Oxime‐induced reactivation of acetylcholinesterase inhibited by organophosphinates

Hanke, Dan W.; Beckett, M. S.; Overton, M.; Burdick, C. K.; Lieske, Claire N.

doi:10.1002/jat.2550100205

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…Early studies demonstrated chiral preferences at the phosphorus moiety and at the attached alkyl carbons for rates of inactivation by the organophosphates (4)(5)(6)(7)(8). Moreover, oxime reactivation kinetics also appear to show structural (9) and chiral preferences for the attached organophosphate (10,11). While these studies point to orientational constraints for organophosphate attack of the active center serine and oxime attack of the phosphoserine, details on ligand accessibility to the active center awaited a structure of the enzyme.…”

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confidence: 99%

Mechanism of Oxime Reactivation of Acetylcholinesterase Analyzed by Chirality and Mutagenesis

et al. 2000

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Organophosphates inactivate acetylcholinesterase by reacting covalently with the active center serine. We have examined the reactivation of a series of resolved enantiomeric methylphosphonate conjugates of acetylcholinesterase by two oximes, 2-pralidoxime (2-PAM) and 1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4'-carbamoyl-1-pyridinium) (HI-6). The S(p) enantiomers of the methylphosphonate esters are far more reactive in forming the conjugate with the enzyme, and we find that rates of oxime reactivation also show an S(p) versus R(p) preference, suggesting that a similar orientation of the phosphonyl oxygen toward the oxyanion hole is required for both efficient inactivation and reactivation. A comparison of reactivation rates of (S(p))- and (R(p))-cycloheptyl, 3,3-dimethylbutyl, and isopropyl methylphosphonyl conjugates shows that steric hindrance by the alkoxy group precludes facile access of the oxime to the tetrahedral phosphorus. To facilitate access, we substituted smaller side chains in the acyl pocket of the active center and find that the Phe295Leu substitution enhances the HI-6-elicited reactivation rates of the S(p) conjugates up to 14-fold, whereas the Phe297Ile substitution preferentially enhances 2-PAM reactivation by as much as 125-fold. The fractional enhancement of reactivation achieved by these mutations of the acyl pocket is greatest for the conjugated phosphonates of the largest steric bulk. By contrast, little enhancement of the reactivation rate is seen with these mutants for the R(p) conjugates, where limitations on oxime access to the phosphonate and suboptimal positioning of the phosphonyl oxygen in the oxyanion hole may both slow reactivation. These findings suggest that impaction of the conjugated organophosphate within the constraints of the active center gorge is a major factor in influencing oxime access and reactivation rates. Moreover, the individual oximes differ in attacking orientation, leading to the presumed pentavalent transition state. Hence, their efficacies as reactivating agents depend on the steric bulk of the intervening groups surrounding the tetrahedral phosphorus.

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confidence: 99%

Mechanism of Oxime Reactivation of Acetylcholinesterase Analyzed by Chirality and Mutagenesis

et al. 2000

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“…The ATNAA is a single-dose autoinjector that contains atropine the chloride salt of 2-PAM [2] (Figure 19). As mentioned, to reactivate inactivated AChE, oximes must be administered [87]. The history of the development of oxime reactivators has been reviewed elsewhere [88].…”

Section: V-agent Antidotesmentioning

confidence: 99%

“…As mentioned, to reactivate inactivated AChE, oximes must be administered [87]. The history of the development of oxime reactivators has been reviewed elsewhere [88].…”

Section: V-agent Antidotesmentioning

confidence: 99%

Chemical, Physical, and Toxicological Properties of V-Agents

Pampalakis

Kostoudi

2023

IJMS

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V-agents are exceedingly toxic organophosphate nerve agents. The most widely known V-agents are the phosphonylated thiocholines VX and VR. Nonetheless, other V-subclasses have been synthesized. Here, a holistic overview of V-agents is provided, where these compounds have been categorized based on their structures to facilitate their study. A total of seven subclasses of V-agents have been identified, including phospho(n/r)ylated selenocholines and non-sulfur-containing agents, such as VP and EA-1576 (EA: Edgewood Arsenal). Certain V-agents have been designed through the conversion of phosphorylated pesticides to their respective phosphonylated analogs, such as EA-1576 derived from mevinphos. Further, this review provides a description of their production, physical properties, toxicity, and stability during storage. Importantly, V-agents constitute a percutaneous hazard, while their high stability ensures the contamination of the exposed area for weeks. The danger of V-agents was highlighted in the 1968 VX accident in Utah. Until now, VX has been used in limited cases of terrorist attacks and assassinations, but there is an increased concern about potential terrorist production and use. For this reason, studying the chemistry of VX and other less-studied V-agents is important to understand their properties and develop potential countermeasures.

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Biological Activity of Phosphonic and Phosphinic Acids

Kalir

2009

Patai's Chemistry of Functional Groups

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Oxime‐induced reactivation of acetylcholinesterase inhibited by organophosphinates

Cited by 6 publications

References 13 publications

Mechanism of Oxime Reactivation of Acetylcholinesterase Analyzed by Chirality and Mutagenesis

Mechanism of Oxime Reactivation of Acetylcholinesterase Analyzed by Chirality and Mutagenesis

Chemical, Physical, and Toxicological Properties of V-Agents

Biological Activity of Phosphonic and Phosphinic Acids

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