Concentration‐dependent reversible activation‐inhibition of human butyrylcholinesterase by tetraethylammonium ion

Stojan, Jure; Goličnik, Marko; Froment, Marie-Thérèse; Estour, François; Masson, Patrick

doi:10.1046/j.1432-1033.2002.02749.x

Cited by 23 publications

(16 citation statements)

References 35 publications

(46 reference statements)

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“…The inhibitory potencies of these separated enantiomers were evaluated, whereby eutomer (−)-2 had an IC 50 of 4.5 nM and was a 3.4-fold more potent huBChE inhibitor than the distomer ( + ) -2 (IC 50 = 15.3 nM). Given the affinity of compound (−)-2 for its target enzyme huBChE, standard methods for K i determination (e.g., Lineweaver-Burk plots) or approximation (e.g., Cheng-Prusoff equations) are inappropriate, as i) the target enzyme huBChE does not obey the typical Michaelis-Menten kinetics34 and ii) the concentration of the inhibitor is approaching the enzyme concentration (50 and 8.2 nM, respectively) in the assay system. This situation is referred to as tight binding inhibition.…”

Section: Resultsmentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

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125

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Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

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Section: Resultsmentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

Self Cite

125

102

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“…For example, at low concentrations of the substrate butyrylthiocholine, hydrolysis can be described by simple Michaelis-Menten kinetics (Amitai et al, 1998). The hydrolysis rate of butyrylthiocholine at intermediate levels exceeds that predicted by Michaelis-Menten kinetics, while very high concentrations of butyrylthiocholine slightly inhibit butyrylcholinesterase (Masson et al, 1996; Masson et al, 1997; Stojan et al, 2002). Within the conditions of the current study, hydrolysis of butyrylthiocholine by butyrylcholinesterase was adequately described by simple Michaelis-Menten kinetics (Fig.…”

Section: Discussionmentioning

confidence: 84%

An evaluation of the inhibition of human butyrylcholinesterase and acetylcholinesterase by the organophosphate chlorpyrifos oxon

Shenouda¹,

Green²,

Sultatos

2009

Toxicology and Applied Pharmacology

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Acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8) are enzymes that belong to the superfamily of α/β-hydrolase fold proteins. While they share many characteristics, they also possess many important differences. For example, whereas they have about 54% amino acid sequence identity, the active site gorge of acetylcholinesterase is considerably smaller than that of butyrylcholinesterase. Moreover, both have been shown to display simple and complex kinetic mechanisms, depending on the particular substrate examined, the substrate concentration, and incubation conditions. In the current study, incubation of butyrylthiocholine in a concentration range of 0.005 mM – 3.0 mM, with 317 pM human butyrylcholinesterase in vitro resulted in rates of production of thiocholine that were accurately described by simple Michaelis-Menten kinetics, with a Km of 0.10 mM. Similarly, the inhibition of butyrylcholinesterase in vitro by the organophosphate chlorpyrifos oxon was described by simple Michaelis-Menten kinetics, with a ki of 3,048 nM−1h−1, and a KD of 2.02 nM. In contrast to inhibition of butyrylcholinesterase, inhibition of human acetylcholinesterase by chlorpyrifos oxon in vitro followed concentration-dependent inhibition kinetics, with the ki increasing as the inhibitor concentration decreased. Chlorpyrifos oxon concentrations of 10 nM and 0.3 nM gave kis of 1.2 nM−1h−1 and 19.3 nM−1h−1, respectively. Although the mechanism of concentration-dependent inhibition kinetics is not known, the much smaller, more restrictive active site gorge of acetylcholinesterase almost certainly plays a role. Similarly, the much larger active site gorge of butyrylcholinesterase likely contributes to its much greater reactivity towards chlorpyrifos oxon, compared to acetylcholinesterase.

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“…Stimulation of BuChE by neutral amines is in contrast with observations made with other BuChE activators, such as choline esters and other tetraalkylammonium salts, compounds that have a permanent cationic moiety (Masson et al, 1999;Stojan et al, 2002). These latter compounds are known to effect activation of BuChE by conformational changes resulting from binding of these cationic compounds to a peripheral anionic site (Masson et al, 1999).…”

Section: Structure-activity Relationshipsmentioning

confidence: 79%

Homocysteine Thiolactone and Human Cholinesterases

2006

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1. The cholinergic system is important in cognition and behavior as well as in the function of the cerebral vasculature. 2. Hyperhomocysteinemia is a risk factor for development of both dementia and cerebrovascular disease. 3. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine, a key process in the regulation of the cholinergic system. 4. It has been hypothesized that the deleterious effects of elevated homocysteine may, in part, be due to its actions on cholinesterases. 5. To further test this hypothesis, homocysteine and a number of its metabolites and analogues were examined for effects on the activity of human cholinesterases. 6. Homocysteine itself did not have any measurable effect on the activity of these enzymes. 7. Homocysteine thiolactone, the cyclic metabolite of homocysteine, slowly and irreversibly inhibited the activity of human AChE. 8. Conversely, this metabolite and some of its analogues significantly enhanced the activity of human BuChE. 9. Structure-activity studies indicated that the unprotonated amino group of homocysteine thiolactone and related compounds represents the essential feature for activation of BuChE, whereas the thioester linkage appears to be responsible for the slow AChE inactivation. 10. It is concluded that hyperhomocysteinemia may exert its adverse effects, in part, through the metabolite of homocysteine, homocysteine thiolactone, which is capable of altering the activity of human cholinesterases, the most pronounced effect being BuChE activation.

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Concentration‐dependent reversible activation‐inhibition of human butyrylcholinesterase by tetraethylammonium ion

Cited by 23 publications

References 35 publications

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

An evaluation of the inhibition of human butyrylcholinesterase and acetylcholinesterase by the organophosphate chlorpyrifos oxon

Homocysteine Thiolactone and Human Cholinesterases

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