Scholarlink

<p>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. H<sub>2</sub>O<sub>2</sub> 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, H<sub>2</sub>O<sub>2</sub> 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 <i>NIT2</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月17日

查看全文
  • 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 U G Wagner,
  • Ilka Wittig,
  • Stefanie Dimmeler,
  • Marcel H Schulz,
  • J B Richards,
  • Ralf Gilsbach,
  • Travis T Denton,
  • Ingrid Fleming,
  • Luciana Hannibal,
  • Ralf P Brandes,
  • Flávia Rezende

摘要

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.