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At least 19 recordsLinked to original sources
PubMed1980

Pyrimidine nucleotide pool changes during the cell cycle and quiescence. Pyrimidine excretion and metabolic isolation of the pyrimidine mononucleoside polyphosphate pool.

We have measured the pyrimidine nucleotide contents of the culture fluid, acid-soluble fraction, and acid-insoluble fraction of cultures of hamster embryo fibroblasts (third subculture) through the final two divisions of growth in culture. The cells show a growth delay between the penultimate and ultimate division periods and a concomitant biochemical synchrony of pyrimidine metabolism. The cells exhibit normal excretion of pyrimidine nucleotides beginning with the ultimate division cycle. This excretion results from the net breakdown of ribonucleic acid and a cell-regulated maximum for pyrimidine mononucleoside polyphosphate content. This upper limit for the pyrimidine nucleoside polyphosphate content is not a steady state phenomenon but rather an absence of both synthesis and utilization. The hamster embryo fibroblast exhibits a directed flow of salvage uridine for ribonucleic acid synthesis. We show that de novo synthetic uridine 5'-monophosphate also can be used for ribonucleic acid synthesis without prior entry into the cytoplasmic uridine nucleoside polyphosphate pool. During attachment and first division salvage uridine does enter the cytoplasmic nucleotide pool. The properties of the cytidine pools differ from the uridine pools in specific activity and levels of cytidine, due to turnover of the terminal C-C-A of cytoplasmic transfer ribonucleic acid and the delay in conversion of of nonradioactive de novo synthetic uridine 5'-monophosphate to cytidine 5'-triphosphate. The partial synchrony in these cultures has been used as a temporal marker of the observed events.

Animals↗
PubMed1989

Synthesis of substituted pyrimidines, pyrazole[3,4-d]pyrimidines and imidazo[4,5-d]pyrimidines and evaluation of their antifungal activity.

Some pyrimidines, pyrazolo[3,4-d]pyrimidines and imidazo[4,5-d]pyrimidines bearing the 5-nitro- and 5-aminothienyl-2-sulfide functionalities on the pyrimidine nucleus were synthesized and evaluated for their antifungal activity against several strains of yeasts and dermatophytes. 4-Amino-2-pyrimidinyl-5'-nitro-2'-thienylsulfide (Va) resulted active against both yeasts and dermatophytes (about 30 fold less potent than Miconazole). Compds. (II b), (V b) and (VIII b) showed only a slight activity against dermatophytes, while the other compounds were inactive.

Acetylation↗
PubMed1987

Metabolism of pyrimidine bases and nucleosides by pyrimidine-nucleoside phosphorylases in cultured human lymphoid cells.

The anabolism of pyrimidine ribo- and deoxyribonucleosides from uracil and thymine was investigated in phytohemagglutinin-stimulated human peripheral blood lymphocytes and in a Burkitt's lymphoma-derived cell line (Raji). We studied the ability of these cells to synthesize pyrimidine nucleosides by ribo- and deoxyribosyl transfer between pyrimidine bases or nucleosides and the purine nucleosides inosine and deoxyinosine as donors of ribose 1-phosphate and deoxyribose 1-phosphate, respectively: these reactions involve the activities of purine-nucleoside phosphorylase, and of the two pyrimidine-nucleoside phosphorylases (uridine phosphorylase and thymidine phosphorylase). The ability of the cells to synthesize uridine was estimated from their ability to grow on uridine precursors in the presence of an inhibitor of pyrimidine de novo synthesis (pyrazofurin). Their ability to synthesize thymidine and deoxyuridine was estimated from the inhibition of the incorporation of radiolabelled thymidine in cells cultured in the presence of unlabelled precursors. In addition to these studies on intact cells, we determined the activities of purine- and pyrimidine-nucleoside phosphorylases in cell extracts. Our results show that Raji cells efficiently metabolize preformed uridine, deoxyuridine and thymidine, are unable to salvage pyrimidine bases, and possess a low uridine phosphorylase activity and markedly decreased (about 1% of peripheral blood lymphocytes) thymidine phosphorylase activity. Lymphocytes have higher pyrimidine-nucleoside phosphorylases activities, they can synthesize deoxyuridine and thymidine from bases, but at high an non-physiological concentrations of precursors. Neither type of cell is able to salvage uracil into uridine. These results suggest that pyrimidine-nucleoside phosphorylases have a catabolic, rather than an anabolic, role in human lymphoid cells. The facts that, compared to peripheral blood lymphocytes, lymphoblasts possess decreased pyrimidine-nucleoside phosphorylases activities, and, on the other hand, more efficiently salvage pyrimidine nucleosides, are consistent with a greater need of these rapidly proliferating cells for pyrimidine nucleotides.

Cells, Cultured↗
PubMed1979

Metabolism of pyrazolo(3,4-d)pyrimidines in Leishmania braziliensis and Leishmania donovani. Allopurinol, oxipurinol, and 4-aminopyrazolo(3,4-d)pyrimidine.

Leishmania donovani and Leishmania braziliensis grown in culture formed millimolar concentrations of allopurinol ribonucleoside 5'-monophosphate from [6-14C]allopurinol. In addition, allopurinol 1-ribonucleoside, oxipurinol riboside 5'-monophosphate, and three new metabolites of allopurinol, namely, 4-aminopyrazolo(3,4-d)pyrimidine ribonucleoside 5'-monophosphate and the corresponding di- and triphosphates (1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-diphosphate and 1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-triphosphate) were identified in the parasitic cells. They were formed via a unique amination reaction from 1-ribosyl allopurinol 5'-phosphate, analogous to the conversion of IMP to AMP. [6-14C]Allopurinol was incorporated into RNA of L. donovani in the form of 4-aminopyrazolo(3,4-d)pyrimidine. Adenine reversed the growth inhibition of allopurinol and prevented its metabolism to all of the ribonucleotide metabolites. L. donovani was 2- to 4-fold more active in its metabolism of allopurinol to ribonucleotides than L. braziliensis. 4-Aminopyrazolo(3,4-d)pyrimidine inhibited cell growth and resulted in high intracellular levels of 1-ribosyl allopurinol 5'-phosphate and smaller amounts of the 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides. The metabolism of allopurinol to 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides and its resultant cytotoxicity occurs in these parasitic protozoans, but not in mammalian cells.

Adenine↗
PubMed1997

Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides.

Two cytoplasmic forms of pyrimidine nucleotidase (PN-I and PN-II) have been purified from human erythrocytes to apparent homogeneity and partially characterized. They preferentially hydrolyse pyrimidine 5'-monophosphates and 3'-monophosphates respectively. PN-I and PN-II operate as interconverting activities, capable of transferring the phosphate from the pyrimidine nucleoside monophosphate donor(s) to various nucleoside acceptors, including important drugs like 3'-azido-3'-deoxy-thymidine (AZT), cytosine-beta-D-arabinofuranoside (AraC) and 5-fluoro-2'-deoxy-uridine (5FdUrd), pyrimidine analogues widely used in chemotherapy. Kinetic analysis showed linear behaviour for both PN-I and PN-II. PN-I phosphotransferase activity revealed higher affinity for oxynucleosides with respect to deoxy-nucleosides, whereas the contrary seems to be true for PN-II. These results show for the first time that soluble pyrimidine nucleotidases are endowed with pyrimidine-specific phosphotransferase activity.

Erythrocytes↗
PubMed1993

Human nucleotide excision nuclease incises synthetic double-stranded DNA containing a pyrimidine dimer at the fourth phosphodiester linkage 3' to the pyrimidine dimer.

Linear 75mer double-stranded DNA containing a single pyrimidine dimer at a unique site was used to investigate pyrimidine dimer-dependent endonuclease activities from human cells. HeLaS3 cell extract incised the target DNA at the fourth phosphodiester linkage 3' to the pyrimidine dimer. However, incision of the DNA at 5' side of the pyrimidine dimer was not detected. The incision was also detected in cell extracts prepared from other excision repair-proficient cell lines. Incision was detected only on the DNA strand containing a pyrimidine dimer in the presence of poly(dI-dC)-poly(dI- dC) double strand. The reaction required Mg2+ but not ATP. The extract prepared from excision repair-deficient xeroderma pigmentosum (XP) cells belonging to the complementation group A was unable to incise the DNA. Extracts from the complementation groups C, D, and G incised the DNA very weakly at the third phosphodiester linkage 3' to the pyrimidine dimer, a site different from that incised by normal human cell extract. These results suggest that the observed incision reaction is associated with excision repair in human cells.

Adenosine Triphosphate↗
PubMed1968

Biosynthesis of the pyrimidine moiety of thiamine. A new route of pyrimidine biosynthesis involving purine intermediates.

1. The pattern of distribution on the purine pathway of mutants of Salmonella typhimurium LT2 that had the double growth requirement for a purine plus the pyrimidine moiety of thiamine (ath mutants) indicated that purines and the pyrimidine moiety of thiamine share the early part of their biosynthetic pathways, and that 4-aminoimidazole ribonucleotide (AIR) is the last common intermediate. Two mutants that at first appeared anomalous were further investigated and found not to affect this deduction. 2. The ribonucleoside form of AIR (AIR(s)) satisfied the requirements both for a purine and for the pyrimidine moiety of thiamine of an ath mutant. 3. Methionine was required for the conversion of AIR into the pyrimidine moiety. 4. Radioactive AIR(s) was converted into radioactive pyrimidine moiety by an ath mutant without significant dilution of specific radioactivity. 5. Possible mechanisms for pyrimidine-moiety biosynthesis from AIR are discussed.

Autoradiography↗
PubMed1994

Evidence from CD spectra that d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrids are in different structural classes.

CD spectra and difference CD spectra of four d(oligopurine).r(oligopyrimidine) and four r(oligopurine).d(oligopyrimidine) hybrid duplexes containing mixed A.T(U) and G.C base pairs were compared with the spectra of four DNA.DNA and four RNA.RNA oligomer duplexes of similar repeating sequences. The 16 duplexes were formed by mixing oligomers that were 24 nucleotides long. The buffer was 0.05 M Na+ (phosphate), pH 7.0. DNA.DNA and RNA.RNA oligomer duplexes were used as reference B-form and A-form structures. We found that the CD spectra of d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrid duplexes were different from the CD spectra of either DNA.DNA or RNA.RNA duplexes. The data suggested that these hybrids have intermediate structures between A-form RNA and B-form DNA structures. The CD spectra of d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrid duplexes were different from each other, but the hybrids in each class had consistent CD spectra as indicated by nearest-neighbor comparisons. Thus, it appeared that the two types of hybrids belonged to different structural classes. The negative 210 nm band found in difference CD spectra was correlated with the presence of an r(purine) strand in the hybrid duplexes. The melting temperatures (Tm values) of these hybrids were compared with the Tm values of the DNA.DNA and RNA.RNA duplexes. The order of the thermal stability was: RNA.RNA duplex > r(purine).d(pyrimidine) hybrid > DNA.DNA duplex > d(purine).r(pyrimidine) hybrid, when comparing analogous sequences.

Base Composition↗
PubMed1988

Combination effects of cis-dichlorodiammineplatinum with selected metahalones, pyrimidine sulfoxides and pyrimidine sulfones on human NHIK 3025 cells in vitro.

Synergistic cell inactivating effects were displayed when human NHIK 3025 cells cultivated in vitro were treated with cis-dichlorodiammineplatinum(II) (cis-DDP) in simultaneous combination with selected metahalones, pyrimidine sulfoxides and sulfones. Cell inactivation was measured as the percentage of single cells surviving and able to give rise to macroscopic colonies following drug treatment. Selection of compounds was made according to the presence and position of certain structural groups. For 5-halo-pyrimidin-2-ones (the metahalones), a propargyl substituent attached to the pyrimidine ring at the 1-position resulted in compounds causing potentiation of cis-DDP-induced cell inactivation. An iodo or trifluoromethyl substituent at the 5-position led to a reduction in cis-DDP + metahalone synergism respective to a 5-chloro substituent. Cell survival following 1 h treatment with the metahalones alone was always near 100%. The cell inactivating effect of pyrimidine sulfoxides and sulfones alone and in simultaneous combination with cis-DDP was also investigated. Treatment of human cells with pyrimidine sulfoxides and sulfones alone resulted in reduced cell survival relative to the metahalones. When tested in combination with cis-DDP, pyrimidine sulfoxides and sulfones containing a propargyl moiety bound at the sulfur atom were found to potentiate the cell inactivating effect of cis-DDP. Other substituents induced only minor effects.

Cell Survival↗
PubMed1990

Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents.

Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7, guanosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H) trione (8, xanthosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the beta-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.

Adenosine↗
PubMed1976

Imidazo(1,2-c)pyrimidine nucleosides. Synthesis and biological evaluation of certain 1-(beta-D-arabinofuranosyl)imidazo(1,2-c)pyrimidines.

The first chemical syntheses of the arabinosylhypoxanthine and arabinosylguanine analogues of the imidazo-[1,2-c]pyrimsdine series are described. Condensation of trimethylsilyl-7-chloroimidazo[1,2-c]pyrimidin-5-one (1) with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride (2) gave 7-chloro-1-(2,3,5-tri-O-benzyl-beta-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (3) which on catalytic dehalogenation furnished 1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (4). Amination of 3 gave 7-amino-1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (5). Reductive hydrogenolysis of 4 and 5 gave 1-(betaD-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (6), the arabinosylhypoxantine analogue, and the corresponding 7-amino isomer 7, the arabinoosylguanine analogue, respectively. The unequivocal assignment of the site of glycosylation and the anomeric configuration have been established. None of the compounds exhibited significant antiviral or antimicrobial activity in vitro.

Anti-Bacterial Agents↗
PubMed1984

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines.

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.

Animals↗
PubMed1991

Inhibition of hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides in hereditary pyrimidine 5' nucleotidase deficiency.

Recent reports have suggested that haemolytic anaemia in pyrimidine 5' nucleotidase (P5'N) deficiency might be due to impaired erythrocyte hexose monophosphate shunt (HMS). To investigate the relationship between pyrimidine accumulation, HMS impairment and shortened red-cell survival, we tested glucose 6-phosphate dehydrogenase (G-6PD), HMS, P5'N activities and the UV spectrum in whole red cells and in red cells of different age from 2 P5'N-deficient patients with different degrees of haemolytic anaemia. In whole red cells we found a reduction of both G-6PD and stimulated HMS activity in the presence of a variable amount of pyrimidine nucleotides (37.79 and 17.88 mumol/gHb respectively). A drastic inhibition of stimulated HMS activity was already present in the lightest red-cell fractions from patient 1, who presented a more severe haemolytic anaemia. The variable degree of pyrimidines found among red cell fractions, with a minor accumulation in the older red cells, supports the hypothesis that pyrimidine accumulation and HMS impairment occur in the younger erythrocytes of P5'N-deficient patients.

5'-Nucleotidase↗
PubMed1970

Pyrimidine pools and macromolecular composition of pyrimidine-limited Escherichia coli.

The growth rate of a pyrimidine-requiring strain was controlled by limiting the concentration of exogenous orotic acid. As the steady state, pyrimidine-limited growth rate was decreased, the intracellular pyrimidine pools and the total nucleic acid per unit mass of culture also decreased. The ratio of deoxyribonucleic acid to protein remained constant, whereas the ratio of ribonucleic acid to protein decreased 30% over a threefold variation in growth rate (50- to 150-min doubling times). The intracellular uridine triphosphate and cytosine triphosphate pools also decreased (although not coordinately), and the pyrimidine biosynthetic enzymes were derepressed. Cell size was unaffected by pyrimidine-mediated variation of the growth rate.

Bacterial Proteins↗
PubMed1998

Adenosine 3':5'-cyclic monophosphate (cAMP)-inducible pyrimidine 5'-nucleotidase and pyrimidine nucleotide metabolism of chick embryonic erythrocytes.

Terminally differentiating erythrocytes degrade most of their RNA with subsequent release of mononucleotides. Pyrimidine mononucleotides are preferentially cleaved by an erythrocyte-specific pyrimidine 5'-nucleotidase; deficiency of this enzyme causes hemolytic anemia in humans. Details of the regulation of its activity during erythroid differentiation are unknown. The present study arose from the observation that the immature red blood cells (RBCs) of mid-term chick embryos contain high concentrations of uridine 5'-triphosphate (UTP) (5 to 6 mmol/L), which decline rapidly from days 13 to 14 onward. We analyzed two key enzymes of RBC pyrimidine nucleotide metabolism: pyrimidine nucleoside phosphorylase (PNP) and pyrimidine 5'-nucleotidase (P-5'-N), to evaluate if changes of enzyme activity during embryonic development are correlated with changes of RBC UTP. Secondly, we tested if these enzymes are under hormonal control. The results show that embryonic RBCs contain only minimal activity of PNP. In contrast, P-5'-N increases from day 13 on, suggesting that the enzyme is a limiting factor in UTP degradation. Activation of beta-adrenergic and A2A-adenosine receptors causes transcription-dependent de novo synthesis of P-5'-N. Because beta-adrenergic and adenosine receptors are also found on adult erythroid cells, P-5'-N might be an enzyme of differentiating RBCs whose expression is in part controlled by adenosine 3':5'-cyclic monophosphate (cAMP).

5'-Nucleotidase↗