title: An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP.
abstract: Brain glycogen and its metabolism are increasingly recognized as major players in brain functions. Moreover, alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. In the brain, both muscle and brain glycogen phosphorylase isozymes regulate glycogen mobilization. However, given their distinct regulatory features, these two isozymes could confer distinct metabolic functions of glycogen in brain. Interestingly, recent proteomics studies have identified isozyme-specific reactive cysteine residues in brain glycogen phosphorylase (bGP). In this study, we show that the activity of human bGP is redox-regulated through the formation of a disulfide bond involving a highly reactive cysteine unique to the bGP isozyme. We found that this disulfide bond acts as a redox switch that precludes the allosteric activation of the enzyme by AMP without affecting its activation by phosphorylation. This unique regulatory feature of bGP sheds new light on the isoform-specific regulation of glycogen phosphorylase and glycogen metabolism.
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.
authors.forename: Romain
authors.initials: R
authors.lastname: Duval
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.
authors.forename: Angélique
authors.initials: A
authors.lastname: Cocaign
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.
authors.forename: Emile
authors.initials: E
authors.lastname: Petit
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.
authors.forename: Linh-Chi
authors.initials: LC
authors.lastname: Bui
authors.affiliation: ESPCI Paris, PSL Research University, Spectrométrie de Masse Biologique et Protéomique (SMPB), CNRS USR 3149, 10 rue Vauquelin, F75231 Paris cedex 05, France.
authors.forename: Iman
authors.initials: I
authors.lastname: Haddad
authors.affiliation: ESPCI Paris, PSL Research University, Spectrométrie de Masse Biologique et Protéomique (SMPB), CNRS USR 3149, 10 rue Vauquelin, F75231 Paris cedex 05, France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Vinh
authors.affiliation: INSERM, UMR S1134, Université Paris Diderot, F-75015 Paris.|Université Paris Diderot, Sorbonne Paris Cité, F-75013 Paris.|Institut National de la Transfusion Sanguine (INTS), 75015 Paris.|GR-Ex, Laboratoire d'excellence, 75015 Paris, and.|UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Etchebest
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris.|UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Dupret
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, fernando.rodrigues-lima@univ-paris-diderot.fr.|UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D003545:Cysteine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D006003:Glycogen / Q000737:chemistry / Q000378:metabolism; D025002:Glycogen Phosphorylase, Brain Form / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000502:physiology; D011817:Rabbits; D051381:Rats
chemical_list: D004220:Disulfides; D007527:Isoenzymes; D000249:Adenosine Monophosphate; D006003:Glycogen; D025002:Glycogen Phosphorylase, Brain Form; D003545:Cysteine
keywords: allosteric regulation; brain metabolism; carbohydrate metabolism; disulfide; glycogen; glycogen storage disease; redox regulation