Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.
Identifieur interne : 000007 ( PubMed/Corpus ); précédent : 000006; suivant : 000008Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.
Auteurs : Cécile Mathieu ; Linh-Chi Bui ; Emile Petit ; Iman Haddad ; Onnik Agbulut ; Joelle Vinh ; Jean-Marie Dupret ; Fernando Rodrigues-LimaSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2017.
Abstract
Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.
DOI: 10.1074/jbc.M116.766725
PubMed: 27965358
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France.</nlm:affiliation></affiliation></author><author><name sortKey="Petit, Emile" sort="Petit, Emile" uniqKey="Petit E" first="Emile" last="Petit">Emile Petit</name><affiliation><nlm:affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Haddad, Iman" sort="Haddad, Iman" uniqKey="Haddad I" first="Iman" last="Haddad">Iman Haddad</name><affiliation><nlm:affiliation>ESPCI ParisTech, Université Paris Sciences et Lettres, Laboratoire de Spectrométrie de Masse Biologique et Protéomique, CNRS USR, 3149 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Agbulut, Onnik" sort="Agbulut, Onnik" uniqKey="Agbulut O" first="Onnik" last="Agbulut">Onnik Agbulut</name><affiliation><nlm:affiliation>the Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine, UMR CNRS 8256, Biological Adaptation and Ageing, 75005 Paris, France, and.</nlm:affiliation></affiliation></author><author><name sortKey="Vinh, Joelle" sort="Vinh, Joelle" uniqKey="Vinh J" first="Joelle" last="Vinh">Joelle Vinh</name><affiliation><nlm:affiliation>ESPCI ParisTech, Université Paris Sciences et Lettres, Laboratoire de Spectrométrie de Masse Biologique et Protéomique, CNRS USR, 3149 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Dupret, Jean Marie" sort="Dupret, Jean Marie" uniqKey="Dupret J" first="Jean-Marie" last="Dupret">Jean-Marie Dupret</name><affiliation><nlm:affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Rodrigues Lima, Fernando" sort="Rodrigues Lima, Fernando" uniqKey="Rodrigues Lima F" first="Fernando" last="Rodrigues-Lima">Fernando Rodrigues-Lima</name><affiliation><nlm:affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France, fernando.rodrigues-lima@univ-paris-diderot.fr.</nlm:affiliation></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">27965358</PMID><DateCreated><Year>2016</Year><Month>12</Month><Day>14</Day></DateCreated><DateRevised><Year>2017</Year><Month>02</Month><Day>08</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><Volume>292</Volume><Issue>5</Issue><PubDate><Year>2017</Year><Month>Feb</Month><Day>03</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. Chem.</ISOAbbreviation></Journal><ArticleTitle>Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.</ArticleTitle><Pagination><MedlinePgn>1603-1612</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M116.766725</ELocationID><Abstract><AbstractText NlmCategory="UNASSIGNED">Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.</AbstractText><CopyrightInformation>© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mathieu</LastName><ForeName>Cécile</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bui</LastName><ForeName>Linh-Chi</ForeName><Initials>LC</Initials><AffiliationInfo><Affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Petit</LastName><ForeName>Emile</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haddad</LastName><ForeName>Iman</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>ESPCI ParisTech, Université Paris Sciences et Lettres, Laboratoire de Spectrométrie de Masse Biologique et Protéomique, CNRS USR, 3149 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Agbulut</LastName><ForeName>Onnik</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>the Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine, UMR CNRS 8256, Biological Adaptation and Ageing, 75005 Paris, France, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vinh</LastName><ForeName>Joelle</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>ESPCI ParisTech, Université Paris Sciences et Lettres, Laboratoire de Spectrométrie de Masse Biologique et Protéomique, CNRS USR, 3149 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dupret</LastName><ForeName>Jean-Marie</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodrigues-Lima</LastName><ForeName>Fernando</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France, fernando.rodrigues-lima@univ-paris-diderot.fr.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>12</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Parkinson disease</Keyword><Keyword MajorTopicYN="N">allosteric regulation</Keyword><Keyword MajorTopicYN="N">brain metabolism</Keyword><Keyword MajorTopicYN="N">carbohydrate metabolism</Keyword><Keyword MajorTopicYN="N">disulfide</Keyword><Keyword MajorTopicYN="N">glycogen</Keyword><Keyword MajorTopicYN="N">glycogen storage disease</Keyword><Keyword MajorTopicYN="N">toxicology</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>11</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2016</Year><Month>12</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="pmc-release"><Year>2018</Year><Month>02</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27965358</ArticleId><ArticleId IdType="pii">M116.766725</ArticleId><ArticleId IdType="doi">10.1074/jbc.M116.766725</ArticleId><ArticleId IdType="pmc">PMC5290938</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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