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PubMed1996

Purine and pyrimidine nucleotide metabolism of vascular smooth muscle cells in culture.

1. Cultures of vascular smooth muscle cells accumulate extracellular breakdown products of purine and pyrimidine nucleotides that, over 9 hr, represent 60 +/- 7 and 78 +/- 17%, respectively, of the intracellular nucleotide content. 2. The accumulation is stimulated during contracture with 20 mM KCl or 70 microM carbachol, consistent with the notion that both pyrimidine and purine nucleotides are involved in the energetics of smooth muscle contracture. 3. Because the intracellular levels of pyrimidine and purine nucleotides remain constant, it appears likely that rates of synthesis match the rates of release. 4. Ectonucleotidases are present that can degrade ATP, UTP, and CTP. High-energy nucleotides may be the primary products released.

Animals↗

PubMed1992

Pyrimidine nucleotide synthesis in the rat mammary gland: changes in the lactation cycle and effects of diabetes.

Measurements have been made of the activities of the enzymes of the de novo and salvage pathways of pyrimidine synthesis (carbamoyl phosphate synthetase II (glutamine) (EC 6.3.5.5); dihydroorotate dehydrogenase (EC 1.3.99.11); the overall activity of Complex II (orotate phosphoribosyl pyrophosphate transferase (EC 2.4.2.10) and orotidine 5-phosphate decarboxylase (EC 4.1.1.23); uracil phosphoribosyltransferase (EC 2.4.2.9)) in the mammary gland of rats at different stages of the lactation cycle and the effects of diabetes on the activity of these enzymes in lactation have been studied. From a consideration of the changes in enzyme activities and the changes in the tissue concentration of phosphoribosyl pyrophosphate, an activator of the de novo pathway and substrate for both the de novo and salvage routes, it is concluded that the de novo pathway is the major route of pyrimidine synthesis in mammary tissue. Diabetes decreases the activity of the enzymes of the de novo pathway; the effects are particularly marked for Complex II. The present results on pyrimidine synthesis are compared to the pattern for purine synthesis previously published.

Animals↗

PubMed1993

Aphidicolin inhibits excision repair of UV-induced pyrimidine photodimers in low serum cultures of mitotic and mitomycin C-induced postmitotic human skin fibroblasts.

The rates of formation and excision of UVC light-induced cyclobutane-type pyrimidine photodimers were determined in cultures of foreskin-derived normal human fibroblasts in mitotic (MF) and mitomycin-C (MMC)-induced postmitotic fibroblasts (PMF). Characteristic morphological changes support the notion that MMC accelerates the differentiation pathway from MF to PMF. In cultures treated with aphidicolin, I am able to show that this inhibitor of alpha and/or delta polymerases significantly inhibits the repair of pyrimidine photodimers in foreskin-derived mitotic and MMC-induced postmitotic fibroblasts in low serum cultures (0.5%) following UVC irradiation. Over the concentration range of 0-2 micrograms/ml of aphidicolin, there is a strong concentration-dependent inhibition of repair in cells treated with 10 J/m2 of UVC and incubated with aphidicolin during the post-incubation time (0-24 h). The results demonstrate that pyrimidine photodimers are repaired in low serum cultures by an alpha- and/or delta-polymerase-dependent pathway. These data also imply that the fibroblast differentiation system is a very useful tool to unravel the complex mechanisms of UV-induced DNA damage and repair.

Aphidicolin↗

PubMed1990

Wavelength dependence for UV-induced pyrimidine dimer formation in DNA of human peripheral blood lymphocytes.

An action spectrum for the induction of pyrimidine dimers in human peripheral lymphocytes was determined between 254 and 405 nm. The presence of pyrimidine dimers was determined as UV-induced lesions that were sensitive to the dimer-specific endonuclease from Micrococcus luteus in conjunction with agarose gel electrophoresis. The rate of induction of pyrimidine dimers was maximal at 254 nm. These values can be compared with action spectra for UV-induced in vitro responses of lymphocytes.

Cell Survival↗

PubMed1992

(6-4) photoproducts and not cyclobutane pyrimidine dimers are the main UV-induced mutagenic lesions in Chinese hamster cells.

A partial revertant (RH1-26) of the UV-sensitive Chinese hamster V79 cell mutant V-H1 (complementation group 2) was isolated and characterized. It was used to analyze the mutagenic potency of the 2 major UV-induced lesions, cyclobutane pyrimidine dimers and (6-4) photoproducts. Both V-H1 and RH1-26 did not repair pyrimidine dimers measured in the genome overall as well as in the active hprt gene. Repair of (6-4) photoproducts from the genome overall was slower in V-H1 than in wild-type V79 cells, but was restored to normal in RH1-26. Although V-H1 cells have a 7-fold enhanced mutagenicity, RH1-26 cells, despite the absence of pyrimidine dimer repair, have a slightly lower level of UV-induced mutagenesis than observed in wild-type V79 cells. The molecular nature of hprt mutations and the DNA-strand specificity were similar in V79 and RH1-26 cells but different from that of V-H1 cells. Since in RH1-26 as well as in V79 cells most hprt mutations were induced by lesions in the non-transcribed DNA strand, in contrast to the transcribed DNA strand in V-H1, the observed mutation-strand bias suggests that normally (6-4) photoproducts are preferentially repaired in the transcribed DNA strand. The dramatic influence of the impaired (6-4) photoproduct repair in V-H1 on UV-induced mutability and the molecular nature of hprt mutations indicate that the (6-4) photoproduct is the main UV-induced mutagenic lesion.

Animals↗

PubMed1990

SKH-1 hairless mice repair UV-induced pyrimidine dimers in epidermal DNA.

The SKH-1 hairless mouse strain has been used extensively as a model for human photocarcinogenesis, photoimmunology and photoaging, but little is known about DNA repair in living mouse skin. Mice were irradiated with UV-B light at doses which produce mild to severe sunburn, and the frequency of pyrimidine dimers in epidermal DNA was measured immediately and 6 h after irradiation using T4 endonuclease V treatment and alkaline agarose gel electrophoresis. The results demonstrate significant removal of pyrimidine dimers in mouse skin in vivo, with a dimer half-life of 7.4 h. These findings are similar to the repair of dimers in human skin in vivo. The SKH-1 hairless mouse is thus a useful model for pyrimidine dimer repair in human skin.

Animals↗

PubMed2006

Design, synthesis and antibacterial activity of novel 1,3-thiazolidine pyrimidine nucleoside analogues.

The synthesis of a new class of 1,3-thiazolidine nucleoside analogues in which furanose oxygen atom was replaced with nitrogen atom and 2'-carbon atom with sulfur atom is described. N-tert-butoxycarbonyl-2-acyloxy-4-trityloxymethyl-1,3-thiazolidine was coupled with the pyrimidine bases like uracil, thymine, etc. in the presence of lewis acids stannic chloride or trimethyl silyl triflate following Vorbruggen procedure. The antibacterial activity of the novel 1,3-thiazolidine pyrimidine nucleoside analogues is highlighted. All compounds (7a-e) with free NH group in the pyrimidine moiety showed significant biological activity against all the standard strains used and in that compounds 7d and 7e showed significant activity against 14 human pathogens tested.

Anti-Bacterial Agents↗

PubMed2006

Discovery of substituted 4-anilino-2-(2-pyridyl)pyrimidines as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. Part 1: structure-activity relationships of the 4-anilino group.

A series of 4-anilino-2-(2-pyridyl)pyrimidines has been discovered as a new class of potent inducers of apoptosis using a cell-based HTS assay. Compound 5a was found to arrest T47D cells in G2/M and induced apoptosis. SAR studies showed that a small and electron-donating group at the meta-position of the anilino ring is important for activity. A 20-fold increase in potency, from hit compound 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5a) to lead compound 4-(2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5l), was obtained through the SAR studies. Compound 5l is highly active with an EC50 value of 18 nM in the caspase activation assay in T47D breast cells. Interestingly, 5a and other meta-mono-substituted compounds were active against T47D cells but were not active against H1299 and HT29 cells, while 5l and other 2,5-disubstituted compounds were active against all the three cells. In a tubulin polymerization assay, compound 5l inhibited tubulin polymerization with an IC50 value of < 0.5 microM, while 5a was not active up to 50 microM.

Aniline Compounds↗

PubMed2004

Synthesis and antileishmanial profile of some novel terpenyl pyrimidines.

Some novel terpenyl pyrimidine derivatives 2(a-d) and 6(a-b) have been synthesised from alpha/beta-ionone keteneacetals 1 and 5. The terpenyl pyrimidine 2e has been synthesised from beta-ionone 3 in two steps in quantitative yield. The pyrimidine derivatives were screened for in-vivo antilesihmanial activity. The compounds 2d, 2e, 6a and 6b showed promising in-vivo antileishmanial activity.

Animals↗

PubMed2004

Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents.

Synthesis of some new 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines (3a-k) has been accomplished by the oxidation of 4,6-dimethyl-2-pyrimidinylhydrazones of various aldehydes with iodobenzene diacetate in dichloromethane. Nine new compounds (3b-g and 3i-k) were tested in vitro for their antibacterial activity. Two compounds, namely 3-(4'-pyridyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3k) and 3-(3',4'-dimethoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3f), were associated with substantially higher antibacterial activity than some commercial antibiotics against Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Salmonella typhi at MIC (minimum inhibitory concentration) i.e. 10 microg/ml.

Anti-Bacterial Agents↗

PubMed2005

Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy.

Purine salvage is an essential function for all obligate parasitic protozoa studied to date and most are also capable of efficient uptake of preformed pyrimidines. Much progress has been made in the identification and characterisation of protozoan purine and pyrimidine transporters. While the genes encoding protozoan or metazoan pyrimidine transporters have yet to be identified, numerous purine transporters have now been cloned. All protozoan purine transporter-encoding genes characterised to date have been of the Equilibrative Nucleoside Transporter family conserved in a great variety of eukaryote organisms. However, these protozoan transporters have been shown to be sufficiently different from mammalian transporters to mediate selective uptake of therapeutic agents. Recent studies are increasingly addressing the structure and substrate recognition mechanisms of these vital transport proteins.

Animals↗

PubMed2004

Purine and pyrimidine-specific repression of the Escherichia coli carAB operon are functionally and structurally coupled.

Transcription of the carAB operon encoding the sole carbamoylphosphate synthetase of Escherichia coli proceeds from a tandem pair of promoters. P2, downstream, is repressed by arginine and the ArgR protein, whereas P1 is submitted to pyrimidine-specific regulation and as shown here to purine-specific control exerted by binding of the PurR protein to a PUR box sequence centered around nucleotide -128.5 with respect to the start of P1 transcription. In vivo analyses of the effects of trans and cis-acting mutations on the regulatory responses and single round in vitro transcription assays indicated that ligand-bound PurR is by itself unable to inhibit P1 promoter activity. To exert its effect PurR relies on the elaborated nucleoprotein complex that governs P1 activity in a pyrimidine-specific manner. Thus we reveal the existence of an unprecedented functional and structural coupling between the modulation of P1 activity by purine and pyrimidine residues that appears to result from the unique position of the PUR box in the carAB control region, far upstream of the promoter. Missing contact and premethylation binding interference studies revealed the importance of base-specific groups and of structural aspects of the PUR box sequence in complex formation. Permutation assays indicated that the overall PurR-induced bending of the carAB control region is slightly less pronounced than that of the purF operator. The PUR boxes of the carAB operon of E.coli and Salmonella typhimurium are unique in that they have a guanine residue at position eight. Interestingly, guanine at this position has been proposed to be extremely unfavorable on the basis of modeling and binding studies, as its exocyclic amino group would enter into a steric clash with the side-chain of lysine 55. To analyze the effect of guanine at position eight in the upstream half-site of the carAB operator we constructed the adenine derivative and assayed in vivo repressibility of P1 promoter activity and in vitroPurR binding to the mutant operator, and constructed a molecular model for the unusual lysine 55-guanine 8 interaction.

Bacterial Proteins↗

PubMed2005

Modeling allosteric regulation of de novo pyrimidine biosynthesis in Escherichia coli.

With the emergence of multifaceted bioinformatics-derived data, it is becoming possible to merge biochemical and physiological information to develop a new level of understanding of the metabolic complexity of the cell. The biosynthetic pathway of de novo pyrimidine nucleotide metabolism is an essential capability of all free-living cells, and it occupies a pivotal position relative to metabolic processes that are involved in the macromolecular synthesis of DNA, RNA and proteins, as well as energy production and cell division. This regulatory network in all enteric bacteria involves genetic, allosteric, and physiological control systems that need to be integrated into a coordinated set of metabolic checks and balances. Allosterically regulated pathways constitute an exciting and challenging biosynthetic system to be approached from a mathematical perspective. However, to date, a mathematical model quantifying the contribution of allostery in controlling the dynamics of metabolic pathways has not been proposed. In this study, a direct, rigorous mathematical model of the de novo biosynthesis of pyrimidine nucleotides is presented. We corroborate the simulations with experimental data available in the literature and validate it with derepression experiments done in our laboratory. The model is able to faithfully represent the dynamic changes in the intracellular nucleotide pools that occur during metabolic transitions of the de novo pyrimidine biosynthetic pathway and represents a step forward in understanding the role of allosteric regulation in metabolic control.

Allosteric Regulation↗

PubMed2005

Visible light (>395 nm) causes micronuclei formation in mammalian cells without generation of cyclobutane pyrimidine dimers.

Solar radiation gives rise to DNA damage in mammalian cells not only directly by excitation of DNA, which generates predominantly pyrimidine dimers, but also indirectly by the excitation of endogenous photosensitizers, which causes oxidative DNA modifications. The latter mechanism has a low quantum yield, but it is the only one proceeding in the visible range of the spectrum. To investigate its relevance for the genotoxicity of sunlight, we have analysed the generation of micronuclei associated with the induction of oxidative DNA damage by visible light in melanoma cells and primary human skin fibroblasts. Similar yields of light-induced oxidative DNA base modifications sensitive to the repair glycosylase Fpg (7,8-dihydro-8-oxoguanine and other oxidative purine modifications) were observed in the normal fibroblasts and the malignant melanoma cells of the same donor. When irradiations were carried out at intervals to compensate for a photodecomposition of the endogenous chromophore, a significant generation of micronuclei was observed in both cell types. Cyclobutane pyrimidine dimers could be excluded to be responsible for the micronuclei induction at wavelengths >395 nm. Experiments with a cut-off filter indicate that the ratio of pyrimidine dimers and Fpg-sensitive oxidative modifications in irradiated cells not only reflects the relative contributions of direct and indirect mechanisms, but is also similar to the ratio by which the two mechanisms contribute to the generation of the micronuclei. The results suggest that indirectly generated oxidative DNA modifications can contribute significantly to the adverse effects of sunlight.

Animals↗

PubMed2006

C. elegans pharyngeal morphogenesis requires both de novo synthesis of pyrimidines and synthesis of heparan sulfate proteoglycans.

The C. elegans pharynx undergoes elongation and morphogenesis to its characteristic bi-lobed shape between the 2- and 3-fold stages of embryogenesis. During this period, the pharyngeal muscles and marginal cells forming the isthmus between the anterior and posterior pharyngeal bulbs elongate and narrow. We have identified the spontaneous mutant pyr-1(cu8) exhibiting defective pharyngeal isthmus elongation, cytoskeletal organization defects, and maternal effect lethality. pyr-1 encodes CAD, a trifunctional enzyme required for de novo pyrimidine synthesis, and pyr-1(cu8) mutants are rescued by supplying exogenous pyrimidines. Similar pharyngeal defects and maternal effect lethality were found in sqv-1, sqv-8, rib-1 and rib-2 mutants, which affect enzymes involved in heparan sulfate proteoglycan (HSPG) synthesis. rib-1 mutant lethality was enhanced in a pyr-1 mutant background, indicating that HSPG synthesis is very sensitive to decreased pyrimidine pools, and HS disaccharides are moderately decreased in both rib-1 and pyr-1 mutants. We hypothesize that HSPGs are necessary for pharyngeal isthmus elongation, and pyr-1 functions upstream of proteoglycan synthesizing enzymes by providing precursors of UDP-sugars essential for HSPG synthesis.

Amino Acid Sequence↗

PubMed1968

Evidence for excision of ultraviolet-induced pyrimidine dimers from the DNA of human cells in vitro.

Within 12-24 hr after human cells were irradiated with ultraviolet light, approximately 50% of the ultraviolet-induced pyrimidine dimers were lost from the DNA. Pyrimidine dimers were found in the TCA-soluble fraction of ultraviolet-irradiated cells at 24 hr. Excess thymidine, caffeine, or hydroxyurea had no effect on the loss of pyrimidine dimers from the DNA of ultraviolet-irradiated cells.

Amnion↗

PubMed1998

Synthesis and in vitro antitumor activity of some amino-deoxy 7-hexofuranosylpyrrolo[2,3-d]pyrimidines.

7-(6-amino-6-deoxy-beta-D-glucofuranosyl)-5-cyanopyrrolo[2,3 -d]pyrimidine (22) and 7-(3-amino-methyl-3-deoxy-beta-D-allofuranosyl)-5- cyanopyrrolo[2,3-d]pyrimidine (28) were synthesized by sequentially coupling silylated 4-amino-6-bromo-5- cyanopyrrolo[2,3-d]pyrimidine with the corresponding protected sugars 9 and 17, followed by deblocking and catalytic hydrogenation. Conversion of the 5-nitrile in 22 and 28 into a carboxamide gave the corresponding sangivamycin derivatives 23 and 29. Whereas 5'-aminomethyl nucleosides 22 and 23 inhibited the growth of four different human tumor cell lines at microM concentrations, the 3'-aminomethyl analogs 28 and 29 were much less active against these cells.

Antibiotics, Antineoplastic↗

PubMed2003

Purine and pyrimidine metabolites in children's urine.

Various enzyme defects in the metabolic pathways of purines and pyrimidines are known, which result in different diseases occurring in children. They mainly affect kidney function, central nervous system, immunological and blood system. For example, complete deficiency of HPRT (hypoxanthine-guanine-phosphoribosyl-transferase) causes the Lesch Nyhan syndrome, which is characterized by hyperuricemia, mental retardation, choreoathetosis and compulsive self-mutilation. XDH deficiency (xanthine-dehydrogenase) causes in arthropathia and myopathia. For screening for these and other enzyme defects, urinary purine and pyrimidine excretion is considered a simple diagnostic tool. The purpose of the present study was to establish a reverse phase HPLC screening method for urinary purines and pyrimidines and to establish age related reference ranges in children for the urinary excretion of orotic acid, uracile, pseudouridine, uric acid, hypoxanthine, xanthine, thymine, 7-methylguanine, inosine, guanosine and adenosine.

Adolescent↗