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Peracchi, Alessio; Veiga-da-Cunha, Maria; Kuhara, Tomiko; Ellens, Kenneth W.; Paczia, Nicole; Stroobant, Vincent; Seliga, Agnieszka K.; Marlaire, Simon; Jaisson, Stephane; Bommer, Guido T.; Sun, Jin; Huebner, Kay; Linster, Carole L.; Cooper, Arthur J. L.; Van Schaftingen, Emile

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

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  • Medientyp: E-Artikel
  • Titel: Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione
  • Beteiligte: Peracchi, Alessio; Veiga-da-Cunha, Maria; Kuhara, Tomiko; Ellens, Kenneth W.; Paczia, Nicole; Stroobant, Vincent; Seliga, Agnieszka K.; Marlaire, Simon; Jaisson, Stephane; Bommer, Guido T.; Sun, Jin; Huebner, Kay; Linster, Carole L.; Cooper, Arthur J. L.; Van Schaftingen, Emile
  • Erschienen: National Academy of Sciences, 2017
  • Erschienen in: Proceedings of the National Academy of Sciences of the United States of America
  • Sprache: Englisch
  • ISSN: 0027-8424; 1091-6490
  • Entstehung:
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  • Beschreibung: <p>The mammalian gene <italic>Nit1</italic> (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently α-ketoglutaramate (a known physiological substrate of Nit2), and its actual enzymatic function has so far remained a puzzle. In the present study, we demonstrate that both the mammalian Nit1 and its yeast ortholog are amidases highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group). We further show that <italic>Nit1</italic>-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of <italic>Nit1</italic>-KO mice. Finally, we show that several mammalian aminotransferases (transaminases), both cytosolic and mitochondrial, can form dGSH via a common (if slow) side-reaction and provide indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells. Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzymes of primary metabolism leads to the formation of a useless and potentially harmful compound, which needs a suitable “repair enzyme” to be destroyed or reconverted into a useful metabolite. The need for a dGSH repair reaction does not appear to be limited to eukaryotes: We demonstrate that Nit1 homologs acting as excellent dGSH amidases also occur in <italic>Escherichia coli</italic> and other glutathione-producing bacteria.</p>
  • Zugangsstatus: Freier Zugang