Human paraoxonase: A promising approach for pre-treatment and therapy of organophosphorus poisoning

Rochu, Daniel; Chabrière, Éric; Masson, Patrick

doi:10.1016/j.tox.2006.08.037

Cited by 141 publications

(81 citation statements)

References 68 publications

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“…Some pharmaceutical effort has even been aimed at developing PON1, or PON1-HDL complexes, as an injectable biological agent for various indications ranging from the treatment of exposure to organophosphate nerve agents to the prevention or treatment of cardiovascular diseases (80,81). Progress in this arena has been hampered by poor stability of the injected PON1 into the systemic circulation, and it has been suggested that an improved understanding of specific structural features critical to PON1 docking to the HDL particle and that are functionally important for maintenance of PON1 stability and catalytic activity may assist in these endeavors (82,83). This study may thus help with future therapeutic agent efforts using PON1.…”

Section: Discussionmentioning

confidence: 99%

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

Gu¹,

Huang²,

Levison³

et al. 2016

Journal of Biological Chemistry

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However, specific residues on PON1 involved in the HDL-PON1 interaction remain unclear. Unambiguous identification of protein residues involved in docking interactions to lipid surfaces poses considerable methodological challenges. Here we describe a new strategy that uses a novel synthetic photoactivatable and click chemistry-taggable phospholipid probe, which, when incorporated into HDL, was used to identify amino acid residues on PON1 that directly interact with the lipoprotein phospholipid surface. Several specific PON1 residues (Leu-9, Tyr-185, and Tyr-293) were identified through covalent crosslinks with the lipid probes using affinity isolation coupled to liquid chromatography with on-line tandem mass spectrometry. Based upon the crystal structure for PON1, the identified residues are all localized in relatively close proximity on the surface of PON1, defining a domain that binds to the HDL lipid surface. Site-specific mutagenesis of the identified PON1 residues (Leu-9, Tyr-185, and Tyr-293), coupled with functional studies, reveals their importance in PON1 binding to HDL and both PON1 catalytic activity and stability. Specifically, the residues identified on PON1 provide important structural insights into the PON1-HDL interaction. More generally, the new photoactivatable and affinity-tagged lipid probe developed herein should prove to be a valuable tool for identifying contact sites supporting protein interactions with lipid interfaces such as found on cell membranes or lipoproteins.

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Section: Discussionmentioning

confidence: 99%

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

Gu¹,

Huang²,

Levison³

et al. 2016

Journal of Biological Chemistry

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“…134,135 Several enzymes are being evaluated for use as scavengers, such as human serum BChE, recombinant human BChE expressed in the milk of transgenic goats, genetic variants of AChE and human paraoxonase. [134][135][136][137][138] Oximes can be employed for pretreatment, improving the post-treatment by atropine and other oximes 132,139 (see below), but some questions should be addressed for their use, such as timing, duration and achievement of adequate concentrations after administration. 132,133 The chemotherapy employed for the treatment of intoxication with OPCs includes the use of three types of drugs: 1,3,13,128 (i) an anticholinergic substance, to antagonize the effects of ACh accumulation in the cholinergic receptors; (ii) a central nervous system (CNS) depressor, which acts as an anticonvulsive; and (iii) an oxime to reactivate inhibited AChE.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

231

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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“…''PON'' gets name from one of the most commonly used in vitro substrates, paraoxon 3 . It also hydrolyzes aromatic carboxyl esters such, lactones, thiolactones and cyclic carbonate esters [4][5][6][7] . Furthermore, PON1 hydrolyzes some organophosphate-derived nerve agents such as sarin and soman and pesticide diazoxon 1 ; however, physiological substrate and biological function of this enzyme have not known yet.…”

Section: Introductionmentioning

confidence: 99%

Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors

Karataş

Uslu

Alıcı

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, we aimed to investigate the effect of some coumarin and benzoxazinone derivatives on the activity of human PON1. Human serum paraoxonase 1 was purified from fresh human serum blood by two-step procedures that are ammonium sulfate precipitation (60-80%) and then hydrophobic interaction chromatography (Sepharose 4B, L-tyrosine and 1-napthylamine). The enzyme was purified 232-fold with a final specific activity of 27.1 U/mg. In vitro effects of some previously synthesized ionic coumarin or benzoxazinone derivatives (1-21) on purified PON1 activity were investigated. Compound 14 (1-(2,3,4,5,6)-pentamethylbenzyl-3-(6,8-dimethyl-2H-chromen-2-one-4-yl))benzimidazolium chloride was found out as the strongest inhibitor (IC 50 ¼ 7.84 mM) for PON1 among the compounds. Kinetic investigation and molecular docking study were evaluated for one of the most active compounds (compound 12) and obtained data showed that this compound is competitive inhibitor of PON1 and interact with Leu262 and Ser263 in the active site of PON1. Moreover, coumarin derivatives were found out as the more potent inhibitors for PON1 than benzoxazinone derivatives.

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Human paraoxonase: A promising approach for pre-treatment and therapy of organophosphorus poisoning

Cited by 141 publications

References 68 publications

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

Organophosphorus compounds as chemical warfare agents: a review

Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors

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