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

Hemmert, Andrew; Otto, Tamara C.; Wierdl, Monika; Edwards, Carol C.; Fleming, Christopher D.; MacDonald, Mary; Cashman, John R.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

doi:10.1124/mol.109.062356

Cited by 50 publications

(41 citation statements)

References 40 publications

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“…Thus, we present here for the first time the determination of the bimolecular rate constants for the reaction of pure recombinant human CES1, CES2, and MGL with these oxons. The bimolecular rates of inhibition for CES1 and pesticide oxons reported here are between one and four orders of magnitude higher than those seen for CES1 and nerve agent analogs (sarin, soman, and cyclosarin) (Hemmert et al , 2010). Therefore, CES1 appears to be very efficient at quenching pesticide oxons and is likely a critical enzyme that protects against OP poisoning in humans.…”

Section: Discussioncontrasting

confidence: 53%

Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon

Crow

Bittles

Herring

et al. 2012

Toxicology and Applied Pharmacology

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Oxons are the bioactivated metabolites of organophosphorus insecticides formed via cytochrome P450 monooxygenase-catalyzed desulfuration of the parent compound. Oxons react covalently with the active site serine residue of serine hydrolases, thereby inactivating the enzyme. A number of serine hydrolases other than acetylcholinesterase, the canonical target of oxons, have been reported to react with and be inhibited by oxons. These off-target serine hydrolases include carboxylesterase 1 (CES1), CES2, and monoacylglycerol lipase. Carboxylesterases (CES, EC 3.1.1.1) metabolize a number of xenobiotic and endobiotic compounds containing ester, amide, and thioester bonds and are important in the metabolism of many pharmaceuticals. Monoglyceride lipase (MGL, EC 3.1.1.23) hydrolyzes monoglycerides including the endocannabinoid, 2-arachidonoylglycerol (2-AG). The physiological consequences and toxicity related to the inhibition of off-target serine hydrolases by oxons due to chronic, low level environmental exposures are poorly understood. Here, we determined the potency of inhibition (IC 50 values; 15 min preincubation, enzyme and inhibitor) of recombinant CES1, CES2, and MGL by chlorpyrifos oxon, paraoxon and methyl paraoxon. The order of potency for these three oxons with CES1, CES2, and MGL was chlorpyrifos oxon > paraoxon > methyl paraoxon, although the difference in potency for chlorpyrifos oxon with CES1 and CES2 did not reach statistical significance. We also determined the bimolecular rate constants (k inact /K I ) for the covalent reaction of chlorpyrifos oxon, paraoxon and methyl paraoxon with CES1 and CES2. Consistent with the results for the IC 50 values, the order of reactivity for each of the three oxons with CES1 and CES2 was chlorpyrifos oxon > paraoxon > methyl paraoxon. The bimolecular rate constant for the reaction of chlorpyrifos oxon with MGL was also determined and was less than the values determined for chlorpyrifos oxon with CES1 and CES2 respectively. Together, the results define the kinetics of inhibition of three important hydrolytic enzymes by activated metabolites of widely used agrochemicals.

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Section: Discussioncontrasting

confidence: 53%

Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon

Crow

Bittles

Herring

et al. 2012

Toxicology and Applied Pharmacology

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“…For example, following determination of the crystal structures of hCE1 in complex with Soman, Tabun or cyclosarin [25, 26], it was observed that substitution of a pair of amino acids (V146H and L363E) might allow a water molecule to act as an intermediate nucleophile to remove the phosphorylated adducts on the serine Oγ atom. Mutagenesis, biochemistry and in vitro kinetic assays confirmed that this could be accomplished, with the greatest activity being observed with cyclosarin [24].…”

Section: Interaction Of Carboxylesterases By Organophosphatesmentioning

confidence: 99%

Carboxylesterases: General detoxifying enzymes

Hatfield

Umans

Hyatt

et al. 2016

Chemico-Biological Interactions

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137

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Carboxylesterases (CE) are members of the esterase family of enzymes, and as their name suggests, they are responsible for the hydrolysis of carboxylesters into the corresponding alcohol and carboxylic acid. To date, no endogenous CE substrates have been identified and as such, these proteins are thought to act as a mechanism to detoxify ester-containing xenobiotics. As a consequence, they are expressed in tissues that might be exposed to such agents (lung and gut epithelia, liver, kidney, etc.). CEs demonstrate very broad substrate specificities and can hydrolyze compounds as diverse as cocaine, oseltamivir (Tamiflu), permethrin and irinotecan. In addition, these enzymes are irreversibly inhibited by organophosphates such as Sarin and Tabun. In this overview, we will compare and contrast the two human enzymes that have been characterized, and evaluate the biology of the interaction of these proteins with organophosphates (principally nerve agents).

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“…Moreover, development of CES1-based protein therapeutics is being pursued by the Redinbo and Potter groups with the goal of preventing OP nerve agent toxicity and protecting against the long-term side effects of these agents, which could be released on populations in a terrorist attack, during warfare, and following deliberate or accidental exposure to OP agrochemicals. 32 )…”

Section: Role Of Carboxylesterases In Xenobiotic Metabolismmentioning

confidence: 99%

Carboxylesterases: dual roles in lipid and pesticide metabolism

Ross

Streit

Herring

et al. 2010

Journal of Pesticide Science

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Carboxylesterases (CES, EC 3.1.1.1) are members of a superfamily of serine hydrolases that hydrolyze ester, amide, and carbamate bonds. Several different CES genes exist in mammalian species with evidence of multiple gene duplication events occurring throughout evolutionary history. There are five CES genes reported in the Human Genome Organization database, although CES1 and CES2 are the two best characterized human genes. An emerging picture of the CES family suggests that these enzymes have dual roles in the metabolism of xenobiotic and endobiotic compounds. Pesticides, such as the pyrethroids, are important xenobiotic substrates that are metabolized by CES, whereas cholesteryl esters, triacylglycerols, and 2-arachidonoylglycerol are examples of endobiotics known to be substrates for CES. Functional studies using selective chemical inhibitors, siRNA, and gene knockout models are providing valuable insights into the physiological functions of CES, and suggest that CES may be a novel target for the treatment of diseases such as diabetes and atherosclerosis. This review will examine the known physiological functions of CES, the interactions between xenobiotics (primarily pesticides) and lipids that occur with CES enzymes, and where possible the implications that these findings may have in terms of health and disease.

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

Cited by 50 publications

References 40 publications

Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon

Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon

Carboxylesterases: General detoxifying enzymes

Carboxylesterases: dual roles in lipid and pesticide metabolism

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