A new post-intoxication treatment of paraoxon and parathion poisonings using an evolved PON1 variant and recombinant GOT1

Goldsmith, Moshe; Ashani, Yacov; Margalit, Raanan; Nyska, Abraham; Mirelman, David; Tawfik, Dan S.

doi:10.1016/j.cbi.2016.05.034

Cited by 19 publications

(8 citation statements)

References 56 publications

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“…Their progressive neutralization in the bloodstream can be achieved, using variants of human PON‐1 that were shown to improve post‐exposure therapy (Goldsmith et al . ). Similarly, infusion of PTEs could scavenge traces of OPs continuously released from their depot sites.…”

Section: Post‐exposure Treatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

124

105

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Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for postexposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre-and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE.

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Section: Post‐exposure Treatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

124

105

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“…The pH profile of the activity (Figure S4 in the Supporting Information) is consistent with a single water deprotonation step with an effective p K a of 8.3. While the resulting k cat / k uncat ratio of 3.5 × 10 3 at pH 8.0 is inferior to those observed for engineered enzymes, ,− it is on par with catalytic antibodies , and small molecule catalysts. − It compares well to many polymer-based heterogeneous catalysts, albeit it is difficult to draw a direct comparison, because experimental conditions vary widely (see Table S1 in the Supporting Information).…”

mentioning

confidence: 99%

“…Paraoxon is a challenging substrate for hydrolysis (background hydrolysis: k uncat = 7.97 × 10 −7 min −1 at pH 7.8); 22 thus, this pesticide persists in the environment for a prolonged period of time. While many highly efficient paraoxonases have been already developed using directed evolution of related proteins, 23 catalytic amyloids offer several practical advantages, such as robustness, low cost, and ease of modification. Hydrolysis of paraoxon is often facilitated by metallocofactors, Cu II being one of the most reactive ones.…”

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confidence: 99%

Copper-Containing Catalytic Amyloids Promote Phosphoester Hydrolysis and Tandem Reactions

et al. 2017

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Self-assembly of short de novo designed peptides gives rise to catalytic amyloids capable of facilitating multiple chemical transformations. We show that catalytic amyloids can efficiently hydrolyze paraoxon, a widely used, highly toxic organophosphate pesticide. Moreover, these robust and inexpensive metal-containing materials can be easily deposited on various surfaces producing catalytic flow devices. Finally, functional promiscuity of catalytic amyloids promotes tandem hydrolysis/oxidation reactions. High efficiency discovered in a very small library of peptides suggests an enormous potential for further improvement of catalytic properties both in terms of catalytic efficiency and substrate scope.

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“…With the advent of industrialization, modern environments now have an additional source of P-containing compounds: anthropogenic organophosphates (AOPs), which includes phosphotriesters as well as diesters of both phosphonates and phosphites (5) . These man-made compounds are used in an array of applications; phosphotriesters are pesticides (6) , flame retardants (7) and plasticizers (8) , while phosphonate diesters can act as potent nerve agents (9) . Over the last several decades, the concentration of AOPs in the ocean has been steadily increasing (10,11) and can potentially exceed the concentration of phosphate in P-depleted environments (1,10) raising the question: Are AOPs a viable alternative P source in environments with limiting concentrations of labile phosphate?…”

Section: Main Textmentioning

confidence: 99%

Widespread Utilization of Diverse Organophosphate Pollutants by Marine Bacteria

Despotović

Aharon

Trofimyuk

et al. 2021

Preprint

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Anthropogenic organophosphates (AOPs), such as phosphotriesters, are used extensively as plasticizers, flame retardants, nerve agents and pesticides. Soil bacteria bearing a phosphotriesterase (PTE) can degrade AOPs, but whether bacteria are capable of utilizing AOPs as a phosphorus source, and how widespread PTEs are in nature, remains unclear. Here, we report the utilization of diverse AOPs by four model marine bacteria and seventeen bacterial isolates from seawater samples. To unravel the details of AOP utilization, two novel PTEs from marine bacteria were isolated and characterized. When expressed in E. coli, these PTEs enabled growth on a pesticide analog as the sole phosphorus source. Utilization of AOPs provides bacteria with a source of phosphorus in depleted environments and offers a new prospect for the bioremediation of a pervasive class of anthropogenic pollutants.

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A new post-intoxication treatment of paraoxon and parathion poisonings using an evolved PON1 variant and recombinant GOT1

Cited by 19 publications

References 56 publications

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Copper-Containing Catalytic Amyloids Promote Phosphoester Hydrolysis and Tandem Reactions

Widespread Utilization of Diverse Organophosphate Pollutants by Marine Bacteria

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