Example sentences for: diadenosine

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  • The human FHIT gene, located at the chromosome 3 fragile site FRA3B, is inactivated early in the development of many tumors [ 1 ] . Murine Fhit is also located at a fragile site [ 2 3 ] and mice heterozygous for disruption of Fhit , given low intragastric doses of the mutagen N-nitrosomethylbenzylamine, develop stomach and sebaceous tumors [ 4 ] that can be prevented by viral Fhit expression [ 5 ] . Fhit, a dimer of 147 amino acid subunits, is a member of the histidine triad (HIT) superfamily of nucleotide hydrolases and transferases [ 6 7 ] . Members of the Hint branch of the HIT superfamily are found in all forms of life [ 8 ] . The S. cerevisiae Hint homolog, Hnt1, and rabbit Hint possess adenosine monophosphoramidase activity that functions in yeast to positively regulate function of Kin28, Ccl1 and Tfb3, which constitute the kinase component of general transcription factor TFIIH [ 9 ] . A new Hint related protein, Aprataxin, is mutated in individuals with ataxia with oculomotor apraxia [ 10 11 ] and has a yeast homolog termed Hnt3 [ 9 ] . Members of the Fhit branch of the HIT superfamily have been found in fungi [ 12 13 ] , animals [ 2 14 15 ] and plants [ 7 ] and hydrolyze diadenosine tetraphosphate, diadenosine triphosphate and other 5'-5"'-dinucleoside polyphosphates.

  • Human Fhit [ 14 ] and the S. cerevisiae Fhit homolog [ 13 ] , which was called Aph1 but is here termed Hnt2 under nomenclature aproved by the Saccharomyces Genome Database, cleave ApppA more readily while Aph1, the S. pombe homolog, cleaves AppppA more readily [ 20 ] . Consistent with the ApppA hydrolase activity of purified Fhit protein, most cancer cell lines that are Fhit negative at the protein level have higher levels of ApppA than cell lines that are Fhit positive [ 21 ] . Nonetheless, the actual concentrations of dinucleoside polyphosphates were submicromolar in every cell culture sample [ 21 ] and thus, under the reported culture conditions, the measured dinucleoside polyphosphates would not be expected to occupy the Fhit active site substantially [ 19 ] . Dinucleoside polyphosphate levels were measured in adenine-requiring S. cerevisiae strains before or after disruption of the Fhit-homologous HNT2 gene [ 13 ] and in adenine-requiring S. pombe strains as a function of disruption and overexpression of the Fhit-homologous aph1 gene [ 22 ] . Recently, it was observed that diadenosine polyphosphates undergo a divalent cation-dependent conformational change that might mediate their biosynthesis, catabolism or signaling properties [ 23 ] .

  • When diadenosine 5',5"'-( P 1, P 2-methylene- P 3-thio)- P 1, P 3-triphosphate [ 17 ] was crystallized with wild-type and mutant Fhit, the α-phosphorothioate group was found in the mutant but not wild-type active site, suggesting that α-phosphorothioate inhibitors may be slow substrates [ 12 ] . Similarly, Frey and co-workers found that Fhit slowly cleaves both R p and S p stereoisomers of γ-( m -nitrobenzyl)-adenosine 5'- O -(l-thiotriphosphate) with modest and similar beneficial effects on K m as compared to the corresponding phosphate [ 13 ] .

  • Because diadenosine polyphosphate levels vary with time in culture, generating a higher or lower range of values in independently conducted experiments, we did not average values obtained in separate experiments.

  • On the basis that Fhit binds diadenosine polyphosphates with one AMP group buried and the other adenosine solvent-exposed in a specific conformation [ 12 ] , effective tri and tetrapodal inhibitors such as 12b, 13b and HC(ADP) 3 [ 15 ] may exist in solution predominantly in a conformation that resembles Fhit-bound AppppA.

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