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Publication : Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione.

First Author  Peracchi A Year  2017
Journal  Proc Natl Acad Sci U S A Volume  114
Issue  16 Pages  E3233-E3242
PubMed ID  28373563 Mgi Jnum  J:242138
Mgi Id  MGI:5904538 Doi  10.1073/pnas.1613736114
Citation  Peracchi A, et al. (2017) Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione. Proc Natl Acad Sci U S A 114(16):E3233-E3242
abstractText  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 approximately 35% sequence identical to omega-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently alpha-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highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group).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.
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