Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In clinical anaesthesia, galanthamine hydrobromide (Nivalin), an alkaloid of galanthus nivalis (common snowdrop) is used to reverse the neuromuscular blocking effect of curare-type muscle relaxants. A comparative study of the inhibition by galanthamine of acetylcholinesterase (AChE; PH 7,2; substrate; acetylthiocholine) and of pseudocholinesterase (ChE; ph 7,7; substrate: butyrylthiocholine) was carried out by means of a colorimetric assay technique at 25 degrees C. AChE (pI50 = 5.5; Ki = 5.2 X 10(-8) M) has an approximately 100-fold higher affinity to galanthamine than has ChE (pI50 = 3.7; Ki = 2.9 X 10(-6) M). The kinetic analysis of the inhibition which is instantaneously reversible upon dilution revealed a pure competitive mechanism of action for both enzymes. Supported by a calculation of the change in free binding energy (AChE: delta F = 9.9 kcal X mole-1; ChE: delta F = -7.6 kcal X mole-1), galanthamine is thought to decrease the rate of hydrolysis by a reversible binding to the anionic site of the active centre ("prosthetic inhibitor") thus impairing the formation of the enzyme-substrate complex.
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PMID:[On the molecular mechanism of action of galanthamine, an antagonist of nondepolarizing muscle relaxants (author's transl)]. 13 19

We have successfully demonstrated that exogenously administered acetyl- or butyrylcholinesterase (AChE, BChE respectively) will sequester organophosphates (OPs) before they reach their physiological targets. In addition, a third enzyme, endogenous carboxylesterase is known to be capable of scavenging OPs. In these studies, we have administered AChE and BChE to three different species of animals (mice, marmosets and monkeys) which were challenged with three different OPs (VX, MEPQ and soman). Results obtained from these systematic studies demonstrate that: (a) a quantitative linear correlation exists between blood AChE levels and the protection afforded by exogenously administered ChEs in animals challenged with OP, (b) approximately one mole of either AChE or BChE sequesters one mole of OP, (c) such prophylactic measures are sufficient to protect animals against OPs without the administration of any supportive drugs. Thus the OP dose, the blood-level of esterase, the ratio of the circulating enzyme to OP challenge, and the rate of reaction between them determine the overall efficacy of an enzyme as a pretreatment drug. The biochemical mechanism underlying the sequestration of various OPs by the use of exogenously administered scavenging esterases is the same in all species of animals studied. Therefore, the extrapolation of the results obtained by the use of ChE prophylaxis in animals to humans should be more reliable and effective than extrapolating the results from currently used multidrug antidotal modalities.
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PMID:Enzymes as pretreatment drugs for organophosphate toxicity. 205 84

Fetal bovine serum acetylcholinesterase (FBS-AChE) protected mice from multiple LD50 doses of organophosphorus (OP) nerve agents. Mice were injected intraperitoneally (ip) with up to 3.3 mg (11,000 U) of FBS-AChE which exhibited a relatively long serum half-life and appeared well tolerated. The enzyme protected mice from the OP ethyl-S-2-diisopropylamino-ethylmethylphosphonothiolate (VX) with a stoichiometry equal to approximately 2 moles of enzyme active site per mole of VX. FBS-AChE, at a lower enzyme OP ratio, protected mice from 2 LD50s of the nerve agent methylphosphonofluoridic acid 1,2,2,-trimethylpropyl ester (soman) when used in conjunction with atropine and 2[(hydroxyimino)methyl]-1-methylpyridinium chloride. It is concluded that sequestration of highly toxic OPs by administration of AChE occurs in mice and suggests a new approach to treatment of OP intoxication.
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PMID:Acetylcholinesterase prophylaxis against organophosphate toxicity. 365 68

Extensive pharmacokinetic studies in both mice and rhesus macaques, with biochemically well defined forms of native and recombinant AChEs from bovine, rhesus and human origin, allowed us to determine an hierarchical pattern by which post-translation-related factors and specific amino-acid epitopes govern the pharmacokinetic performance of the enzyme molecule. In parallel, we demonstrated that controlled conjugation of polyethylene-glycol (PEG) side-chains to lysine residues of rHuAChE also results in the generation of active enzyme with improved pharmacokinetic performance. Here, we show that equally efficient extension of circulatory residence can be achieved by specific conditions of PEGylation, regardless of the post-translation-modification state of the enzyme. The masking effect of PEGylation, which is responsible for extending circulatory lifetime, also contributes to the elimination of immunological responses following repeated administration of AChE. Finally, in vivo protection studies in mice allowed us to determine that the PEGylated AChE protects the animal from a high lethal dose (2.5 LD(50)) of soman. On a mole basis, both the recombinant AChE and its PEGylated form provide higher levels of protection against soman poisoning than the native serum-derived HuBChE. The findings that circulatory long-lived PEGylated AChE can confer superior protection to mice against OP-compound poisoning while exhibiting reduced immunogenicity, suggest that this chemically modified version of rHuAChE may serve as a highly effective bioscavenger for prophylactic treatment against OP-poisoning.
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PMID:Polyethylene-glycol conjugated recombinant human acetylcholinesterase serves as an efficacious bioscavenger against soman intoxication. 1704 22

Selected mutagenesis of acetylcholinesterase (AChE; EC 3.1.1.7) may enable one to develop more effective scavenging agents in which AChE itself, in combination with an oxime, will complete a catalytic cycle of hydrolysis of the organophosphate by rapid conjugation followed by enhanced nucleophile-mediated hydrolysis of the phosphonyl enzyme conjugate. Through enlargement of the active site gorge of mouse AChE by mutations Y337A, F295L and F297I, we studied continuous enzymatic degradation of S(P)-cycloheptyl methylphosphonyl thiocholine (S(P)-CHMPTCh) in the presence of HI-6. Continuous hydrolysis of S(P)-CHMPTCh was measured spectrophotometrically from thiocholine released during hydrolysis with DTNB as the thiol reagent. The rates of hydrolysis expressed as moles of formed thiocholine per mole of enzyme per minute were 3.3, 0.69, 0.34 and 0.15min(-1) for F295L/Y337A, Y337A, F297I/Y337A and AChE wild-type, respectively. These rates did not depend on the initial S(P)-CHMPTCh concentration range employed. However, by increasing HI-6 concentrations, the rates approached a limiting value, indicating that oxime reactivation is the rate-limiting step in S(P)-CHMPTCh hydrolysis. Our results confirm that a mixture of a mutant enzyme and an oxime might serve as an in vivo catalytic scavenger of organophosphates.
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PMID:Mutation of acetylcholinesterase to enhance oxime-assisted catalytic turnover of methylphosphonates. 1704 38