New light on phosphate transfer from triesters

Kirby, Anthony J.; Mora, José R.; Nome, Faruk

doi:10.1016/j.bbapap.2012.04.010

Cited by 35 publications

(49 citation statements)

References 29 publications

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“…butyrylcholinesterase [BuChE]) cholinesterases (ChEs) by a nucleophilic reaction in which the associative two-step additionelimination reaction with the serine hydroxyl group at their active sites results in phosphorylated and inactivated enzymes. 1,2 AChE is primarily found in nervous tissue and erythrocytes; erythrocytic ChE activity more accurately reflects nervous tissue AChE activity than BuChE, which is primarily produced in the liver and appears in plasma, with its activity varying with a number of disorders including liver disease. 3,4 The irreversible inactivation of ChEs by the dealkylation of the OP moiety of the OP-ChE complex is known as ageing, in which the phosphorusoxygen bond of the OP-ChE complex strengthens.…”

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confidence: 99%

In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases

Mohammadi

Jalilian

Karimi

et al. 2017

SQUMJ

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Objectives: Organophosphate (OP) pesticides inhibit both red blood cell (RBC) and plasma cholinesterases (ChEs). Oximes, especially pralidoxime (2-PAM), are widely used as antidotes to treat OP poisoning. In addition, N-acetylcysteine (NAC) is sometimes used as an adjuvant antidote. The current study aimed to assess the feasibility of using NAC as a single therapeutic agent for OP poisoning in comparison to in vitro 2-PAM. Methods: This study was carried out at the Razi Drug Research Center of Iran University of Medical Sciences, Tehran, Iran, between April and September 2014. A total of 22 healthy human subjects were recruited and 8 mL citrated blood samples were drawn from each subject. Dichlorvos-inhibited blood samples were separately exposed to low and high doses (final concentrations of 300 and 600 μmol.L-1 , respectively) of 2-PAM, NAC and cysteine. Plasma and RBCs were then separated by centrifugation and their ChE activity was measured using spectrophotometry. Results: Although cysteine-and not NAC-increased the ChE activity of both plasma and RBCs over those of dichlorvos, it did not increase them over those of a high dose of 2-PAM. Conclusion: These results suggest that the direct reactions of 2-PAM and cysteine with dichlorvos and the reactivation of phosphorylated ChEs occurr via an associative stepwise addition-elimination process. High therapeutic blood concentrations of cysteine are needed for the elevation of ChE activity in plasma and RBCs; however, both this agent and NAC may still be effective in the reactivation of plasma and RBC ChEs.

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confidence: 99%

In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases

Mohammadi

Jalilian

Karimi

et al. 2017

SQUMJ

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“…Kirby and Nome recently summarized our understanding of the reactions of phosphate esters, including triesters, pointing out the possibility of formation, under certain conditions, of intermediate phosphoranes during A N + D N degradation reactions; as also reported elsewhere in studies that only considered the characteristics of the leaving group, OR * . Kirby and Nome go further, reporting that in addition to the OR * group (Figure ), the equatorial OR substituent groups also contribute to the stability of the intermediate . In addition, they pointed out that the half‐lives of the intermediates are reduced in the case of electron‐withdrawing groups in the apical position, which is the preferential position for the strongest electron‐withdrawing group.…”

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confidence: 95%

Cleaving paraoxon with hydroxylamine: Ammonium oxide isomer favors a Frontside attack mechanism

Lima

Cruz

Fernandes

et al. 2018

J of Physical Organic Chem

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A detailed molecular understanding of the mechanisms of the dephosphorylation of phosphate triesters due to nucleophilic attack can be very useful for the design of nucleophiles that are more efficient. In this work, we report a combined experimental and theoretical study of the reaction of hydroxylamine with paraoxon. The profile of the reaction rate according to pH was determined, and it was found that protonated hydroxylamine was unreactive, while the neutral form reacted via the zwitterion tautomer, with an overall free energy barrier of 23.0 kcal mol‐1. The anionic form was the most reactive, with a free energy barrier of 18.1 kcal mol‐1. Computational calculations revealed 2 mechanisms for the nucleophilic attack of the zwitterion form: the usual backside attack and a new frontside attack mechanism. The former proceeded according to a 2‐step associative mechanism, while the latter was a concerted single‐step mechanism involving attack of the hydroxylamine oxygen on the phosphorus center and interaction of the NH3+ group with the oxygen of the P═O group. The calculations indicated that the free energy barrier for the frontside attack was more favorable than the backside attack by 3 kcal mol‐1, supporting the notion that the observed reaction occurs by frontside attack. The reaction with the anionic hydroxylamine form occurred according to a single‐step concerted ANDN mechanism.

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“…Assim, no panorama mais recente da hidrólise de triésteres fosfóricos, os parâmetros de sensibilidade para os sistemas triarílicos são β LG = -0,42 e β NLG = -0,28, e para os sistemas dialquil arílicos, β LG = -0,99 e β NLG = -0,61. 18 Figura 6. Gráficos de Brønsted referentes aos grupos de saída arílicos ( -OAr) para a hidrólise de três séries de triésteres de fosfato, obtidas a 25°C ou, para a série de triésteres (1), normalizada a 25°C.…”

Section: Figura 5 Famílias De Triésteres De Fosfato Estudadasunclassified

Recent Advances on the Decomposition of Neurotoxic Phosphorous Triesters

Wanderlind¹,

Medeiros²,

Souza³

et al. 2014

Revista Virtual De Química

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The anti-cholinesterase activity exhibited by several organophosphorus compounds brings interest to the development of new antidotes for poisoning cases with such chemicals. The advance of more efficient methods for destruction of stockpiles of chemical warfare agents is also currently important. In this sense, the aim of this work is to present a review of the recent progress in the investigation of the reactivity of phosphate triesters in several different systems, which can give insights into the development of novel strategies for application in chemical defense.

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New light on phosphate transfer from triesters

Cited by 35 publications

References 29 publications

In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases

In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases

Cleaving paraoxon with hydroxylamine: Ammonium oxide isomer favors a Frontside attack mechanism

Recent Advances on the Decomposition of Neurotoxic Phosphorous Triesters

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