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At least 19 recordsLinked to original sources
PubMedDate not supplied

New adducts of chloroethylene oxide and chloroacetaldehyde with pyrimidine nucleosides.

Pyrimidine nucleosides were treated with chloroethylene oxide (CEO) and 2-chloroacetaldehyde (CAA) in methanol and, following trimethylsilylation, the products were analysed by combined gas chromatography-mass spectrometry (GC-MS). Reaction of CEO with 2'-deoxycytidine gave 3,N4-etheno-2'-deoxycytidine and diadduct isomers in which a 1-hydroxy-2-chloroethyl group was substituted for hydrogen on either deoxyribose hydroxyl group. When the N-3-position of 2'-deoxycytidine was blocked by a methyl group, CEO or CAA added a 2-chlorovinyl group at the exocyclic N4 amino nitrogen, as evidenced by a pair of cis/trans isomers. Reaction of 3-methylcytidine and CEO also gave the cis/trans 2-chlorovinyl base adducts, as well as six isomers with a 1-hydroxy-2-chloroethyl group attached to ribose and nine isomeric diadducts, which are possibly positional and optical isomers. Although CEO and CAA were less reactive towards uracil in 3-methyluridine than to cytosine in 3-methyl(deoxy)-cytidine, both electrophiles were able to alkylate 3-methyluridine on ribose, yielding 1-hydroxy-2-chloroethyl derivatives. These data suggest that CEO and CAA may also yield non-cyclic adducts with cytosine in double-stranded DNA where the N-3 position is of low accessibility. Such adducts are of interest in view of their potential promutagenic properties. The data also imply a new mechanism of reaction of CEO with nucleophiles.

Acetaldehyde↗
PubMed1991

Production of 5-methyluridine by immobilized thermostable purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase from Bacillus stearothermophilus JTS 859.

5-Methyluridine was produced continuously from thymine and inosine by immobilized enzymes, which consisted of thermostable purine nucleoside phosphorylase and thermostable pyrimidine nucleoside phosphorylase obtained from Bacillus stearothermophilus JTS 859. The process was carried out in a column reactor at 60 degrees C for 17 d without any bacterial contamination under non-aseptical conditions. Half-lives of the activity of the immobilized enzymes were 47 d and 4.5 d at 60 degrees C and 70 degrees C, respectively, although half-life of the crude enzyme was only 14 h at 70 degrees C.

Bacterial Proteins↗
PubMed1996

Purification and characterization of purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase from Bacillus stearothermophilus TH 6-2.

The purine nucleoside phosphorylase (Pu-NPase) and the pyrimidine nucleoside phosphorylase (Py-NPase) have been purified from Bacillus stearothermophilus TH 6-2. The Pu-NPase is a trimer of 30-kDa subunits and the Py-NPase is a dimer of 46-kDa subunits. The isoelectric points of Pu-NPase and Py-NPase were pH 4.3 and 4.6, respectively. The Pu-NPase could catalyze the phosphorolysis of inosine and guanosine, but not adenosine. the Py-NPase could phosphorolyze both uridine and thymidine.

Amino Acid Sequence↗
PubMed1975

Pyrimidine nucleoside analogues as inducers of pyrimidine nucleoside catabolizing enzymes in Salmonella typhimurium.

Various structural analogues of cytosine and uracil nucleosides were tested as potential inducers of the nucleoside catabolizing (cyt) enzymes in Salmonella typhimurium. Some analogues, e.g. 5'-O-alkyl cytidines and uridines, resistant to catabolic enzymes, were as effective as the natural inducers cytidine and uridine; but etherification of one of the cis 2' or 3'hydroxyls fully abolished activity, pointing to a requirement of an intact ribose cis-glycol system for activity. A uridine analogue in the syn conformation, 6-methyluridine, a good substrate for uridine phosphorylase, was inactive as an inducer. The behavior of various other analogues, in relation to their structure, conformation and substrate properties, indicated the absence of any correlation between inducing activity and substrate susceptibility. The overall findings are consistent with conclusions derived from genetic experiments. The active analogues apparently act via similar pathways, and probably affect the same regulatory mechanism(s) as the natural inducers.

Cytidine↗
PubMedDate not supplied

Evidence for separate carriers for purine nucleosides and for pyrimidine nucleosides in the renal brush border membrane.

The aim of the present study was to test if the transport of all nucleosides in rat renal brush border membranes occurs via a common carrier or if specific carriers exist for various groups of nucleosides. We measured the inward transport of radiolabeled nucleosides into brush border vesicles. The effect of unlabeled nucleosides present inside of the vesicles (trans-stimulation) or outside of the vesicles (cis-inhibition) was studied. Uphill influx of a nucleoside into the vesicles could be driven by the efflux of another nucleoside (trans-stimulation) if they were both purines or both pyrimidines but not if one nucleoside was a purine and the other one a pyrimidine. Thus, there exist a carrier that transports various purine nucleosides, and a carrier that transports various pyrimidine nucleosides, but the tested purine nucleosides and the tested pyrimidine nucleosides do not appear to be transported by the same carrier. Uridine and thymidine were similarly potent for the inhibition of cytidine transport whereas uridine was much more potent than thymidine for the inhibition of adenosine transport. This suggests that cytidine and adenosine can use different carriers. Preincubation of the vesicles with N-ethylmaleimide resulted in a marked decrease of the rate of transport of purine nucleosides but it had little effect on the transport of pyrimidine nucleosides. These data are best explained by the presence in the renal brush border membrane of two carriers, one for purine nucleosides, the other one for pyrimidine nucleosides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Phosphorylation of purine and pyrimidine nucleosides by isolated rat liver mitochondria.

Formation of 5'-AMP, 5'-GMP, 5'-CMP and 5'UMP was confirmed in isolated rat liver mitochondria incubated with alpha-ketoglutarate, inorganic phosphate, purine nucleoside and pyrimidine nucleoside. Increased incorporation of 32Pi into ATP, GTP and UTP was observed by adding purine- and pyrimidine nucleosides. The phosphorylation of nucleosides was inhibited severely by arsenite and affected slightly by the addition of nuclear or post-mitochondrial fraction.

Animals↗
PubMed2006

Analysis of urinary nucleosides. V. Identification of urinary pyrimidine nucleosides by liquid chromatography/electrospray mass spectrometry.

Modified urinary nucleosides are potentially invaluable in cancer diagnosis, as they reflect altered RNA turnovers. High-performance liquid chromatography (HPLC) was combined with full-scan mass spectrometry, tandem mass spectrometry, MS(n) analysis and accurate mass measurements in order to identify pyrimidine nucleosides purified from urine. Potential nucleosides were assessed by their evident UV absorbance in the HPLC chromatogram and then further examined by the various mass spectrometric techniques. In this manner numerous pyrimidine nucleosides were identified in the urine samples from cancer patients including pseudouridine, cytidine, two methylcytidines and an acetylcytidine. Furthermore, a number of novel modified pyrimidine nucleosides were tentatively identified via critical interpretation of the combined mass spectrometric data.

Biomarkers, Tumor↗
PubMed1996

Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNT1rat) by transient expression in cultured mammalian cells.

We have demonstrated that monkey kidney (COS-1) cells have a single type of nucleoside transport process, which, because it was equilibrative, sodium-independent and could be inhibited by nitrobenzylthioinosine (NBMPR), was identified as the 'equilibrative sensitive' or 'es' transporter. Using NBMPR or dilazep to inhibit the endogenous nucleoside transport activity, we have transiently expressed a cDNA that encodes an inhibitor-insensitive, concentrative nucleoside transporter protein (cNT1rat) of rat intestine in COS-1 cells. The production of recombinant cNT1rat was examined by immunoblotting using an epitope-tagged construct and by analysis of inward fluxes of 3H-labelled nucleosides. Recombinant cNT1rat was sodium-dependent and selective for pyrimidine nucleosides, with approximately Km values of 21 microM, 12.5 microM and 15 microM for uridine, thymidine and adenosine, respectively. Although adenosine exhibited high affinity for the recombinant transporter, its Vmax value was low. A variety of anti-viral and anti-cancer nucleoside drugs inhibited cNT1rat-mediated uptake of uridine by transfected COS-1 cells although to different extents (Floxidine > Idoxuridine > Zidovudine > Zalcitabine > Cytarabine > Gemcitabine), suggesting that the concentrative pyrimidine-selective nucleoside transporters, of which cNT1rat is a representative, may play a role in cellular uptake of these drugs. The cNT1rat/COS-1 expression system is a useful tool for analysis of cNT1rat-mediated transport processes.

Adenosine↗
PubMed1974

Nucleoside conformations. 15. Flexibility of natural pyrimidine nucleosides around the glycosidic bond.

The flexibility of pyrimidine nucleosides has been investigated by measuring their circular dichroism in hydroalcoholic solutions over a large temperature range (-100 degrees to +40 degrees C). It was observed that ss-Uridine (Urd) and ss-Cytidine (Cyd) showed a decrease of the main dichroic band of about 40 percent, while sterically hindered nucleosides (alphaUrd, ara-Uracile, 02-2' anhy-dro-Urd, 2'3'-0-isopropylidene-Urd) showed only small decreases. It is concluded that the flexibility of the glycosidic linkage in conjunction with the pseudo-rotation of the sugar residue is responsible for these changes; the thermodynamic values which can be deduced from these decreases are compatible with an oscillatory motion around the glycosidic bond, but exclude anti-syn transformations in pyrimidine nucleosides.

Circular Dichroism↗
PubMed1987

Pyrimidine nucleoside monophosphate kinase hyperactivity in hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency.

The pyrimidine nucleoside triphosphates (CTP, UTP) increase in the pyrimidine 5'-nucleotidase (P5N) deficient red blood cell (RBC) to a greater degree than do the pyrimidine nucleoside monophosphates (CMP, UMP). Pyrimidine nucleoside monophosphate (PNMP) kinase phosphorylates CMP and UMP to their respective phosphodiesters. We tested the hypothesis that increased PNMP kinase activity contributes to the disproportionate increase in CTP and UTP in the P5N deficient RBC. CMP and UMP kinase activities were increased in high reticulocyte (4.4 +/- 2.1 and 8.5 +/- 3.3 mumol/ml RBC per minute) compared to normal RBC (2.8 +/- 1.0 and 6.0 +/- 2.5 mumol/ml RBC per minute). P5N deficient RBC (n = 2) had significantly increased CMP and UMP kinase activities (14.0 and 26.5 mumol/ml RBC per minute). UMP and CDP-ethanolamine were able to increase the activity of CMP kinase in crude haemolysate and the activity of partially purified enzyme. Since the Km for CMP of CMP kinase was 33 mumol/l in P5N deficient RBC and since the CMP concentration is 25-90 mumol/l in the P5N deficient RBC, the enzyme should be nearly saturated with CMP in the P5N deficient RBC. Thus, PNMP kinase hyperactivity appears to contribute to the disproportionate increase in CTP and UTP in the P5N deficient RBC.

5'-Nucleotidase↗
PubMed1987

2',3'-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis.

The antiretroviral action of 2',3'-dideoxycytidine (ddCyd) depends on its intracellular conversion to the 5'-triphosphate metabolite ddCTP. The effect of natural pyrimidines and pyrimidine nucleosides, as well as of a number of inhibitors of pyrimidine nucleotide synthesis (i.e., N-(phosphonacetyl)-L-aspartate, 6-azauridine, pyrazofurin, 3-deazauridine, and hydroxyurea) on the metabolism of the potent anti-human immunodeficiency virus drug ddCyd has been investigated in human and murine cell lines. Deoxycytidine (dCyd) and cytidine (Cyd) effectively blocked the intracellular phosphorylation of ddCyd: dCyd by competition with ddCyd for 2'-deoxycytidine kinase, and Cyd probably by competition with the higher nucleoside mono- and diphosphate kinases. These conclusions are supported by the observations that (i) the cytostatic effects of ddCyd against human Molt/4F cells are significantly reversed by dCyd; (ii) the antiviral effects of ddCyd against hman immunodeficiency virus-infected human ATH8 cells are reversed by dCyd and Cyd; (iii) phosphorylated metabolites of ddCyd could not be detected in a 2'-deoxycytidine kinase-deficient murine leukemia (L1210)/araC cell line; and (iv) ddCyd lacked any cytostatic effect against this araC-resistant L1210 cell line. In contrast to dCyd and Cyd, thymidine (dThd) stimulated formation of phosphorylated ddCyd metabolites. The degree of this stimulation proved dependent on preincubation time and dThd concentration. There was a correlation between the increased ddCTP levels upon preincubation of the cells with dThd, and decreased dCyd-5'-triphosphate pools, presumably caused by inhibition of cytidine-5' -diphosphate reductase by dThd-5'-triphosphate. In an attempt to discover compounds other than dThd that are able to stimulate ddCTP formation, a number of inhibitors of pyrimidine nucleotide metabolism were also studied. Under our experimental conditions, 3-deazauridine and hydroxyurea proved equally as effective as dThd in stimulating ddCyd phosphorylation. Finally, we could demonstrate that dThd significantly enhanced the protective effect of ddCyd against human immunodeficiency virus-infected ATH8 cells.

Animals↗
PubMed2003

Pyrimidine nucleoside analogs in cancer treatment.

Pyrimidine nucleoside analogs are essential components of hematological malignancy therapy and are also used in the treatment of solid tumors. These agents act as antimetabolites, compete with physiologic pyrimidine nucleosides and, consequently, interact with a large number of intracellular targets to induce cytotoxicity. Pyrimidine nucleoside analogs share some common characteristics, such as requiring both transport by specific membrane transporters and intracellular metabolism. However, these compounds differ in regards to their preferential interaction with certain targets, which may explain why some compounds are more effective against rapidly proliferating tumors and others against neoplasias with a more protracted evolution. Recent progress in the identification and characterization of nucleoside transporters and the enzymes of nucleoside metabolism, as well as an understanding of the molecular mechanisms of anticancer nucleoside activity, provides opportunities for the development of new pyrimidine nucleoside analogs. Strategies to optimize intracellular analog accumulation and to enhance cancer cell selectivity are proving beneficial in clinical trials.

Animals↗