Reference : Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Human health sciences : Endocrinology, metabolism & nutrition
Systems Biomedicine
http://hdl.handle.net/10993/38261
Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione
English
Peracchi, Alessio []
Veiga-da-Cunha, Maria []
Kuhara, Tomiko []
Ellens, Kenneth W [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)]
Paczia, Nicole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Stroobant, Vincent []
Seliga, Agnieszka K []
Marlaire, Simon []
Jaisson, Stephane []
Bommer, Guido T []
Sun, Jin []
Huebner, Kay []
Linster, Carole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Cooper, Arthur J.L. []
Van Schaftingen, Emile []
3-Apr-2017
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
1613736114
3233-3242
Yes (verified by ORBilu)
International
0027-8424
1091-6490
Washington DC
DC
[en] metabolite repair ; deaminated glutathione ; amidase ; aminotransferases
[en] The mammalian gene Nit1 (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highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group).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 Nit1-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of Nit1-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 Escherichia coli and other glutathione-producing bacteria.
Luxembourg Centre for Systems Biomedicine (LCSB)
Researchers ; Students
http://hdl.handle.net/10993/38261

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