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The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells

Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and ident...

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Hauptverfasser: Herrle, Niklas (VerfasserIn) , Malacarne, Pedro F. (VerfasserIn) , Warwick, Timothy (VerfasserIn) , Cabrera-Orefice, Alfredo (VerfasserIn) , Chen, Yiheng (VerfasserIn) , Gheisari, Maedeh (VerfasserIn) , Chatterjee, Souradeep (VerfasserIn) , Leisegang, Matthias S. (VerfasserIn) , Sarakpi, Tamim (VerfasserIn) , Wionski, Sarah (VerfasserIn) , Lopez, Melina (VerfasserIn) , Kader, Carine (VerfasserIn) , Teichmann, Tom (VerfasserIn) , Drekolia, Maria-Kyriaki (VerfasserIn) , Koch, Ina (VerfasserIn) , Keßler, Marcus (VerfasserIn) , Klein, Sabine (VerfasserIn) , Erhard Uschner, Frank (VerfasserIn) , Trebicka, Jonel (VerfasserIn) , Brunst, Steffen (VerfasserIn) , Proschak, Ewgenij (VerfasserIn) , Günther, Stefan (VerfasserIn) , Rosas-Lemus, Mónica (VerfasserIn) , Baumgarten, Nina (VerfasserIn) , Klatt, Stephan (VerfasserIn) , Speer, Thimoteus (VerfasserIn) , Bibli, Sofia-Iris (VerfasserIn) , Segarra, Marta (VerfasserIn) , Acker-Palmer, Amparo (VerfasserIn) , Wagner, Julian U. G. (VerfasserIn) , Wittig, Ilka (VerfasserIn) , Dimmeler, Stefanie (VerfasserIn) , Schulz, Marcel H. (VerfasserIn) , Richards, J. B. (VerfasserIn) , Gilsbach, Ralf (VerfasserIn) , Denton, Travis T. (VerfasserIn) , Fleming, Ingrid (VerfasserIn) , Hannibal, Luciana (VerfasserIn) , Brandes, Ralf P. (VerfasserIn) , Rezende, Flávia (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: February 2026
In: The EMBO journal
Year: 2026, Jahrgang: 45, Heft: 3, Pages: 820-855
ISSN:1460-2075
DOI:10.1038/s44318-025-00642-7
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44318-025-00642-7
Volltext
Verfasserangaben:Niklas Herrle, Pedro F Malacarne, Timothy Warwick, Alfredo Cabrera-Orefice, Yiheng Chen, Maedeh Gheisari, Souradeep Chatterjee, Matthias S Leisegang, Tamim Sarakpi, Sarah Wionski, Melina Lopez, Carine Kader, Tom Teichmann, Maria-Kyriaki Drekolia, Ina Koch, Marcus Keßler, Sabine Klein, Frank Erhard Uschner, Jonel Trebicka, Steffen Brunst, Ewgenij Proschak, Stefan Günther, Mónica Rosas-Lemus, Nina Baumgarten, Stephan Klatt, Thimoteus Speer, Sofia-Iris Bibli, Marta Segarra, Amparo Acker-Palmer, Julian UG Wagner, Ilka Wittig, Stefanie Dimmeler, Marcel H Schulz, JB Richards, Ralf Gilsbach, Travis T Denton, Ingrid Fleming, Luciana Hannibal, Ralf P Brandes & Flávia Rezende
Beschreibung
Zusammenfassung:Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.
Beschreibung:Online veröffentlicht: 17. Dezember 2025
Gesehen am 19.02.2026
Beschreibung:Online Resource
ISSN:1460-2075
DOI:10.1038/s44318-025-00642-7

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