title: Loss of Glyoxalase 1 Induces Compensatory Mechanism to Achieve Dicarbonyl Detoxification in Mammalian Schwann Cells.
abstract: The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock-out model (GLO1-/-) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1-/-cells. Alternative detoxification of MG in GLO1-/-is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused byS-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1-/-cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG.
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry. Electronic address: jakob.morgenstern@med.uni-heidelberg.de.
authors.forename: Jakob
authors.initials: J
authors.lastname: Morgenstern
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.affiliation: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Schumacher
authors.affiliation: Medicine V, University Hospital Heidelberg, Im Neuenheimer Feld 410.
authors.forename: Volker
authors.initials: V
authors.lastname: Eckstein
authors.affiliation: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg.
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.affiliation: German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; German Institute for Diabetes and Cancer (IDC).
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; German Institute for Diabetes and Cancer (IDC).
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D011765:Pyruvaldehyde / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D011765:Pyruvaldehyde; D000449:Aldehyde Reductase; D007791:Lactoylglutathione Lyase
keywords: CRISPR/Cas; aldose reductase; cell metabolism; diabetes; diabetic neuropathy; enzyme kinetics; glycation; glyoxalase system; methylglyoxal; toxicity