Phosphorylation of T107 by CamKIIδ Regulates the Detoxification Efficiency and Proteomic Integrity of Glyoxalase 1
Jakob Morgenstern,
Sylvia Katz,
Jutta Krebs-Haupenthal,
Jessy Chen,
Alireza Saadatmand,
Fabiola Garcia Cortizo,
Alexandra Moraru,
Johanna Zemva,
Marta Campos Campos,
Aurelio Teleman,
Johannes Backs,
Peter Nawroth,
Thomas Fleming
Affiliations
Jakob Morgenstern
Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg 69120, Germany; Corresponding author
Sylvia Katz
Department Molecular Cardiology and Epigenetics, University Hospital of Heidelberg, Heidelberg 69120, Germany
Jutta Krebs-Haupenthal
Department Molecular Cardiology and Epigenetics, University Hospital of Heidelberg, Heidelberg 69120, Germany
Jessy Chen
Department Molecular Cardiology and Epigenetics, University Hospital of Heidelberg, Heidelberg 69120, Germany
Alireza Saadatmand
Department Molecular Cardiology and Epigenetics, University Hospital of Heidelberg, Heidelberg 69120, Germany
Fabiola Garcia Cortizo
German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Alexandra Moraru
German Center for Diabetes Research (DZD), Neuherberg 85764, Germany
Johanna Zemva
Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg 69120, Germany
Marta Campos Campos
Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg 69120, Germany
Aurelio Teleman
German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Johannes Backs
Department Molecular Cardiology and Epigenetics, University Hospital of Heidelberg, Heidelberg 69120, Germany
Peter Nawroth
Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg 69120, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany
Thomas Fleming
Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg 69120, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany
Summary: The glyoxalase system is a highly conserved and ubiquitously expressed enzyme system, which is responsible for the detoxification of methylglyoxal (MG), a spontaneous by-product of energy metabolism. This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). Additionally, we observe proteasomal degradation of non-phosphorylated Glo1 via ubiquitination does occur more rapidly as compared with native Glo1. The absence of CamKIIδ is associated with poor detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knockout model. Therefore, phosphorylation of T107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity, which is experimentally linked to an altered Glo1 status in cancer, diabetes, and during aging.
