Fluorinated aldehydes and ketones acting as quasi-substrate inhibitors of acetylcholinesterase

Brodbeck, Urs; Schweikert, K.; Gentinetta, R.; Rottenberg, Max

doi:10.1016/0005-2744(79)90122-0

Cited by 80 publications

(43 citation statements)

References 25 publications

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“…TFK-containing inhibitors are based upon the inclusion of an electron deficient carbonyl moiety in the molecule, which covalently binds to the enzyme. 38,39) These compounds are slow tight-binding inhibitors, but the covalent bond is reversible and the enzyme is reactivated on the order of days to weeks. 40) The oxonforms of OP insecticides, such as paraoxon (O,O-diethyl p-nitrophenyl phosphate), can be very potent CaE inhibitors (k i ϭ1.4ϫ10 6 M Ϫ1 min Ϫ1 for rat serum CaE 41) ), and potentially lead to aging of the enzyme following phosphorylation.…”

Section: Figmentioning

confidence: 99%

Overview of Carboxylesterases and Their Role in the Metabolism of Insecticides

Shan²,

2005

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Carboxylesterases hydrolyze numerous endogenous and exogenous ester-containing compounds. They play a role in the detoxification of many agrochemicals including pyrethroids, organophosphates, and carbamates. Research on these enzymes is still developing and there are several topics that should be addressed to further investigations in this area. This paper focuses on a number of these issues including enzyme nomenclature, catalytic mechanism, substrate specificity, agrochemical metabolism, role in insecticide resistance and environmental significance. It is expected that carboxylesterase research will increase with specific emphasis on isozyme and substrate identification. Future research directions are discussed and the current state of the field is evaluated.

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Section: Figmentioning

confidence: 99%

Overview of Carboxylesterases and Their Role in the Metabolism of Insecticides

Shan²,

2005

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“…Reactivity toward the Transition State Analog TMTFA-The kinetics of AChE inhibition by TMTFA has been studied extensively since the tetrahedral covalent adduct is believed to mimic the transition state of the acylation process (21,28,29). TMTFA was shown to behave as a tight binding time-dependent inhibitor, a behavior characteristic of other trifluoroketone inhibitors of serine proteases (30,31).…”

Section: Modification Of Huache Hydrolytic Activity-replacementmentioning

confidence: 99%

Functional Characteristics of the Oxyanion Hole in Human Acetylcholinesterase

Ordentlich¹,

Barak²,

Kronman³

et al. 1998

Journal of Biological Chemistry

148

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The contribution of the oxyanion hole to the functional architecture and to the hydrolytic efficiency of human acetylcholinesterase (HuAChE) was investigated through single replacements of its elements, residues Gly-121, Gly-122 and the adjacent residue Gly-120, by alanine. All three substitutions resulted in about 100-fold decrease of the bimolecular rate constants for hydrolysis of acetylthiocholine; however, whereas replacements of Gly-120 and Gly-121 affected only the turnover number, mutation of residue Gly-122 had an effect also on the Michaelis constant. The differential behavior of the G121A and G122A enzymes was manifested also toward the transition state analog m-(N,N,N-trimethylammonio)trifluoroacetophenone (TMTFA), organophosphorous inhibitors, carbamates, and toward selected noncovalent active center ligands. Reactivity of both mutants toward TMTFA was 2000 -11,000-fold lower than that of the wild type HuAChE; however, the G121A enzyme exhibited a rapid inhibition pattern, as opposed to the slow binding kinetics shown by the G122A enzyme. For both phosphates (diethyl phosphorofluoridate, diisopropyl phosphorofluoridate, and paraoxon) and phosphonates (sarin and soman), the decrease in inhibitory activity toward the G121A enzyme was very substantial (2000 -6700-fold), irrespective of size of the alkoxy substituents on the phosphorus atom. On the other hand, for the G122A HuAChE the relative decline in reactivity toward phosphonates (500 -460-fold) differed from that toward the phosphates (12-95-fold). Although formation of Michaelis complexes with substrates does not seem to involve significant interaction with the oxyanion hole, interactions with this motif are a major stabilizing element in accommodation of covalent inhibitors like organophosphates or carbamates. These observations and molecular modeling suggest that replacements of residues Gly-120 or Gly-121 by alanine alter the structure of the oxyanion hole motif, abolishing the H-bonding capacity of residue at position 121. These mutations weaken the interaction between HuAChE and the various ligands by 2.7-5.0 kcal/mol. In contrast, variations in reactivity due to replacement of residue Gly-122 seem to result from steric hindrance at the active center acyl pocket.

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“…TFKs were first studied as inhibitors of acetylcholinesterase (AChE) (Brodbeck et al, 1979). Shortly thereafter, a number of articles described the use of the TFK moiety as an inhibitor of esterases, including juvenile hormone esterase (Hammock et al, 1982(Hammock et al, , 1984, and mammalian enzymes (Ashour and Hammock, 1987).…”

mentioning

confidence: 99%

Analysis of Mammalian Carboxylesterase Inhibition by Trifluoromethylketone-Containing Compounds

Wadkins¹,

Hyatt²,

Edwards³

et al. 2006

Mol Pharmacol

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Carboxylesterases (CE) are ubiquitous enzymes that hydrolyze numerous ester-containing xenobiotics, including complex molecules, such as the anticancer drugs irinotecan (CPT-11) and capecitabine and the pyrethroid insecticides. Because of the role of CEs in the metabolism of many exogenous and endogenous ester-containing compounds, a number of studies have examined the inhibition of this class of enzymes. Trifluoromethylketone-containing (TFK) compounds have been identified as potent CE inhibitors. In this article, we present inhibition constants for 21 compounds, including a series of sulfanyl, sulfinyl, and sulfonyl TFKs with three mammalian CEs, as well as human acetyl-and butyrylcholinesterase. To examine the nature of the slow tight-binding inhibitor/enzyme interaction, assays were performed using either a 5-min or a 24-h preincubation period. Results showed that the length of the preincubation interval significantly affects the inhibition constants on a structurally dependent basis. The TFK-containing compounds were generally potent inhibitors of mammalian CEs, with K i values as low as 0.3 nM observed. In most cases, thioethercontaining compounds were more potent inhibitors then their sulfinyl or sulfonyl analogs. QSAR analyses demonstrated excellent observed versus predicted values correlations (r 2 ranging from 0.908 -0.948), with cross-correlation coefficients (q 2 ) of ϳ0.9. In addition, pseudoreceptor models for the TKF analogs were very similar to structures and models previously obtained using benzil-or sulfonamide-based CE inhibitors. These studies indicate that more potent, selective CE inhibitors, containing long alkyl or aromatic groups attached to the thioether chemotype in TFKs, can be developed for use in in vivo enzyme inhibition.

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Fluorinated aldehydes and ketones acting as quasi-substrate inhibitors of acetylcholinesterase

Cited by 80 publications

References 25 publications

Overview of Carboxylesterases and Their Role in the Metabolism of Insecticides

Overview of Carboxylesterases and Their Role in the Metabolism of Insecticides

Functional Characteristics of the Oxyanion Hole in Human Acetylcholinesterase

Analysis of Mammalian Carboxylesterase Inhibition by Trifluoromethylketone-Containing Compounds

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