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3 results on '"Glycogen Phosphorylase, Brain Form"'

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

Author

Iman Haddad, Emile Petit, Fernando Rodrigues-Lima, Onnik Agbulut, Cécile Mathieu, Linh-Chi Bui, Joëlle Vinh, Jean-Marie Dupret, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Université Sorbonne Paris Cité (USPC), Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Cytophysiologie et Toxicologie Cellulaire (EA 1553), Université Paris Diderot - Paris 7 (UPD7), Unité de Spectrométrie de Masse Biologique et Protéomique, ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CNRS/ESPCI ParisTech USR 3149, Centre National de la Recherche Scientifique (CNRS), Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech), Laboratoire de Spectrométrie de Masse Biologique & Protéomique (SMBP), Ecole Superieure de Physique et Chimie Industrielles (ESPCI), ESPCI, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), VINH, Joëlle, Université Sorbonne Paris Cité ( USPC ), Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ), ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre National de la Recherche Scientifique ( CNRS ), Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris ( ESPCI ParisTech ), Laboratoire de Spectrométrie de Masse Biologique & Protéomique ( SMBP ), and Ecole Superieure de Physique et Chimie Industrielles ( ESPCI )

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Neurotoxins, Allosteric regulation, [ CHIM ] Chemical Sciences, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Glycogen phosphorylase, 0302 clinical medicine, Ubiquitin, Glycogen Phosphorylase, Brain Form, Thiocarbamates, [CHIM] Chemical Sciences, medicine, Humans, Glycogen storage disease, [CHIM]Chemical Sciences, Molecular Biology, ComputingMilieux_MISCELLANEOUS, [ SDV ] Life Sciences [q-bio], biology, Glycogen, Neurodegeneration, Neurotoxicity, Neurodegenerative Diseases, Cell Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Metabolism, 030104 developmental biology, chemistry, Proteasome, biology.protein, Neurotoxicity Syndromes, 030217 neurology & neurosurgery
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 × 105 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 (Cys318–Cys326), 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.

Published
2017
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2. An isozyme-specific redox switch in human brain glycogen phosphorylase modulates its allosteric activation by AMP

Author

Joëlle Vinh, Jean-Marie Dupret, Angélique Cocaign, Cécile Mathieu, Romain Duval, Emile Petit, Catherine Etchebest, Fernando Rodrigues-Lima, Iman Haddad, Linh-Chi Bui, Université Paris sciences et lettres (PSL), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
0301 basic medicine, Papers of the Week, Biology, Biochemistry, Isozyme, Glycogen debranching enzyme, 03 medical and health sciences, Glycogen phosphorylase, chemistry.chemical_compound, Allosteric Regulation, Glycogen Phosphorylase, Brain Form, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Glycogen storage disease, Cysteine, Disulfides, Phosphorylation, Phosphorylase kinase, Glycogen synthase, Molecular Biology, Glycogen, Cell Biology, medicine.disease, Adenosine Monophosphate, Rats, Isoenzymes, 030104 developmental biology, chemistry, biology.protein, Rabbits, Oxidation-Reduction
Abstract

International audience; Brain glycogen and its metabolism are increasingly recognized as major players inbrain functions. Moreover, alteration of glycogen metabolism in the braincontributes to neurodegenerative processes. In the brain, both muscle and brainglycogen phosphorylase isozymes regulate glycogen mobilization. However, giventheir distinct regulatory features, these two isozymes could confer distinctmetabolic functions of glycogen in brain. Interestingly, recent proteomicsstudies have identified isozyme-specific reactive cysteine residues in brainglycogen phosphorylase (bGP). In this manuscript, we show that the activity ofhuman bGP is redox-regulated through the formation of a disulphide bond involvinga highly reactive cysteine unique to the bGP isozyme. We found that thisdisulphide bond acts as a redox switch that precludes the allosteric activationof the enzyme by AMP without affecting its activation by phosphorylation. Thisunique regulatory feature of bGP sheds new light on the isoform-specificregulation of glycogen phosphorylase and glycogen metabolism.

Published
2016
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3. Insights into Brain Glycogen Metabolism

Author

Mathieu, Cécile, de La Sierra-Gallay, Ines Li, Duval, Romain, Xu, Ximing, Cocaign, Angélique, Léger, Thibaut, Woffendin, Gary, Camadro, Jean-Michel, Etchebest, Catherine, Haouz, Ahmed, Dupret, Jean-Marie, Rodrigues-Lima, Fernando, Université Sorbonne Paris Cité (USPC), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Thermo Fisher Scientific, GR-Ex, Laboratoire d'Excellence, GR-Ex, Université Paris Diderot - Paris 7 - UFR Sciences du Vivant (UPD7 UFR Sciences du Vivant), Université Paris Diderot - Paris 7 (UPD7), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Cristallographie (Plateforme) - Crystallography (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), French Ministry of Research (Ecole Doctorale BioSPC), Région Ile de France (DIM), China Scholarship Council, University Paris Diderot, CNRS, and Institut Pasteur

Subjects
crystal structure, MELF), Nerve Tissue Proteins, glycogen metabolism, Crystallography, X-Ray, Adenosine Monophosphate, Lafora disease (Lafora progressive myoclonic epilepsy, allosteric regulation, brain functions, Isoenzymes, Lafora Disease, Protein Domains, Glycogen Phosphorylase, Brain Form, brain metabolism, glycogen, energy metabolism, Enzymology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

International audience; Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glyco-gen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 A ˚) and in complex with its allos-teric activator AMP (3.4 A ˚). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.

Published
2016
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