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PubMed1991

A binding mode of lambda-[tris(1,10-phenanthroline)ruthenium(II)]2+ exhibiting preference for purine-3',5'-pyrimidine sites of DNA.

Molecular mechanics calculations and molecular dynamics simulations have been used to study the binding of the partially inserted major groove complex of Lambda-[Ru(1,10-phenanthroline)3]2+ with DNA. Energy refinements of this complex showed a clear preference for binding at purine-3',5'-pyrimidine sites over pyrimidine-3',5'-purine sites. The basis for this difference is shown to be a slight change in the binding orientation induced by interchanging the purine and pyrimidine bases. This in turn provides for a better secondary interaction with the helix backbone at a point beyond the immediate binding site. It is this secondary interaction that provides the additional energetic stabilisation for complexes formed at purine-3',5'-pyrimidine sites. Molecular dynamics simulations including explicit representation of solvent support these conclusions and provide an insight into the positional stability of the ligand at a particular site. Repuckering of specific deoxyribose rings to the C3'-endo conformation seems to be an important feature of the DNA/ligand complex.

Base Sequence↗

PubMed2001

Bis(hfac)-copper(II) complexes bridged by pyrimidines showing magnetic interactions.

Crystals of bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)bispyrimidinecopper(II) (1), bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)bis(4-methylpyrimidine)copper(II) (2), bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)bis(quinazoline)copper(II) (3) showed ferromagnetic interactions at extremely low temperature. Crystal structure analyses revealed that these complexes were catena-bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)[mu-pyrimidine-N(1):N(3)]copper(II), [Cu(hfac)(2)(pm)(2)](n), catena-bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)[mu-4-methylpyrimidine-N(1):N(3)]copper(II), [Cu(hfac)(2)(4-Me-pm)](n), and catena-bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)[mu-pyrimidine-N(1):N(3)]copper(II), [Cu(hfac)(2)(qz)](n), for (1), (2) and (3), respectively. In (1) and (2) the pyrimidines bridge the Cu atoms with an axial-equatorial mode to form one-dimensional spiral chains. Complex (3) also forms a one-dimensional chain structure. The coordination mode of (3) is axial-axial at room temperature, while axial-equatorial at 120 K. On the other hand, the structure of the other modification of the 4-methylpyrimidine complex (4), showing paramagnetic properties, was revealed to be a trinuclei complex bridged by two 4-methylpyrimidines, tris[bis-(1,1,1,5,5,5-hexafluoropentane-2,4-dionato)copper(II)][bis-mu-4-methyl-pyrimidine-N(1):N(3)]. The chain structures with an axial-equatorial coordination mode of the bridging organic moieties should play an important role in the appearance of the ferromagnetic interactions.

Journal Article↗

PubMed1995

Evaluation of lead exposure in workers at a lead-acid battery factory in Korea: with focus on activity of erythrocyte pyrimidine 5'-nucleotidase (P5N).

OBJECTIVE: To evaluate lead exposure among lead-acid battery workers in Korea, to evaluate in more detail the erythrocyte pyrimidine 5'-nucleotidase (P5N) test for lead exposure, and to evaluate the abnormal accumulation of erythrocyte pyrimidine nucleotides in the battery workers. METHODS: Activity of P5N and other biological variables were examined in 66 exposed workers in a lead-acid battery factory and in 26 non-exposed workers in Korea. RESULTS: At the factory the time-weighted average of 13 (72%) of 18 air samples for lead exceeded 0.05 (range 0.012-0.468) mg/m3. Blood lead concentration (PbB) in 39 of the 66 exposed workers was above 40 micrograms/dl, and the mean (SD) PbB in the exposed group was 45.7 (15.7) micrograms/dl. Compared with the nonexposed group, free erythrocyte protoporphyrin in the exposed group was significantly increased, whereas erythrocyte P5N activity and activity of erythrocyte delta-aminolevulinic acid dehydratase (ALAD) were significantly inhibited. Erythrocyte P5N activity had valid correlation biologically with PbB and with other biological variables, such as ALAD activity. In 28 exposed workers, the concentration of erythrocyte pyrimidine nucleotides (uridine 5'-diphosphate-glucose and cytidine 5'-triphosphate) correlated inversely with P5N activity and positively with PbB. CONCLUSIONS: These findings show that the depression of erythrocyte P5N activity by lead exposure results in the accumulation of erythrocyte pyrimidine nucleotides. In general, the standard analysis of PbB performed in laboratories around the world remains the most useful index of recent exposure. The results indicate that the erythrocyte P5N activity test provides supporting evidence of lead exposure and shows the effect of lead on nucleotide metabolism.

5'-Nucleotidase↗

PubMed1977

Inhibitory action of the adenine analog, 4-aminopyrazolo(3,4-d)pyrimidine, in Crithidia fasciculata.

The adenine analog 4-aminopyrazolo(3,4-d)pyrimidine inhibits the growth of the kinetoplastid (trypanosomatid) flagellate Crithidia fasciculata. This inhibition is partially overcome only by adenine (of a number of purines tested), with an inhibition index of 0.025. More effective reversal of inhibition is obtained with any of a number of naturally occurring pyrimidine compounds, up to a concentration of 0.18 mM. Higher concentrations of pyrimidines or addition of guanine, as well as adenine and uracil, to the medium increases inhibition. The analog (presumably as the ribonucleotide) was found not to be inhibitory to any enzyme of the pyrimidine biosynthetic pathway that could be tested. It is suggested that the analog competes with adenine for adenine phosphoribosyltransferase (AMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.7), is converted to a ribonucleotide, and is incorporated into nucleic acid.

Adenine↗

PubMed1983

Partial purification and zinc dependence of human red cell pyrimidine-5'-nucleotidase.

Human red cell pyrimidine-5'-nucleotidase (EC 3.1.3.5) was partially purified from the blood of normal subjects by ion-exchange and affinity chromatography. Red cells were lysed in 50 mmol/l Tris-Cl buffer at pH 7.5 containing 1.0 mmol/l dithiothreitol and 0.5 mmol/l EDTA. The lysate was centrifuged and introduced onto a column of Sephadex A-50. After washing, the pyrimidine-5'-nucleotidase activity was eluted from the column with a NaCl gradient from 0 to 200 mmol/l in Tris buffer at pH 7.5. The pyrimidine-5'-nucleotidase was then desalted on Sephadex G-25 and introduced onto a UDP agarose column with a Tris buffer at pH 6.5 containing 150 mmol/l NaCl. This partial purification resulted in an approximately 80,000-fold increase in enzyme concentration. The Km for the partially purified enzyme was 0.32 mmol/l for UMP, 0.16 mmol/l for CMP and 0.11 mmol/l for OMP with a pH maximum of 7.5. This partially purified pyrimidine-5'-nucleotidase was then dialyzed in 50 mmol/l Tris-Cl buffer at pH 7.5 with 0.01 mmol/l CaCl2 and NaCl against 2 X 10(-3) mol/l 1,10-phenanthroline for 24 h at 4 degrees C. This incubation resulted in 73% decrease in enzyme activity which could be restored by the addition of zinc into the mixture, but not by the addition of other divalent metal ions.

5'-Nucleotidase↗

PubMed1986

Growth of Lactobacillus bulgaricus in milk. 2. Characteristics of purine nucleotides, pyrimidine nucleotides, and nucleic acid synthesis.

Lactobacillus bulgaricus incorporated exogenous guanine only into guanine nucleotides and not into adenine nucleotides. Lactobacillus bulgaricus lacks the ability to interconvert adenine nucleotides and guanine nucleotides. Biosynthesis of pyrimidine nucleotides from orotic acid was depressed by addition of guanosine monophosphate or adenosine monophosphate. Some step in pyrimidine biosynthesis from orotic acid may be negatively regulated by the intracellular amount of purine nucleotides. Lactobacillus bulgaricus could not grow in milk from which orotate was removed. This indicates that the activity of de novo pyrimidine synthesis is very low in this organism. When the intracellular amount of purine or pyrimidine base was limited, ribonucleic acid synthesis was markedly depressed, resulting in cell elongation, whereas deoxyribonucleic acid synthesis was not so much affected.

Adenine↗

PubMed2002

Hypoxia may increase rat insulin mRNA levels by promoting binding of the polypyrimidine tract-binding protein (PTB) to the pyrimidine-rich insulin mRNA 3'-untranslated region.

BACKGROUND: Recent reports identify the 3'-UTR of insulin mRNA as crucial for control of insulin messenger stability. This region contains a pyrimidine-rich sequence, which is similar to the hypoxia-responsive mRNA-stabilizing element of tyrosine hydroxylase. This study aimed to determine whether hypoxia affects insulin mRNA levels. MATERIALS AND METHODS: Rat islets were incubated at normoxic or hypoxic conditions and with or without hydrogen peroxide and a nitric oxide donor. Insulin mRNA was determined by Northern hybridization. Islet homogenates were used for electrophoretic mobility shift assay with an RNA-oligonucleotide, corresponding to the pyrimidine-rich sequence of the 3'-UTR of rat insulin I mRNA. The expression of reporter gene mRNA, in islets transfected with reporter gene constructs containing the wild-type or mutated insulin mRNA pyrimidine-rich sequences, was measured by semiquantitive RT-PCR. RESULTS: Insulin mRNA was increased in response to hypoxia. This was paralleled by increased binding of the polypyrimidine tract-binding protein (PTB) to the pyrimidine-rich sequence of the 3'-UTR of insulin mRNA, which was counteracted by hydrogen peroxide. The reporter gene mRNA level containing the wild-type binding site was not increased in response to hypoxia, but mutation of the site resulted in a destabilization of the mRNA. CONCLUSIONS: The complete understanding of different diabetic conditions requires the elucidation of mechanisms that control insulin gene expression. Our data show that hypoxia may increase insulin mRNA levels by promoting the binding of PTB to the insulin mRNA 3'-UTR. Hydrogen peroxide abolishes the hypoxic effect indicating involvement of reactive oxygen species and/or the redox potential in the oxygen-signaling pathway.

3' Untranslated Regions↗

PubMed2004

Pyrimidine 5'nucleotidase I and II activities in acute leukaemias.

BACKGROUND AND OBJECTIVE: Pyrimidine 5'nucleotidase I and II activities of peripheral mononuclear cells were studied to evaluate their role in diagnosis, assessment of therapy and follow up of remission in acute leukaemias. DESIGN AND METHODS: Blood samples were obtained from 40 untreated patients with acute lymphoblastic and myeloid leukaemia and 40 healthy controls, before the therapy and after remission. The correlation between the activity of the enzymes and the efficacy of therapy were established. The enzyme activities were measured by High-Performance Liquid Chromatography (HPLC), using the method described by Amici. For statistical analysis, Mann-Whitney U, Kruskal-Wallis and Wilcoxon methods were used. RESULTS: Before the therapy, Pyrimidine 5'nucleotidase I levels in the leukaemic group were found to be significantly elevated when compared to the control group (p<0.001). Also Pyrimidine 5'nucleotidase II levels were significantly elevated before the therapy and during remission (p<0.02 and p<0.001 respectively). The isoenzyme activities were compared in patients who were in remission, who did not respond to therapy and in patients who died during the therapy, but no significant difference was found. INTERPRETATION AND CONCLUSIONS: We concluded that, Pyrimidine 5'nucleotidase I and II activities can be used as markers for diagnosis and follow up of remission in patients with acute leukaemia. But, they can not have predictive value for prognosis.

5'-Nucleotidase↗

PubMed1986

Biosynthesis of thiamin. Precursor of C-5, C-6, and hydroxymethyl carbon atoms of the pyrimidine moiety in a eucaryote.

We studied the incorporation of radioactive glucose into the pyrimidine moiety of thiamin in the eucaryote Candida utilis. Three carbons of glucose were incorporated into the pyrimidine, and the C-2 of glucose into the C-6 of the pyrimidine. We concluded that the C-5, -6, and hydroxymethyl carbon atoms of the pyrimidine in this eucaryote originate from the C-2, -3 and -4 of glucose via ribose.

Candida↗

PubMed1983

Reaction of enzyme-bound 5-deazaflavin with peroxides. Pyrimidine ring contraction via an epoxide intermediate.

Reaction of peroxides with 5-deazaflavin bound to glucose oxidase, lactate oxidase, or D-amino acid oxidase results in the formation of 5-deazaflavin 4a, 5-epoxide. The reaction of D-amino acid oxidase with m-chloroperoxybenzoate is an exception since the reagent reacts rapidly with the protein moiety to form m-chlorobenzoate which then binds noncovalently near the unmodified coenzyme. Epoxide bound to glucose oxidase is converted to deazaFAD X X in a reaction similar to that observed previously with oxynitrilase and glycolate oxidase. With lactate oxidase the epoxide is quite stable in the absence of light. With D-amino acid oxidase, denaturation of the protein is accompanied by the release of the epoxide into solution where it decomposes in a manner similar to that observed with model epoxide compounds at neutral pH. Reaction of deazaFAD X X with phosphodiesterase and alkaline phosphatase yields deazariboflavin X X. The same compound has been formed in model studies by exposing 5-deazariboflavin 4a,5-epoxide to alkaline conditions. Structural studies indicate that this reaction involves contraction of the pyrimidine ring to yield 4-ribityl-6,7-dimethyloxazolo[ 4,5-b ]quinolin-2(4H)-one. Model reaction studies are consistent with a mechanism initiated by alkaline hydrolysis of the pyrimidine ring at position 4 followed by two additional steps which proceed at neutral pH. A similar mechanism for the enzyme reactions appears likely since analogous intermediates are detected in the glycolate oxidase and the model reactions. The results suggest that position 4 of the coenzyme in oxynitrilase, glycolate oxidase, and glucose oxidase must be accessible to solvent and that the protein moiety must facilitate the initial hydrolysis of the pyrimidine ring since the enzyme reactions occur at neutral pH. Failure to observe formation of deazaFMN X X with lactate oxidase is attributed, at least in part, to the inaccessibility of the pyrimidine ring to solvent.

Animals↗

PubMed1982

Effect of lead chelation therapy with EDTA in children on erythrocyte pyrimidine 5'-nucleotidase and with cytidine triphosphate levels.

Children with elevated whole blood lead levels were treated for 4 days with EDTA. Changes in whole blood lead concentrations, erythrocyte zinc protoporphyrin concentrations, red cell pyrimidine 5'-nucleotidase activities, and erythrocyte cytidine triphosphate (CTP) levels were measured during the course of the EDTA therapy. EDTA treatment decreased blood lead levels by approximately 50% after 4 days. An inverse relationship existed between blood lead levels and erythrocyte pyrimidine 5'-nucleotidase activity. Despite reactivation of pyrimidine 5'-nucleotidase enzyme activity by EDTA, there was no decrease in erythrocyte cytidine triphosphate or in zinc protoporphyrin concentrations. The lack of change in these two parameters during EDTA treatment supports the concept that pyrimidine 5'-nucleotidase inhibition by lead in the reticulocyte cytidine phosphate accumulation in moderate lead poisoning may reflect chronic lead overburden analogous to prolonged elevation of erythrocyte zinc protoporphyrins.

5'-Nucleotidase↗

PubMed1995

[Pharmacological and biochemical investigation of intracavital fluorinated pyrimidine chemotherapy].

We investigated the biochemical and molecular pharmacological parameters of fluorinated pyrimidines using malignant cells in pleural effusion or ascites from patients with malignant disease both before and after fluorinated pyrimidine chemotherapy, either systemically or intravesically. In four out of fifteen cancer patients, we could analyze the alteration of thymidylate synthase (TS) catalytic activity both before and after the treatment, showing that there was a decrease ranging 28% through 96.9%. We also analyzed a level of TS messenger RNA and TS protein using molecular biotechniques. None of these mutual correlations has so far been demonstrated, indicating that the data were analyzed through samples from patients not responding to the fluorinated pyrimidines. In a responding patient with advanced breast cancer, pre-treatment total TS protein was 130 fmol/mg and the TS activity was 3.27 pmol/mg/min. After intrapleural instillation of a combination of 5-FU 250 mg and leucovorin 3 mg, the total amount and the catalytic activity of TS could be measured. On the 11th day of treatment, the TS protein level decreased to 26 fmol/mg and the TS catalytic activity also decreased to 0.1 pmol/mg/min resulting in a TS inhibition rate of 92.3 percent. On the 17th day, the patient's malignant pleural effusion disappeared almost completely, suggesting that substantial TS inhibition may reflect the clinical evidence. This particular data showed that it would be predictable for clinical outcome to evaluate these parameters before and after fluorinated pyrimidine chemotherapy. Further study is warranted to evaluate the exact role of analyzing these parameters in clinical practice.

Aged↗

PubMed1992

Quantum yield for preferential photodimerization in long pyrimidine tracts.

The quantum yield for cyclobutyl-pyrimidine dimerization in DNA has been observed to increase approximately linearly with increasing pyrimidine tract length. A model without adjustable parameters for this yield is proposed based on energy delocalization, vibronic symmetry switching, and saturation statistics that describe the average number of (base pairwise) breathing modes in a given tract of pyrimidines. This average number of modes is an approximately linear function of the tract length. Monte Carlo techniques are used to simulate base sequences and photochemical events, and indicate that this model is consistent with experiment for Tetrahymena pyriformis DNA.

Animals↗

PubMed1986

Use of biological fluids for the rapid diagnosis of potentially lethal inherited disorders of human purine and pyrimidine metabolism.

Inherited purine and pyrimidine disorders may be associated with serious, sometimes life-threatening consequences. Early and accurate diagnosis is essential. Difficulties encountered when using existing high pressure liquid chromatographic (HPLC) methods led to the development of an improved method based on prior fractionation of urine. The advantages are as follows. 1. Production of fingerprints demonstrating altered urinary excretion patterns characteristic of any one of ten different disorders, in 30 minutes. 2. Positive identification and quantification by comparison with established methods (using conventional chromatography, electrophoresis and UV spectrophotometry) in addition to specific retention times and characteristic UV absorbance ratios at two separate wavelengths (245 and 280 nm) by HPLC. 3. Direct analysis of all the purines and pyrimidines normally found in human body fluids as well as identification of abnormal compounds. 4. Short time between successive analyses while maintaining excellent resolution between compounds of interest and column longevity. 5. Improved separation of the different adenine-based compounds encountered in some disorders, plus demonstration of potential interference by dietary or drug metabolites. 6. Applicability to the monitoring of therapy involving a variety of different purine and pyrimidine analogues. Particular attention should be paid to sample preparation. Plasma profiles will confirm the diagnosis in some, but not all, of these disorders.

Chromatography, High Pressure Liquid↗

PubMed1993

Stimulation of astrocyte proliferation by purine and pyrimidine nucleotides and nucleosides.

Proliferation of brain astrocytes as a result of cell death has been well documented in vivo. Dying cells release purine and pyrimidine nucleosides and nucleotides and their deoxy derivatives both from soluble intracellular pools and from DNA and RNA. Previously, we have observed that purine nucleosides and nucleotides stimulate chick astrocyte proliferation in vitro. To further our analysis, we questioned whether pyrimidines or the deoxy derivatives of purine nucleosides and nucleotides might also be astrocyte mitogens. Pyrimidine nucleosides, nucleotides, and their deoxynucleotide derivatives were uniformly inactive. In contrast, deoxyguanosine, deoxyadenosine, and their mono-, di-, and triphosphates stimulated thymidine incorporation into astrocytes at concentrations similar to those at which their ribonucleoside and ribonucleotide analogues were active. Inosine, IMP, ITP, and hypoxanthine were active, whereas xanthine and xanthosine were not. However, XMP, XDP, and XTP stimulated thymidine incorporation. The effects of the nucleosides and deoxynucleosides were inhibited by antagonists of adenosine A2 receptors. These data indicate that most purine nucleosides, deoxynucleosides, and their 5' mono, di-, and triphosphate derivatives released from damaged cells are capable of stimulating astrocyte proliferation in vitro and may contribute to astrocyte proliferation in vivo following injury to the CNS.

Adenosine↗

PubMed1976

Uptake and incorporation of pyrimidines in Euglena gracilis.

In photoorganotrophically grown cells of Euglena gracilis the uptake and incorporation degree of 12 different pyrimidines were tested. The rate of uptake of pyrimidines has distinct maxima in the late log phase and in the stationary phase of cell multiplication. The kinetics of uptake are linear in the first 2 h, do not show saturation at various concentrations and increase with the concetrations. No accumulation of the pyrimidines at various concentrations could be observed in the first 2 h of incubation. Membrane inhibitors as uranyl acetate inhibit the uptake of the reference substance alpha-AIB, which is wellknown transported by an active transport mechanism, but have no effect on uptake rate of uracil and cytosine. It could not be observed an energy requirement tested in temperature dependence and with electron transport inhibitors. Uptake of uridine, uracil, barbituric acid and alpha-AIB is inhibited by cycloheximide in a different manner after 5 - 10 min.

Biological Transport↗

PubMed1992

Precursors of pyrimidine nucleotide biosynthesis for gravid Angiostrongylus cantonensis (Nematoda: Metastrongyloidea).

Gravid Angiostrongylus cantonensis can utilize radiolabelled bicarbonate, orotate, uracil, uridine and cytidine but not cytosine, thymine and thymidine for the synthesis of RNA and DNA. In cell-free extracts of the worm, a phosphoribosyltransferase was shown to convert orotate to OMP and uracil to UMP. A similar reaction was not observed with cytosine and thymine. Uridine was readily phosphorylated by a kinase but a similar reaction for thymidine and deoxyuridine was not found. Cytidine could be phosphorylated by a kinase or be deaminated by a deaminase to uridine. No deaminase for cytosine was detected. There was also no phosphotransferase activity for pyrimidine nucleosides in the cytosolic or membrane fractions. Pyrimidine nucleosides were, in general, converted to the bases by a phosphorylase reaction but only uracil and thymine could form nucleosides in the reverse reaction. The activity of thymidylate synthetase was also measured. These results indicate that the nematode synthesizes pyrimidine nucleotides by de novo synthesis and by utilization of uridine and uracil and that cytosine and thymine nucleotides are formed mainly through UMP. The thymidylate synthetase reaction appears to be vital for the growth of the parasite.

Angiostrongylus↗

PubMed1992

Pyrimidine base and ribonucleoside catabolic enzyme activities of the Pseudomonas diminuta group.

Pyrimidine base and ribonucleoside catabolic enzyme activities of the two type strains of the Pseudomonas diminuta group were investigated for taxonomic classification purposes. The presence of the pyrimidine salvage enzyme nucleoside hydrolase was indicated in both type strains following thin-layer chromatographic analysis. The presence of the hydrolase was also confirmed by enzyme assay. In addition, the activities of the pyrimidine salvage enzymes dihydropyrimidine dehydrogenase and dihydropyrimidinase were measurable in cell-free extracts of both P. diminuta and P. vesicularis. An absence of cytosine deaminase activity was found when assaying extracts of the two type strains. Nucleoside hydrolase and dihydropyrimidine dehydrogenase levels in P. vesicularis were influenced by carbon source while dihydropyrimidinase activity was observed to increase after P. diminuta growth on dihydrothymine as a nitrogen source.

Amidohydrolases↗