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PubMed1990

Memory deficits of aged male rats can be improved by pyrimidine nucleosides and n-acetyl-glutamine.

The pyrimidine nucleosides uridine (URI) and cytidine (CYT), alone or associated with n-acetyl-glutamine (NAG), were injected acutely or subchronically to aged (26 months old) male rats of the Sprague-Dawley strain. Learning and memory abilities of the animals were studied with tests of avoidance behavior. The acquisition of active avoidance behavior was studied with the shuttle-box test. A step-through type of passive avoidance task was used to examine the retention of passive avoidance responses. The acquisition of the active avoidance behavior and the retention of the passive avoidance response were reduced in aged animals as compared with those of young animals. Neither the acute treatment of old rats with URI and CYT alone nor that associated with NAG exerted any effect on the behavioral tests. In contrast, the subchronic treatment with URI and CYT was followed by a facilitation of acquisition of active avoidance behavior in the shuttle box and of retention of passive avoidance responses in the dark box. A more potent effect on the acquisition of the shuttle-box behavior and on the retention of passive avoidance reaction was found in animals treated subchronically with the pyrimidine nucleosides associated with NAG. These effects may be related to the role of pyrimidines in the synthesis of ribonucleic acid, which is indispensable for learning and memory processes.

Aging↗

PubMed1979

Regulation of Pyrimidine Biosynthesis in Intact Cells of Cucurbita pepo.

The occurrence of the complete orotic acid pathway for the biosynthesis de novo of pyrimidine nucleotides was demonstrated in the intact cells of roots excised from summer squash (Cucurbita pepo L. cv. Early Prolific Straightneck). Evidence that the biosynthesis of pyrimidine nucleotides proceeds via the orotate pathway in C. pepo included: (a) demonstration of the incorporation of [(14)C]NaHCO(3), [(14)C]carbamylaspartate, and [(14)C]orotic acid into uridine nucleotides; (b) the isolation of [(14)C]orotic acid when [(14)C]NaHCO(3) and [(14)C]carbamylaspartate were used as precursors; (c) the observation that 6-azauridine, a known inhibitor of the pathway, blocked the incorporation of early precursors into uridine nucleotides while causing a concomitant accumulation of orotic acid; and (d) demonstration of the activities of the component enzymes of the orotate pathway in assays employing cell-free extracts.Regulation of the activity of the orotate pathway by end product inhibition was demonstrated in the intact cells of excised roots by measuring the influence of added pyrimidine nucleosides on the incorporation of [(14)C]NaHCO(3) into uridine nucleotides. The addition of either uridine or cytidine inhibited the incorporation of [(14)C]NaHCO(3) into uridine nucleotides by about 80%. The observed inhibition was demonstrated to be readily reversible upon transfer of the roots to a nucleoside-free medium. Experiments employing various radiolabeled precursors indicated that one or both of the first two enzymes in the orotate pathway are the only site(s) of regulation of physiological importance.

Journal Article↗

PubMed1980

Biological Effects of Cytokinin Antagonists 7-(Pentylamino) and 7-(Benzylamino)-3-Methylpyrazolo(4,3-d)Pyrimidines on Suspension-cultured Tobacco Cells.

We have studied the biological effects of two structural analogs of cytokinins, 3-methyl-7-(pentylamino)pyrazolo(4,3-d)pyrimidine and 3-methyl-7-(benzylamino)pyrazolo(4,3-d)pyrimidine, on tobacco cell suspension cultures. These two cytokinin analogs are highly inhibitory to cytokinin-autonomous and cytokinin-requiring tobacco cells. The growth inhibitory effect is markedly antagonized by benzyladenine, but not by adenine. Cell suspensions of tobacco cells of a cytokinin-autonomous strain become cytokinin-dependent in the presence of 0.1 micromolar 3-methyl-7-(benzylamino)pyrazolo(4,3-d)pyrimidine. It is also demonstrated that growth inhibition of cell suspension cultures is accompanied by cell death and that only dividing cells are sensitive to this cytotoxic effect.

Journal Article↗

PubMed1985

Pyrimidine nucleoside uptake by petunia pollen: specificity and inhibitor studies on the carrier-mediated transport.

Transport of pyrimidine nucleosides into germinating Petunia hybrida pollen is carrier-mediated, and, except for thymidine, is inhibited by the energy poisons N,N'-dicyclohexylcarbodiimide, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, 2,4-dinitrophenol, and carbonylcyanide-m-chlorophenylhydrazone. Kinetic studies with analogs deoxyuridine and 5-bromodeoxyuridine show that they too are taken up faster than thymidine and inhibited by the energy poisons. These and other analogs inhibit uridine and cytidine transport more than thymidine, as do the inhibitors parachloromercuribenzoic acid, N-ethylmaleimide, phenylarsine oxide, o-phenanthroline, ethylene diamenetetraacetate, and ethylene glycol-bis (beta-aminoethyl ether) N,N,N'N'-tetraacetic acid. Citrate, phosphate, succinate, and tartrate inhibited uptake of all pyrimidine nucleosides. The specific inhibitor of nucleoside transport in animal cells, nitrobenzylthioinosine, has little effect on pollen transport. Uridine and deoxyuridine accumulate against a concentration gradient, suggesting active transport. Except for thymidine, however, transported nucleosides were found to be extensively phosphorylated. Until mutant plants are found which do not phosphorylate uridine, it is not possible to decide unequivocally between active and nonactive transport for uridine. However, consistent with a low level of DNA synthesis in germinating Petunia pollen, it is clear that thymidine transport is nonactive and relatively slow. It is apparent from these experiments that a more sensitive way to study DNA repair in this pollen would be to use 5-bromodeoxyuridine or deoxyuridine instead of thymidine to label repaired DNA. The results show that pollen has the transport systems necessary to take up pyrimidine nucleosides from Petunia styles, where it is known that the concentration of free nucleosides increase after pollination.

Journal Article↗

PubMed2001

2-amino-4-(4-pyridyl)pyrimidine and the 1:1 adduct with 4-aminobenzoic acid.

The structure of the title compound, C9H8N4, comprises non-planar molecules that associate via pyrimidine N--H...N dimer R2(2)(8) hydrogen-bonding associations [N...N 3.1870 (17) A] and form linear hydrogen-bonded chains via a pyrimidine N--H...N(pyridyl) interaction [N...N 3.0295 (19) A]. The dihedral angle between the two rings is 24.57 (5) degrees. The structure of the 1:1 adduct with 4-aminobenzoic acid, C9H8N4*C7H7NO2, exhibits a hydrogen-bonding network involving COOH...N(pyridyl) [O...N 2.6406 (17) A], pyrimidine N--H...N [N...N 3.0737 (19) and 3.1755 (18) A] and acid N--H...O interactions [N...O 3.0609 (17) and 2.981 (2) A]. The dihedral angle between the two linked rings of the base is 38.49 (6) degrees and the carboxylic acid group binds to the stronger base group in contrast to the (less basic) complementary hydrogen-bonding site.

Journal Article↗

PubMed2003

A stacked pyrazolo[3,4-d]pyrimidine-based flexible molecule: the effect on stacking of a bulky isopropyl group in comparison with a methyl/ethyl group.

In the crystal structure of 1,3-bis(4,6-diisopropylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane, C(25)H(36)N(8)S(4), the pairs of pyrazolo[3,4-d]pyrimidine rings in the molecule stack as a result of intramolecular pi-pi interactions between the heterocyclic rings. The crystal packing also exhibits an intermolecular C--H...pi interaction between one methyl group of an isopropyl group and a pyrazolo[3,4-d]pyrimidine ring.

Journal Article↗

PubMed2005

Hydrogen-bonding and C-H...pi interactions in 7-hydroxy-3-methoxy-4-methyl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidin-1(9H)-one.

In the title compound, C10H14N2O3, a pyrimidine ring is fused with a piperidine ring. The pyrimidine ring is planar, whereas the piperidine ring adopts a half-chair conformation. The molecules of the title compound are connected via O-H...O intermolecular hydrogen bonds into infinite zigzag chains. The pyrimidine ring is involved in three C-H...pi interactions, which link the hydrogen-bonded chains into a three-dimensional framework.

Antineoplastic Agents↗

PubMed1979

Elevation of pyrimidine enzyme activities in the RBC of patients with congenital hypoplastic anaemia and their parents.

The activities of orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (ODC) were significantly elevated (P less than 0.001) in erythrocytes (RBC) from five patients with prednisone-responsive congenital hypoplastic anaemia (CHA). (OPRT: patients - 10.1--64.2 nmol/h/10(9) RBC; controls - 2.8 +/- 0.3 (mean +/- SEM, n = 37); ODC: patients = 30--124 nmol/h/10(9) RBC; controls = 10.2 +/- 0.7 (mean SEM, n = 37).) Two patients had a less pronounced, but significant, increase of aspartate transcarbamylase activity and three patients had marginal increases of dihydroorotase activity. Dihydroorotate dehydrogenase activity was not detected in any CHA patient or control. In one patient prior to prednisone therapy, the OPRT and ODT activities were elevated 10-fold and remained elevated 3-fold after 16 months of therapy. An elevated enzyme pattern similar to that of RBC from CHA patients was observed in three parents of three CHA patients, but not in three parents of two other CHA patients. The activities of all five pyrimidine enzymes were normal for one patient with transient erythroblastopenia of childhood. In contrast, the activities of all the pyrimidine biosynthetic enzymes were elevated in blood from patients with a young RBC population: sickle cell anaemia, sickle-beta-thalassaemia, hereditary spherocytosis, and DiGuglielmo syndrome and from the newborn. It is postulated that factors which affect the activities of pyrimidine enzymes in CHA may also result in diminished erythropoiesis.

Adolescent↗

PubMed2006

Hereditary pyrimidine 5'-nucleotidase deficiency: from genetics to clinical manifestations.

Hereditary pyrimidine 5'-nucleotidase (P5'N) deficiency is the most frequent abnormality of the red cell nucleotide metabolism causing hereditary non-spherocytic haemolytic anaemia. The disorder is usually characterised by mild-to-moderate haemolytic anaemia associated with the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The precise mechanisms leading to the destruction of P5'N deficient red cells are still unclear. The pyrimidine 5'-nucleotidase type-I (P5'N-1) gene is localised on 7p15-p14 and the cDNA has been cloned and sequenced; 20 mutations have been identified so far in 30 unrelated families, most of them at the homozygous level. Recently, the comparison of recombinant mutants of human P5'N-1 with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.

5'-Nucleotidase↗

PubMed1995

Quantitative analysis of the pyrimidine metabolism in pheochromocytoma PC-12 cells.

A detailed quantitative study of pyrimidine metabolism in exponentially growing rat pheochromocytoma PC-12 cells has been performed. The sizes of ribonucleotide pools have been analysed and the pathways and the rates of metabolism of uridine, cytidine and aspartic acid have been determined, based on the incorporation of radioactive label. The fluxes of radioactive label through uridine-cytidine kinase, cytidine deaminase. CTP synthetase, nucleoside monophosphate kinase and nucleoside diphosphate kinase were obtained, as well as the flux through the pyrimidine de novo pathway. Also, the fluxes of radioactive label towards UDP-sugars, CDP-compounds, DNA and RNA were quantified in situ under steady-state conditions in intact PC-12 cells. From these fluxes of radioactivity, distribution ratios at the branch points of the metabolism were obtained. The pyrimidines synthesised via the de novo pathway were preferentially used for the synthesis of UDP-N-acetylhexosamines and UDP-hexoses, whereas the salvage of precursors from the medium contributed, to a large extent, to the synthesis of RNA. Therefore, we postulate that at least two different UTP pools exist in these cancer cells derived from the neural crest. Furthermore, after metabolism of radiolabeled cytidine and uridine into UTP, radiolabel was distributed in a similar manner from UTP towards UDP-N-acetylhexosamines, UDP-hexoses and RNA-UMP. Uridine, as well as cytidine, was channelled towards nucleic acids via small compartmented ribonucleotide pools.

Animals↗

PubMed1999

Evaluation of purine and pyrimidine analogues in human tumor cells from patients with low-grade lymphoproliferative disorders using the FMCA.

The purine analogues fludarabine and cladribine (CdA) have recently become established to be effective treatment for low-grade non-Hodgkin's lymphoma (NHL). The pyrimidine nucleoside analogue cytarabine (AraC) has an important place in the treatment of acute leukemia, and gemcitabine is a new pyrimidin antimetabolite which has shown clinical activity against solid tumors. We have used the semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA), to study these drugs. Eighty samples from 60 patients with low-grade NHL were studied. Fifty samples from patients with acute lymphoid leukemia (ALL) and 118 samples from patients with acute myeloid leukemia (AML) were included for comparison. The results indicate that the purine- and pyrimidine nucleoside analogues tested may be as active against low-grade NHL as against acute leukemia. In low-grade NHL, AraC seems to be even more active in comparison to CdA (p=<0.0001) and fludarabine (p=0.001). Untreated patients were more drug sensitive than previously treated patients. Gemcitabine showed the highest correlation with AraC (0.90) whereas CdA showed the highest correlation with fludarabine (0.84). Based on these results we propose that AraC and gemcitabine may have a role in the treatment of low-grade NHL.

Acute Disease↗

PubMed1989

Recognition of thymine adenine.base pairs by guanine in a pyrimidine triple helix motif.

Oligonucleotide recognition offers a powerful chemical approach for the sequence-specific binding of double-helical DNA. In the pyrimidine-Hoogsteen model, a binding size of greater than 15 homopurine base pairs affords greater than 30 discrete sequence-specific hydrogen bonds to duplex DNA. Because pyrimidine oligonucleotides limit triple helix formation to homopurine tracts, it is desirable to determine whether oligonucleotides can be used to bind all four base pairs of DNA. A general solution would allow targeting of oligonucleotides (or their analogs) to any given sequence in the human genome. A study of 20 base triplets reveals that the triple helix can be extended from homopurine to mixed sequences. Guanine contained within a pyrimidine oligonucleotide specifically recognizes thymine.adenine base pairs in duplex DNA. Such specificity allows binding at mixed sites in DNA from simian virus 40 and human immunodeficiency virus.

Adenine↗

PubMed1987

Incorporation of Exogenous Purines and Pyrimidines by Methanococcus voltae and Isolation of Analog-Resistant Mutants.

Methanococcus voltae incorporated exogenous adenine, guanine, hypoxanthine, and uracil, but not thymine. Growth of M. voltae was also sensitive to purine and pyrimidine analogs. Of the 20 analogs tested, 12 were inhibitory at 1 mg/ml. The most effective inhibitors were purine analogs with endocyclic substitutions. Nucleoside analogs and analogs with exocyclic substitutions or additions were less effective. Four purine analogs, 8-aza-2,6-diaminopurine, 8-azaguanine, 8-azahypoxanthine, and 6-mercaptopurine and one pyrimidine analog, 6-azauracil, were especially toxic. The MICs were 20, 0.5, 2.0, 80, and 10 mug/ml, respectively. Spontaneous resistance mutants were isolated for these five analogs. The MICs for these mutants were 20.5, 8.2, >65, >41, and 20.5 mg/ml, respectively. These concentrations far exceeded the solubilities of the analogs and represented an increase in resistance of at least three orders of magnitude. In addition to demonstrating cross resistance to several of the analogs, four of these mutants lost the ability to incorporate exogenous bases. These appeared to be mutations in the salvage pathways for purines and pyrimidines. In contrast, the mutant resistant to 6-mercaptopurine was not defective in purine uptake. Instead, it degraded 6-mercaptopurine. In the presence or absence of high concentrations of the analogs, the growth rates of the resistant mutants were no less than one-half of the growth rate of the wild type in the absence of the analog. The high level of resistance and rapid growth are very desirable properties for the application of the mutants in genetic experiments.

Journal Article↗

PubMed1999

Biosynthesis of the pyrimidine moiety of thiamine independent of the PurF enzyme (Phosphoribosylpyrophosphate amidotransferase) in Salmonella typhimurium: incorporation of stable isotope-labeled glycine and formate.

Genetic analyses have suggested that the pyrimidine moiety of thiamine can be synthesized independently of the first enzyme of de novo purine synthesis, phosphoribosylpyrophosphate amidotransferase (PurF), in Salmonella typhimurium. To obtain biochemical evidence for and to further define this proposed synthesis, stable isotope labeling experiments were performed with two compounds, [2-13C]glycine and [13C]formate. These compounds are normally incorporated into thiamine pyrophosphate (TPP) via steps in the purine pathway subsequent to PurF. Gas chromatography-mass spectrometry analyses indicated that both of these compounds were incorporated into the pyrimidine moiety of TPP in a purF mutant. This result clearly demonstrated that the pyrimidine moiety of thiamine was being synthesized in the absence of the PurF enzyme and strongly suggested that this synthesis utilized subsequent enzymes of the purine pathway. These results were consistent with an alternative route to TPP that bypassed only the first enzyme in the purine pathway. Experiments quantitating cellular thiamine monophosphate (TMP) and TPP levels suggested that the alternative route to TPP did not function at the same capacity as the characterized pathway and determined that levels of TMP and TPP in the wild-type strain were significantly altered by the presence of purines in the medium.

Amidophosphoribosyltransferase↗

PubMed1980

Additional data from two kindreds with genetically induced deficiencies of erythrocyte pyrimidine nucleotidase.

Two subjects, not previously reported in detail, had severe inherited deficiencies of erythrocyte pyrimidine nucleotidase. This was manifested hematologically by moderate hemolytic anemia with splenomegaly, morphologically by punctate basophilic stippling of Wright's stained erythrocytes, and biochemically by intraerythrocytic accumulation of pyrimidine nucleotides, elevated concentrations of reduced glutathione, and partial deficiencies of ribosephosphate pyrophosphokinase. All 5 of their children were asymptomatic and phenotypically normal except for intermediate reductions in activities of pyrimidine nucleotidase consistent with heterozygosity for an autosomal recessive defect.

5'-Nucleotidase↗

PubMed2002

2, 4-diamino-6- hydroxy pyrimidine inhibits NSAIDs induced nitrosyl-complex EPR signals and ulcer in rat jejunum.

BACKGROUND: It has been suggested that one aspect of non-steroidal anti-inflammatory drugs induced intestinal damage is due to either uncoupling of mitochondrial oxidative phosphorylation or inhibition of electron transport. We investigated the latter possibility using electron paramagnetic resonance spectroscopy. RESULTS: Electron paramagnetic studies of NSAIDS on sub-mitochondrial particles revealed that indomethacin, but not with nabumetone, bound to a site near to Complex I and ubiquinone to generate a radical species. Normal rats exhibited prominent [3Fe-4S]ox signals (g approximately 2.01) at 20 K. One hour after indomethacin there was a prominent, intense and broad absorption pattern at (g approximately 2.07) suggesting, appearance of radical species overlapping [3Fe-4S]ox and was unaffected by pretreatment with 2,4 diamino -6-hydroxy pyrimidine. At 24 hrs, when macroscopic ulcers were seen, there was a new signal due to a nitric oxide radical (NO*). In contrast, nabumetone and 2,4 diamino-6-hydroxy pyrimidine pre-treated animals receiving indomethacin exhibited electron paramagnetic resonance spectra identical to those of controls at 24 hrs and neither was associated with small intestinal ulcers. Indomethacin and 2,4 diamino hydroxy pyrimidine pre-treated rats, but not nabumetone, had increased intestinal permeability. CONCLUSION: The results suggest that the in vivo effects of indomethacin modulate the mitochondrial respiratory chain directly at 1 h and 24 h through formation of nitric oxide. NO* appears to play an important role in the late pathogenic stages of NSAID enteropathy and may be the site for targeted treatment to reduce their toxicity.

Animals↗

PubMed1998

Enhanced activity of pyrimidine 5'-nucleotidase in rat red blood cells during erythropoiesis.

A nucleotidase that catalyzed selective hydrolysis of pyrimidine 5'-nucleotides was investigated in rat red blood cells (RBCs). The enzyme had similar catalytic properties to human pyrimidine 5'-nucleotidase I (P5N-I). The P5N-I deficiency was known to be closely correlated with the human inherited disease, non-spherocytic hemolytic anemia. Similar to the human P5N-I, the rat enzyme preferentially hydrolyzed 5'-(d)CMP and 5'-UMP but no reactivity was observed with any 3'-nucleotide. Molecular mass of the enzyme was estimated to be approximately 38 kDa by gel filtration and SDS-polyacrylamide gel electrophoresis. Another subclass of pyrimidine 5'-nucleotidase, P5N-II, was also present in rat RBCs. This P5N-II-like enzyme, which resembled a 5'(3')-nucleotidase, preferentially hydrolyzed both 5'- and 3'- of (d)TMP or (d)UMP, but no cytosine nucleotide was hydrolyzed by the enzyme. Results from the reactivity with the antibody against rat 5'(3')-nucleotidase and estimated subunit molecular mass of the enzymes, about 26 kDa, suggested that the P5N-II-like enzyme had a similar structure to the 5'(3')-nucleotidase. The P5N-I-like activity in rat RBCs increased 5 to 6-fold at 4 days after phenylhydrazine injection, and reached a maximum at 6 to 7 days. No change in the activity of P5N-II-like nucleotidase was observed during the experimental period. The increase in rat P5N-I activity coincided with maturation of the erythrocytes.

5'-Nucleotidase↗

PubMed1987

Specific deprotonation reactions of the pyrimidine radical cation resulting from the menadione mediated photosensitization of 2'-deoxycytidine.

Menadione(2-methyl-1,4-naphthoquinone) was shown to sensitize 2'-deoxycytidine to near ultraviolet light according to two main mechanisms. Reaction of a water molecule with the initially photo-induced pyrimidine radical cation and subsequent addition of molecular oxygen leads to the preponderant formation of the four cis and trans diastereoisomers of 5,6-dihydroxy-5,6-dihydro-2'-deoxyuridine. Pyrimidine ring opening and rearrangement products are also generated through the intermediate 6-hydroxy-5,6-dihydro-2'-deoxyurid-5-yl radical. The competitive deprotonation reaction of the radical cation is likely to involve two sites. Loss of an amino group proton is the likely initial event to explain the formation of 2'-deoxyuridine which is resistant to further photooxidation. The second deprotonation reaction involves the osidic carbon C(1'). The resulting radical will further react with oxygen leading to the release of free cytosine with concomitant formation of 2-deoxy-D-ribono-1,4-lactone. This reaction which is not prevented by hydroxyl radical scavengers constitutes to our knowledge the first example of a pyrimidine radical which is able to initiate selective intramolecular reaction at position 1 within the sugar moiety.

Carbon Radioisotopes↗