Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase

Aurbek, Nadine; Thiermann, Horst; Szinicz, L.; Eyer, Peter; Worek, Franz

doi:10.1016/j.tox.2006.04.030

Cited by 119 publications

(61 citation statements)

References 28 publications

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“…These data, collected at 410 nm and 25°C on a Pherastar microplate reader (BMG Labtech, Durham, NC), were corrected for spontaneous pNPB hydrolysis and fit to eq. 1 (Aurbek et al, 2006): …”

Section: Methodsmentioning

confidence: 99%

Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

Hemmert¹,

Otto²,

Wierdl³

et al. 2010

Mol Pharmacol

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Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700-and 2900-fold preference for the P R enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P S isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P S isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

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Section: Methodsmentioning

confidence: 99%

Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

Hemmert¹,

Otto²,

Wierdl³

et al. 2010

Mol Pharmacol

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“…26,[63][64][65][66][67][68][69] Additionally, recent experimental studies conducted with 1,1'-methylene-bis(4-(hydroxyimino)methyl) pyridinium dibromide (MMB-4) showed that, compared to HLö-7 and HI-6, MMB-4 was a less potent reactivator of AChE inhibited by sarin, several sarin analogues, soman, VX, VR or CVX. 3,70 Therefore, despite intensive research activities on this topic, PAM-2, TMB-4, LüH-6, HI-6 and HLö-7 have remained dominant among oximes in experimental work.…”

Section: Oxime Therapymentioning

confidence: 99%

“…However, examination of reactivity towards human and pig AChE demonstrated the following rank order of inhibitory potency: VR>CVX>VX. 3 Structural formulae of some organophosphorus chemical warfare agents are given in figure 1.…”

mentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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“…The absorbance change was continuously monitored for 20 min. The recorded curves were analyzed by non-linear regression analysis and used for the subsequent determination of k i [18]. The second-order inhibition rate constants of carbamates were determined in the absence and presence of 10 lM obidoxime or 2-PAM as representatives for clinically relevant oxime plasma concentrations in the low micromolar range [19,20].…”

Section: Inhibition Kineticsmentioning

confidence: 99%

Investigation of kinetic interactions between approved oximes and human acetylcholinesterase inhibited by pesticide carbamates

Wille¹,

Kaltenbach²,

Thiermann³

et al. 2013

Chemico-Biological Interactions

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Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase

Cited by 119 publications

References 28 publications

Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Investigation of kinetic interactions between approved oximes and human acetylcholinesterase inhibited by pesticide carbamates

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