Nitrilase and Fhit homologs are encoded as fusion proteins in
            <i>Drosophila melanogaster</i>
            and
            <i>Caenorhabditis elegans</i>

Pekarsky, Yuri; Campiglio, Manuela; Siprashvili, Zurab; Druck, Teresa; Sedkov, Yurii; Тиллиб, С. В.; Draganescu, Alexandra; Wermuth, Peter J.; Rothman, Joel H.; Huebner, Kay; Buchberg, Arthur M.; Mazo, Alexander; Brenner, Charles; Croce, Carlo M.

doi:10.1073/pnas.95.15.8744

Cited by 79 publications

(80 citation statements)

References 21 publications

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“…Chromosomal deletions and truncated mRNA products involving Fhit were noted in multiple primary murine lung tumors and lung cancer cell lines, consistent with the analysis of FHIT in human cancer (Sozzi et al, 1996). Gene disruption experiments are underway to further examine the in vivo role of Fhit in tumorigenesis and development (Pekarsky et al, 1998).…”

Section: Murine Lung Cancer: Pathologic and Molecular Characterizationsupporting

confidence: 64%

“…In murine lung adenocarcinoma specimens, LOH at chromosomes 4, 11 and 14, known to involve p16 INK4a , p53 and Rb, respectively, has been described . The murine Fhit gene was cloned and mapped to an aphidicolininducible fragile site on chromosome 14 (Pekarsky et al, 1998;Glover et al, 1998). Chromosomal deletions and truncated mRNA products involving Fhit were noted in multiple primary murine lung tumors and lung cancer cell lines, consistent with the analysis of FHIT in human cancer (Sozzi et al, 1996).…”

Section: Murine Lung Cancer: Pathologic and Molecular Characterizationmentioning

confidence: 99%

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Modeling human lung cancer in mice: similarities and shortcomings

1999

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Lung cancer kills more Americans yearly than any other neoplastic process. Mortality rates have changed little over the past several decades, despite improvements in surgical techniques, radiation therapy and chemotherapy. The identi®cation of mutations in oncogenes and tumor suppressor genes in human lung tumor specimens, including K-ras, p53, p16 INK4a and Rb, o ers molecular explanations for tumor development and resistance to therapy. Mouse models of human lung cancer may advance our understanding of this disease. The examination of mice which develop lung cancer either spontaneously or due to carcinogen exposure, and the creation of mouse strains harboring the speci®c genetic mutations found in human lung cancer are among strategies being pursued.

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Section: Murine Lung Cancer: Pathologic and Molecular Characterizationsupporting

confidence: 64%

Section: Murine Lung Cancer: Pathologic and Molecular Characterizationmentioning

confidence: 99%

Modeling human lung cancer in mice: similarities and shortcomings

1999

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“…Compared with Nit2, however, the Nit1 protein shows only weak ω-amidase activity toward α-KGM (catalytic efficiency <0.1% of that of Nit2) (5). The observation that in many invertebrates Nit1 is expressed as a domain fused with a fragile histidine triad protein (Fhit, suggested to act as a tumor suppressor in mammals) (1), has fueled a substantial interest in deciphering the physiological substrates of this enzyme. Galperin and Koonin even included Nit1 among the "top 10" most attractive targets for functional assignment (10,11), assuming that clarification of its activity could illuminate new aspects of biology.…”

mentioning

confidence: 99%

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Peracchi

Veiga‐da‐Cunha

Kuhara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.metabolite repair | deaminated glutathione | amidase | aminotransferases

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“…Human Fhit (5), which functions as a tumor suppressor protein in human (6 -9) and murine (10,11) epithelial tissues, is the prototypical member of the second branch of the HIT superfamily. Fhit homologs have been found in fungi (12) and animals (13)(14)(15)(16) and exhibit diadenosine polyphosphate hydrolase activity. A third branch of the HIT superfamily contains more distantly related nucleotide transferases including galactose-1-phosphate uridylyltransferase, which is the enzyme deficient in galactosemics (1), budding yeast diadenosine tetraphosphate phosphorylases ApaI and Apa2 (17), and adenylylsulfate:phosphate adenylyltransferase (18).…”

mentioning

confidence: 99%

Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

Bieganowski

Garrison

Hodawadekar

et al. 2002

Journal of Biological Chemistry

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104

163

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The histidine triad superfamily of nucleotide hydrolases and nucleotide transferases consists of a branch of proteins related to Hint and Aprataxin, a branch of Fhitrelated hydrolases, and a branch of galactose-1-phosphate uridylyltransferase (GalT)-related transferases. Although substrates of Fhit and GalT are known and consequences of mutations in Aprataxin, Fhit, and GalT are known, good substrates had not been reported for any member of the Hint branch, and mutational consequences were unknown for Hint orthologs, which are the most ancient and widespread proteins in the Hint branch and in the histidine triad superfamily. Here we show that rabbit and yeast Hint hydrolyze the natural product adenosine-5-monophosphoramidate (AMPNH 2 ) in an active-site-dependent manner at second order rates exceeding 1,000,000 M ؊1 s ؊1 . Yeast strains constructed with specific loss of the Hnt1 active site fail to grow on galactose at elevated temperatures. Loss of Hnt1 enzyme activity also leads to hypersensitivity to mutations in Ccl1, Tfb3, and Kin28, which constitute the TFIIK kinase subcomplex of general transcription factor TFIIH and to mutations in Cak1, which phosphorylates Kin28. The target of Hnt1 regulation in this pathway was shown to be downstream of Cak1 and not to affect stability of Kin28 monomers. Functional complementation of all Hnt1 phenotypes was provided by rabbit Hint, which is only 22% identical to yeast Hnt1 but has very similar adenosine monophosphoramidase activity. Histidine triad (HIT)1 proteins are a superfamily of nucleotide-binding proteins named for a near C-terminal HXHXHXX motif (X is a hydrophobic amino acid) positioned at the ␣-phosphate of nucleotide substrates (1). The first branch of the superfamily is named for rabbit Hint, which had been purified as an abundant protein from cardiac cytosol by adenosine affinity chromatography (2) and shown to have homologs in all forms of life (1). Recently, Aprataxin, a gene located at 9p13 that is inactivated in ataxia with oculomotor apraxia, the second most common of the autosomal recessive ataxias, was identified as a member of the Hint branch of the HIT superfamily (3, 4). Human Fhit (5), which functions as a tumor suppressor protein in human (6 -9) and murine (10, 11) epithelial tissues, is the prototypical member of the second branch of the HIT superfamily. Fhit homologs have been found in fungi (12) and animals (13-16) and exhibit diadenosine polyphosphate hydrolase activity. A third branch of the HIT superfamily contains more distantly related nucleotide transferases including galactose-1-phosphate uridylyltransferase, which is the enzyme deficient in galactosemics (1), budding yeast diadenosine tetraphosphate phosphorylases ApaI and Apa2 (17), and adenylylsulfate:phosphate adenylyltransferase (18). Ironically, although Hint is the most ancient and widespread of the HIT proteins, reasonable Hint substrates remained unidentified, and the consequences of mutations in Hint or Hint orthologs were unknown (19).Recently, human Hint was identified as...

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Nitrilase and Fhit homologs are encoded as fusion proteins in Drosophila melanogaster and Caenorhabditis elegans

Cited by 79 publications

References 21 publications

Modeling human lung cancer in mice: similarities and shortcomings

Modeling human lung cancer in mice: similarities and shortcomings

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

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