Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction of the triple bond in the leaving group of the organophosphorus inhibitor molecule gives a sharp raise of the inhibitor activity but does not change principal characteristics of the cholinesterase inhibition mechanism. The reactivation experiments suggest that inactivation of cholinesterases by these compounds occurs due to phosphorylating of the serine hydroxyl by the corresponding phosphoric acid. A close similarity was shown between acetylenic and saturated organophosphorus inhibitors in altering ka upon change of pH and tetraalkylammonium ions action. It is demonstrated that S-alkynyl esters of thioacetic acid are slowly hydrolyzed by acetylcholinesterase and cholinesterase without irreversible inhibition of the enzymes.
 ...
PMID:[The mechanism of anticholinesterase action of acetylene organophosphorus inhibitors]. 144 34

Studies were made (at 37 degrees, pH 7.6) on the interaction of some organophosphorus compounds and carboxylic acid esters with cholinesterases (EC 3.1.1.7 and EC 3.1.1.8) and A-esterases (EC 3.1.1.2) in homogenates of Schistosoma mansoni (adults and cercariae) and Schistosoma haematobium (adults). The results are compared with those obtained from the same reactions in other parasitic helminths and in mammalian tissues. Metrifonate (0,0-dimethyl-2,2,2-trichloro-1-hydroxyethyl phosphonate) does not seem to react with cholinesterases from parasites or mammals. Dichlorvos (0,0-dimethyl-2,2-dichlorovinyl phosphate) is a phosphorylating inhibitor; the rate constants of inhibition of cholinesterases from schistosomes are in the order of 10(5) M-1 min.-1. Similar or lower rate constants (10(4) M-1 min.-1) are found for cholinesterase inhibition in other parasitic helminths and mammals. S. mansoni and S. haematobium hydrolyse carboxylic acid esters (10 mM) in decreasing order: phenylacetate (about 2 mumol per hour per mg protein), acetylthiocholine, propionylthiocholine, butyrylthiocholine. Dichlorvos (10 mM) is hydrolysed by S. mansoni and S. haematobium at about the same rate as by mammalian erythrocytes and human sera (about 10 mumol per hour per gram wet weight). Neither paraoxon (0,0-diethyl-4-nitrophenyl phosphate) nor methyl-paraoxon are hydrolysed by S. mansoni and S. haematobium, although both compounds are good substrates for mammalian A-esterases. The stability of metrifonate and dichlorvos in buffer solutions was also determined (at 37 degrees). Metrifonate is about equally stable in bicarbonate buffer (pH 7.6) and phosphate buffer (pH 7.4) (t 1/2 = 1.5 and 2.6 hrs, respectively), while dichlorvos is considerably more stable in bicarbonate (t 1/2 = (36 hrs) than in phosphate buffer (t 1/2 = 2.9 hrs).
 ...
PMID:Esterases in schistosomes: reaction with substrates and inhibitors. 734 15

Acetylcholinesterase (AChE) inhibitors were first administered in Europe to human subjects in the 1860s, and synthetic derivatives of the natural alkaloid inhibitors were developed in the 1930s to modulate peripheral cholinergic function. However, only within the last decade have these agents been systematically studied for therapy of central cholinergic deficits. This time interval parallels the cloning of the gene and determination of the structure of the target molecule, AChE. Because AChE in mammals is encoded by a single gene and the portion of the gene encoding the catalytic domain is invariant, selectivity of action can be achieved only by altering parameters of disposition and pharmacokinetics of action of the inhibitor rather than its specificity for particular AChE isozymes in various regions of the CNS. This article describes the mechanism of action of short-acting, carbamoylating, and phosphorylating inhibitors of cholinesterase and suggests possible strategies for enhancing therapeutic efficacy.
 ...
PMID:Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease. 967 60

Ethephon [(2-chloroethyl)phosphonic acid] has two seemingly unrelated types of biological activity. It is a major agrochemical absorbed by crops, slowly releasing ethylene as a plant growth regulator. Ethephon also inhibits the activity of plasma butyrylcholinesterase (BuChE) in humans, dogs, rats, and mice. This is totally unexpected for an ionized phosphonic acid (mostly the dianion at physiological pH), in contrast to the classical inhibitors (nonionized triester phosphates) which phosphorylate serine at the active site. This study tests the hypothesis that ethephon (as the dianion) also acts as a phosphorylating agent in inhibiting BuChE activity. The sensitivity of plasma BuChE to ethephon (90 min preincubation at 25 degrees C) is greatest for humans, dogs, and mice (IC(50) = 6-23 microM), intermediate for chickens, rabbits, rats, and guinea pigs (IC(50) = 26-53 microM), and lowest for pigs and horses (IC(50) = 92-172 microM). The IC(50) decreases linearly with time on a log-log scale to values of 0.15-0. 3 microM for human, dog, and horse BuChE at 24 h. The inhibition rate is generally related to ethephon concentration, consistent with a bimolecular reaction, e.g., phosphorylation. The extent of inhibition of the esteratic activity of BuChE by ethephon is directly proportional to the extent of inhibition of [(3)H]diisopropyl phosphorofluoridate ([(3)H]DFP) postlabeling which is not reversible on removing the ethephon, either directly or after further incubation for 24 h at 25 degrees C. These observations strongly suggest that ethephon, as DFP, phosphorylates human plasma BuChE at Ser-198 of the esteratic site, or more generally, the formation of a phosphobutyrylcholinesterase. With human plasma BuChE, (2-bromoethyl)- and (2-iodoethyl)phosphonic acids have lower affinities for the site than ethephon but higher phosphorylation rate constants, consistent with their relative hydrolysis rates at pH 7.4 (phosphorylation of water). (2-Chlorohexyl)phosphonic acid is a poor inhibitor, perhaps being too reactive with water. Thus, potency differences for ethephon and its analogues with BuChE of various species depend on both the affinities and phosphorylation rates, i.e., the binding and reactivity of the (2-haloalkyl)phosphonic acid dianion in the esteratic site.
 ...
PMID:Phosphobutyrylcholinesterase: phosphorylation of the esteratic site of butyrylcholinesterase by ethephon [(2-chloroethyl)phosphonic acid] dianion. 1089 97

Phosphorus oxychloride (POCl(3)) is an intermediate in the synthesis of many organophosphorus insecticides and chemical warfare nerve gases that are toxic to insects and mammals by inhibition of acetylcholinesterase (AChE) activity. It was therefore surprising to observe that POCl(3), which is hydrolytically unstable, also itself gives poisoning signs in ip-treated mice and fumigant-exposed houseflies similar to those produced by the organophosphorus ester insecticides and chemical warfare agents. In mice, POCl(3) inhibits serum butyrylcholinesterase (BuChE) at a sublethal dose and muscle but not brain AChE at a lethal dose. In houseflies, POCl(3)-induced brain AChE inhibition is correlated with poisoning and the probable cause thereof. POCl(3) in vitro is selective for AChE (IC(50) = 12-36 microM) compared with several other serine hydrolases (BuChE, carboxylesterase, elastase, alpha-chymotrypsin, and thrombin) (IC(50) = 88-2000 microM). With electric eel AChE, methylcarbamoylation of the active site with eserine reversibly protects against subsequent irreversible inhibition by POCl(3). Most importantly, POCl(3)-induced electric eel AChE inhibition prevents postlabeling with [(3)H]diisopropyl phosphorofluoridate; i.e., both compounds phosphorylate at Ser-200 in the catalytic triad. Pyridine-2-aldoxime methiodide does not reactivate POCl(3)-inhibited AChE, consistent with an anionic phosphoserine residue at the esteratic site. The actual phosphorylating agent is formed within seconds from POCl(3) in water, has a half-life of approximately 2 min, and is identified as phosphorodichloridic acid [HOP(O)Cl(2)] by (31)P NMR and derivatization with dimethylamine to HOP(O)(NMe(2))(2). POCl(3) on reaction with water and HOP(O)Cl(2) have the same potency for inhibition of AChE from either electric eel or housefly head as well as the same toxicity for mice. In summary, the acute toxicity of POCl(3) is attributable to hydrolytic activation to HOP(O)Cl(2) that phosphorylates AChE at the active site to form enzymatically inactive [O-phosphoserine]AChE.
 ...
PMID:Phosphoacetylcholinesterase: toxicity of phosphorus oxychloride to mammals and insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid. 1089 98

Three phosphotrichlorides [phosphorus trichloride (PCl(3)), phosphorus oxychloride (POCl(3)), and thiophosphoryl chloride (PSCl(3))] with an annual U.S. production of >500,000,000 pounds and their diethyl esters are intermediates in the production of organophosphorus pesticides, plastics, flame retardants, and hydraulic fluids. They are classified as highly toxic to mammals based on acute oral and inhalation data with rats. This study considers their mechanisms of toxicity. PCl(3) and POCl(3) inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from several species with in vitro IC(50) values of 5-36 and 88-1200 microM, respectively; PSCl(3) is a less potent inhibitor. These phosphotrichlorides have high vapor toxicity to houseflies with in vivo inhibition of brain AChE activity correlating with mortality. PCl(3) and POCl(3) produce cholinergic poisoning signs on ip administration to mice, and all three phosphotrichlorides give marked in vivo inhibition of serum BChE but not brain AChE activity. PCl(3) is a direct acting AChE inhibitor. Our earlier proposed activation of POCl(3) is confirmed here by preparing pure Cl(2)P(O)OH and its potassium and dicyclohexylamine salts that reproduce the action of POCl(3) as in vitro AChE inhibitors and toxicants in mice. PSCl(3) on hydrolysis yields Cl(2)P(O)SH [which oxidizes with peracid to Cl(2)P(O)SOH] as the proposed activation product. Vapors of (EtO)(2)PCl, (EtO)(2)P(O)Cl, and (EtO)(2)P(S)Cl are lethal to houseflies as in vivo AChE inhibitors, the first two acting directly and the last one on oxidative activation to (EtO)(2)P(O)Cl (possibly by P450) or (EtO)(2)P(O)SCl (a phosphorylating agent in a peracid oxidation system). Thus PCl(3), (EtO)(2)PCl, and (EtO)(2)P(O)Cl act directly as AChE inhibitors whereas POCl(3) and PSCl(3) undergo hydrolytic activation and (EtO)(2)P(S)Cl undergoes oxidative activation. In contrast, the toxicity to mice of phosphofluorides [FP(O)Cl(2), F(Cl)P(O)OH, and F(2)P(O)OH; studied as model compounds for comparison] may be due to liberating fluoride ion.
 ...
PMID:Major intermediates in organophosphate synthesis (PCl3, POCl3, PSCl3, and their diethyl esters) are anticholinesterase agents directly or on activation. 1264 35

We firstly synthesized derivatives of 6-methyluracil, alloxazine, and xanthine, containing omega-tetraalkylammonium (TAA) groups at the N(1) and N(3) atoms in a pyrimidine cycle and assayed their anticholinesterase activities. Compounds with triethylpentylammoniumalkyl groups behaved as typical reversible inhibitors of acetylcholinesterase (AChE) (pI(50) 3.20-6.22) and butyrylcholinesterase (BuChE) (pI(50) 3.05-5.71). Compounds, containing two ethyl residues and a substituted benzyl fragment in the tetraalkylammonium group at N(3) atoms or two similar TAA groups at N(1) and N(3) atoms, possessed very high anticholinesterase activity. Although these compounds displayed the activity of typical irreversible AChE inhibitors (a progressive AChE inactivation; k(i) 7.6 x 10(8) to 3.5 x 10(9)M(-1)min(-1)), they were reversible inhibitors of BuChE (pI(50) 3.9-6.9). The efficiency of AChE inhibition by some of these compounds was more than 10(4) times higher than the efficiency of BuChE inhibition. Several synthesized TAA derivates of 6-methyluracil reversibly inhibited electric eel and cobra venom AChEs and horse serum BuChE. However, depending on their structure, the tested compounds possessed the time-progressing inhibition of mammalian erythrocyte AChE, typically of irreversible inhibitors. As shown upon dialysis and gel-filtration, the formed mammalian AChE-inhibitor complex was stable. Thus, a new class of highly active, selective, and irreversible inhibitors of mammalian AChE was described. In contrast to classical phosphorylating or carbamoylating AChE inhibitors, these compounds are devoid of acylating functions. Probably, these inhibitors interact with certain amino acid residues at the entrance to the active-site gorge.
 ...
PMID:Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals. 1858 70

Nerve agents are chiral organophosphate compounds (OPs) that exert their acute toxicity by phosphorylating the catalytic serine of acetylcholinesterase (AChE). The inhibited cholinesterases can be reactivated using oximes, but a spontaneous time-dependent process called aging alters the adduct, leading to resistance toward oxime reactivation. Human butyrylcholinesterase (BChE) functions as a bioscavenger, protecting the cholinergic system against OPs. The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhibited in solution or in cristallo with racemic V-agents (VX, Russian VX, and Chinese VX) systematically show the formation of the P(S) adduct. In this configuration, no catalysis of aging seems possible as confirmed by the three-dimensional structures of the three conjugates incubated over a period exceeding a week. Crystals of BChE soaked in optically pure VX(R)-(+) and VX(S)-(-) solutions lead to the formation of the P(S) and P(R) adduct, respectively. These structural data support an in-line phosphonylation mechanism. Additionally, they show that BChE reacts with VX(R)-(+) in the presence of racemic mixture of V-agents, at odds with earlier kinetic results showing a moderate higher inhibition rate for VX(S)-(-). These combined results suggest that the simultaneous presence of both enantiomers alters the enzyme stereoselectivity. In summary, the three-dimensional data show that BChE reacts preferentially with P(R) enantiomer of V-agents and does not age, in complete contrast to AChE, which is selectively inhibited by the P(S) enantiomer and ages.
 ...
PMID:Structural study of the complex stereoselectivity of human butyrylcholinesterase for the neurotoxic V-agents. 2145 98

CBDP [2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide] is a toxic organophosphorus compound. It is generated in vivo from tri-ortho-cresyl phosphate (TOCP), a component of jet engine oil and hydraulic fluids. Exposure to TOCP was proven to occur on board aircraft by finding CBDP-derived phospho-butyrylcholinesterase in the blood of passengers. Adducts on BChE, however, do not explain the toxicity of CBDP. Critical target proteins of CBDP are yet to be identified. Our goal was to facilitate the search for the critical targets of CBDP by determining the range of amino acid residues capable of reacting with CBDP and characterizing the types of adducts formed. We used human albumin as a model protein. Mass spectral analysis of the tryptic digest of CBDP-treated human albumin revealed adducts on His-67, His-146, His-242, His-247, His-338, Tyr-138, Tyr-140, Lys-199, Lys-351, Lys-414, Lys-432, and Lys-525. Adducts formed on tyrosine residues were different from those formed on histidines and lysines. Tyrosines were organophosphorylated by CBDP, while histidine and lysine residues were alkylated. This is the first report of an organophosphorus compound with both phosphorylating and alkylating properties. The o-hydroxybenzyl adduct on histidine is novel. The ability of CBDP to form stable adducts on histidine, tyrosine, and lysine allows one to consider new mechanisms of toxicity from TOCP exposure.
 ...
PMID:Cresyl saligenin phosphate, an organophosphorus toxicant, makes covalent adducts with histidine, lysine, and tyrosine residues of human serum albumin. 2279 78