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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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Main Authors: Herrle, Niklas (Author) , Malacarne, Pedro F. (Author) , Warwick, Timothy (Author) , Cabrera-Orefice, Alfredo (Author) , Chen, Yiheng (Author) , Gheisari, Maedeh (Author) , Chatterjee, Souradeep (Author) , Leisegang, Matthias S. (Author) , Sarakpi, Tamim (Author) , Wionski, Sarah (Author) , Lopez, Melina (Author) , Kader, Carine (Author) , Teichmann, Tom (Author) , Drekolia, Maria-Kyriaki (Author) , Koch, Ina (Author) , Keßler, Marcus (Author) , Klein, Sabine (Author) , Erhard Uschner, Frank (Author) , Trebicka, Jonel (Author) , Brunst, Steffen (Author) , Proschak, Ewgenij (Author) , Günther, Stefan (Author) , Rosas-Lemus, Mónica (Author) , Baumgarten, Nina (Author) , Klatt, Stephan (Author) , Speer, Thimoteus (Author) , Bibli, Sofia-Iris (Author) , Segarra, Marta (Author) , Acker-Palmer, Amparo (Author) , Wagner, Julian U. G. (Author) , Wittig, Ilka (Author) , Dimmeler, Stefanie (Author) , Schulz, Marcel H. (Author) , Richards, J. B. (Author) , Gilsbach, Ralf (Author) , Denton, Travis T. (Author) , Fleming, Ingrid (Author) , Hannibal, Luciana (Author) , Brandes, Ralf P. (Author) , Rezende, Flávia (Author)
Format: Article (Journal)
Language:English
Published: February 2026
In: The EMBO journal
Year: 2026, Volume: 45, Issue: 3, Pages: 820-855
ISSN:1460-2075
DOI:10.1038/s44318-025-00642-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44318-025-00642-7
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Author Notes: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
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Summary: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.
Item Description:Online veröffentlicht: 17. Dezember 2025
Gesehen am 19.02.2026
Physical Description:Online Resource
ISSN:1460-2075
DOI:10.1038/s44318-025-00642-7

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