Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione.

Autor: Peracchi A; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium; alessio.peracchi@unipr.it maria.veiga@uclouvain.be emile.vanschaftingen@uclouvain.be.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.; Department of Life Sciences, Laboratory of Biochemistry, Molecular Biology, and Bioinformatics, University of Parma, 43124 Parma, Italy., Veiga-da-Cunha M; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium; alessio.peracchi@unipr.it maria.veiga@uclouvain.be emile.vanschaftingen@uclouvain.be.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Kuhara T; Japan Clinical Metabolomics Institute, Kahoku, Ishikawa 929-1174, Japan.; Human Genetics, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan., Ellens KW; Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, L-4367 Belvaux, Luxembourg., Paczia N; Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, L-4367 Belvaux, Luxembourg., Stroobant V; Ludwig Institute for Cancer Research, de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Seliga AK; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Marlaire S; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Jaisson S; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Bommer GT; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium., Sun J; Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210., Huebner K; Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210., Linster CL; Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, L-4367 Belvaux, Luxembourg., Cooper AJL; Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595., Van Schaftingen E; Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium; alessio.peracchi@unipr.it maria.veiga@uclouvain.be emile.vanschaftingen@uclouvain.be.; de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Apr 18; Vol. 114 (16), pp. E3233-E3242. Date of Electronic Publication: 2017 Apr 03.
DOI: 10.1073/pnas.1613736114
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE