Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals

Mathieu, Cécile; Bui, Linh‐Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joëlle; Dupret, Jean‐Marie; Rodrigues‐Lima, Fernando

doi:10.1074/jbc.m116.766725

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…So far, a limited number of enzymes have been reported to be inhibited by Thiram (Lippmann and Lloyd, 1969; Caroldi De Paris, 1995;Atanasov et al, 2003;Garbrecht et al, 2006;van Boxtel et al, 2010;Mathieu et al, 2017). In addition to these enzymes, our data show that Thiram is also able to inhibit a phase II xenobiotic-metabolizing enzyme known to play a major role in the metabolism of arylamine xenobiotics.…”

Section: Discussionmentioning

confidence: 49%

“…Certain metabolites of DTCs (such as sulfoxide or sulfone forms) are also reactive. The toxic effects of DTC are thus thought to be due to the parent compounds and their metabolites (Jin et al, 1994;Staub et al, 1998;Mathieu et al, 2015Mathieu et al, , 2017. So far, Thiram pesticide has been clearly shown to impair the activity of few enzymes, i.e., dopamine b-hydroxylase, 11b-hydroxysteroid dehydrogenase, lysyl oxidase, and brain glycogen phosphorylase (Lippmann and Lloyd, 1969;Caroldi and De Paris, 1995;Atanasov et al, 2003;Garbrecht et al, 2006;van Boxtel et al, 2010;Mathieu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Human Arylamine N-Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram

Xu¹,

Mathieu²,

Berthelet³

et al. 2017

Mol Pharmacol

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Thiram (tetramethylthiuram disulfide) is a representative dithiocarbamate (DTC) pesticide used in both the field and as a seed protectant. The widespread use of Thiram and other DTC pesticides has raised concerns for health, because these compounds can exert neuropathic, endocrine disruptive, and carcinogenic effects. These toxic effects are thought to rely, at least in part, on the reaction of Thiram (and certain of its metabolites) with cellular protein thiols with subsequent loss of protein function. So far, a limited number of molecular targets of Thiram have been reported, including few enzymes such as dopamine -hydroxylase, 11-hydroxysteroid dehydrogenase, and brain glycogen phosphorylase. We provide evidence that Thiram is an inhibitor ( = 23 M; = 0.085 second; / = 3691 M⋅s) of human arylamine -acetyltransferase 1 (NAT1), a phase II xenobiotic-metabolizing enzyme that plays a key role in the biotransformation of aromatic amine xenobiotics. Thiram was found to act as an irreversible inhibitor through the modification of NAT1 catalytic cysteine residue as also reported for other enzymes targeted by this pesticide. We also showed using purified NAT1 and human keratinocytes that Thiram impaired the-acetylation of 3,4-dichloroaniline (3,4-DCA), a major toxic metabolite of aromatic amine pesticides (such as Diuron or Propanil). As coexposure to different classes of pesticides is common, our data suggest that pharmacokinetic drug-drug interactions between DTC pesticides such as Thiram and aromatic amine pesticides may occur through alteration of NAT1 enzymes functions.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Human Arylamine N-Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram

Xu¹,

Mathieu²,

Berthelet³

et al. 2017

Mol Pharmacol

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“…Studies have shown that impairments in carbohydrate metabolism in the brain are associated with ASD [ 71 , 74 ]. It is within reason that this study implicates carbohydrate metabolism in ASD’s etiology, considering that some pesticides exact their neurotoxic effects by targeting carbohydrate metabolism [ 75 , 76 ]. FXR/RXR activation and Type I Diabetes Mellitus ( Table 3 ) are two pathways identified here that support this carbohydrate metabolism hypothesis.…”

Section: Discussionmentioning

confidence: 99%

In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Furnary

García-Milián

Liew

et al. 2021

Toxics

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Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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“…Mathieu et al showed that thiram,aneurotoxic disulfide-containingd ithiocarbamate compoundi nhibits brain glycogenp hosphorylase through the formationo fa ni ntramolecular disulfide bond between Cys 318 and Cys 326 ,k nown to be ar edox-switch that prevents the allosteric activation of the enzyme by AMP. [22,23] The proposed mechanism consistso ft he reactiono ft hiram with ac ysteinet hiol leading to am ixed disulfide followedby the formation of an intramolecular disulfide bond with av icinal cysteiner esidue. Another example describes the inactivationo fa na rginine phosphatase by as eleno-compoundt hat induces an intramolecular disulfide bond betweent wo adjacent actives ite cysteinesv ia an unclear mechanism.…”

Section: Introductionmentioning

confidence: 99%

“…Mathieu et al. showed that thiram, a neurotoxic disulfide‐containing dithiocarbamate compound inhibits brain glycogen phosphorylase through the formation of an intramolecular disulfide bond between Cys 318 and Cys 326 , known to be a redox‐switch that prevents the allosteric activation of the enzyme by AMP . The proposed mechanism consists of the reaction of thiram with a cysteine thiol leading to a mixed disulfide followed by the formation of an intramolecular disulfide bond with a vicinal cysteine residue.…”

Section: Introductionmentioning

confidence: 99%

Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Jänsch¹,

Sugiarto²,

Muth

et al. 2020

Chemistry A European J

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Human histoned eacetylase 8i saw ell-recognized target forT-cell lymphomaa nd particularly childhoodn euroblastoma. PD-404,182 was shown to be as elective covalent inhibitor of HDAC8t hat formsm ixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover,H DAC8 was shown to be regulated by ar edox switch based on the reversible formation of a disulfideb ond between cysteines Cys 102 andC ys 153 .T his study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formationo fi ntramolecular disulfide bridges. Therefore,t he inhibition mechanism of HDAC8b yP D-404,182 involves both, covalentmodification of thiols as well as ligand mediated disulfide formation. Moreover,t his study provides ad eep moleculari nsighti ntot he regulation mechanismo fH DAC8i nvolvings everal cysteines with graduated capability to form reversible disulfide bridges.

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Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals

Cited by 11 publications

References 42 publications

Human Arylamine N-Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram

Human Arylamine N-Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram

In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

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