo aging, e.g. via net loss of the R-group to yield the negatively charged phos-phonyl adduct on the active site serine of the enzyme. Aging is characterized by a first-order rate constant, fcj, and the operational definition of this reaction is the time-dependent... 

Decreased renal excretion of penicillin when coadministered with probenecid, potentiating its therapeutic effect Ops (profenofos, sulprofos, DEF) potentiate the toxicity of fenvalerate and malathion by inhibiting esterase, which detoxifies many pyrethroid insecticides and malathion... 

H46. Hsia, J. C., Kosman, D.., and Piette, L. H., Organophosphate spin-label studies of inhibited esterases, a-chymotrypsin and cholinesterase. Biochem. Biophys. Res. Com-mun. 36, 75-78 (1969). 

B32. Berends, F., Mechanisms of aging of organophosphate-inhibited esterases. In Selectivity and Molecular Mechanisms of Toxicity (F. de Matteis and E. A. Lock, eds.), p. 125-152. McMillan Press, London, UK, 1987. 

Alkaloids such as berberine are known to be antimicrobial. They inhibit esterases as well as DNA and RNA polymerases. Moreover, berberine inhibits cellular respiration and acts in DNA intercalation. As a strong antimicrobial agent, berberine may be used in the treatment of AIDS, as it inhibits HIV-1 reverse transcriptase. Berberine also has been used in the treatment of infections, specifically eye infections and hepatitis. 

Carboxylesterase activity of soil extracts was demonstrated in a sensitive assay based on the formation of a fluorescent product, 7-hydroxy 4-methyl umbellipherone from the hydrolysis of the butyl ester of 7-hydroxy 4-methylcoumarin. EDTA, Cu and competitively inhibited esterase activities, Fe inhibited non-competitively. Activities increased after addition of Ca ", Mg " ", Na" " or... 

Detoxification of organophosphates indicates that in low doses mala-thion will inhibit esterases which normally destroy it before inhibition of cholinesterases,99 although it is not a substrate of serum cholinesterase.1 Sarinase, the enzyme which hydrolyzes sarin, is found to be less effective toward 1-sarin than d-sarin. The microsomal detoxification of parathion has been shown to be accomplished by desulfonation. ... 

The introduction of the organo-phosphorus insecticides, about 1945, greatly widened the spectrum of available types. Like the chlorinated hydrocarbons, these are also nerve poisons, but they act in a quite different way, namely by inhibiting esterases. Unfortunately the early examples, discovered in Germany by Schrader, were as toxic for those who sprayed... 

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