Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase

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dc.catalogadoryvc
dc.contributor.authorBloemen, Rebeca H. J.
dc.contributor.authorRadi, Rafael
dc.contributor.authorDavies, Michael J.
dc.contributor.authorFuentes Lemus Eduardo Felipe
dc.date.accessioned2024-12-31T15:15:22Z
dc.date.available2024-12-31T15:15:22Z
dc.date.issued2024
dc.description.abstractThe active site Cys residue in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to oxidation by hydrogen peroxide (H2O2), with this resulting in enzyme inactivation. This re-routes the carbon flux from glycolysis to the pentose phosphate pathway favoring the formation of NADPH and synthetic intermediates required for antioxidant defense and repair systems. Consequently, GAPDH inactivation serves as a redox switch for metabolic adaptation under conditions of oxidative stress. However, there is a major knowledge gap as to how GAPDH is efficiently oxidized and inactivated, when the increase in intracellular H2O2 is modest, and there is a high concentration of alternative (non-signaling) thiols and efficient peroxide removing systems. We have therefore explored whether GAPDH inactivation is enhanced by two factors of in vivo relevance: macromolecular crowding, an inherent property of biological environments, and the presence of bicarbonate, an abundant biological buffer. Bicarbonate is already known to modulate H2O2 metabolism via formation of peroxymonocarbonate. GAPDH activity was assessed in experiments with low doses of H2O2 under both dilute and crowded conditions (induced by inert high molecular mass polymers and small molecules), in both the absence and presence of 25 mM sodium bicarbonate. H2O2-induced inactivation of GAPDH was observed to be significantly enhanced under macromolecular crowding conditions, with bicarbonate having an additional effect. These data strongly suggest that these two factors are of major importance in redox switch mechanisms involving GAPDH (and possibly other thiol-dependent systems) within the cellular environment.
dc.description.funderNovo Nordisk Foundation
dc.fechaingreso.objetodigital2024-12-31
dc.format.extent12 páginas
dc.fuente.origenScopus
dc.identifier.doi10.1042/BCJ20240597
dc.identifier.issn1470-8728
dc.identifier.scopusidScopus_ID:85211658578
dc.identifier.urihttps:doi.org/10.1042/BCJ20240597
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/89426
dc.identifier.wosidWoS_Id: 001373191200003
dc.information.autorucEscuela de Química; Fuentes Lemus, Eduardo Felipe; 0000-0002-1465-8466; 186720
dc.issue.numero23
dc.language.isoen
dc.nota.accesocontenido completo
dc.pagina.final1866
dc.pagina.inicio1855
dc.publisherPortland Press LTD
dc.revistaThe Biochemical journal
dc.rightsacceso abierto
dc.rights.licenseCC BY Atribución Internacional 40
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectGlyceraldehyde-3-phosphate dehydrogenase
dc.subjectHydrogen peroxide
dc.subjectMacromolecular crowding
dc.subjectPeroxymonocarbonate
dc.subjectProtein oxidation
dc.subjectRedox regulation
dc.subject.ddc510
dc.subject.deweyMatemática física y químicaes_ES
dc.titleMacromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase
dc.typeartículo
dc.volumen481
sipa.codpersvinculados186720
sipa.trazabilidadScopus;2024-12-22
sipa.trazabilidadWoS;2024-12-28
sipa.trazabilidadORCID;2024-12-23
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