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PubMed1994

Synthesis of nucleosides of 5,7-disubstituted pyrido [2,3-d] pyrimidines and their antibacterial activity.

Synthesis of 4-amino-5,7-diphenyl-1-(beta-D-ribofuranosyl)pyrido[2,3-d] pyrimidin-2-ones nucleoside, 4-amino-5,7-disubstituted-1-(beta-D-ribofuranosyl) pyrido [2,3-d] pyrimidin-2-thiones nucleosides, 2-thioxo-3,5,7-triphenyl-1- (beta-D-ribofuranosyl) pyrido [2,3-d] pyrimidin-4 (3H) ones nucleoside and 3,5,7-triphenyl-1-(beta-D-ribofuranosyl) pyrido [2,3-d] pyrimidin-2,4 (3H) diones nucleoside have been reported. The elemental analyses, IR and 1H NMR spectral data confirm the structure of the compounds. The synthesized nucleosides have been tested for antibacterial activity and found to be more active than the pyrido [2,3-d] pyrimidines.

Anti-Bacterial Agents↗

PubMed2002

Regulation of pyrimidine synthesis in Pseudomonas mendocina.

Regulation of the de novo pyrimidine biosynthetic enzymes in the bacterium Pseudomonas mendocina was examined when its cells were grown on succinate as a carbon source. When P. mendocina was grown in the presence of orotic acid or uracil, the de novo enzyme activities were depressed with dihydroorotase activity being significantly depressed after uracil addition. Following pyrimidine limitation of a uracil auxotroph of P. mendocina deficient for orotate phosphoribosyltransferase activity, the pyrimidine biosynthetic pathway enzyme activities were affected indicating possible regulation at the level of enzyme synthesis. Of the de novo pathway enzymes assayed, dihydroorotate dehydrogenase exhibited the highest increase in its activity. The regulation of the pyrimidine biosynthetic pathway by pyrimidines in P. mendocina appeared similar to what was previously observed for the taxonomically-related species P. stutzeri.

Bacterial Proteins↗

PubMed2004

Control of pyrimidine biosynthesis in "Pseudomonas alkanolytica" ATCC 21034.

The control of de novo pyrimidine biosynthesis in the industrially important patent strain "Pseudomonas alkanolytica" ATCC 21034 was investigated. Uracil supplementation of succinate-grown "P. alkanolytica" cells produced the greatest depression of the de novo pyrimidine biosynthetic pathway enzyme activities. After the pyrimidine limitation of a "P. alkanolytica" orotate phosphoribosyltransferase mutant strain grown on succinate, the pyrimidine biosynthetic pathway enzyme activities were derepressed. The pyrimidine biosynthetic pathway enzyme aspartate transcarbamoylase in "P. alkanolytica" was inhibited by pyrophosphate, cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP), and guanosine 5'-triphosphate (GTP).

Aspartate Carbamoyltransferase↗

PubMed1995

carP, involved in pyrimidine regulation of the Escherichia coli carbamoylphosphate synthetase operon encodes a sequence-specific DNA-binding protein identical to XerB and PepA, also required for resolution of ColEI multimers.

The carP gene involved in pyrimidine-specific regulation of the upstream P1 promoter of the Escherichia coli carAB operon has been cloned in vivo on a mini-Mu replicon, sequenced and shown to be identical to the xerB (pepA) gene encoding aminopeptidase A, a protein also involved in the Xer-mediated site-specific recombination at ColEI cer. The trans-dominant allele carP6 was cloned as well and shown to bear a single G-->A transition that converts the TGG codon (Trp473) into a TAG amber stop codon. The truncated mutant protein, missing the 31 C-terminal amino acid residues, was shown to be partially active; in the multicopy state the carP6 allele can restore pyrimidine repressibility of the carAB promoter P1. The trans-dominant character of the single copy carP6 allele was found to be suppressed in the presence of multiple copies of the wild-type gene. The carP (pepA) control region was sequenced and transcription shown to be initiated at three promoters, the most upstream one of which was shown to be subject to negative autoregulation. The aminopeptidase activity of CarP (PepA) was found to be dispensable for its role in pyrimidine-mediated repression of carAB transcription. CarP (PepA) was shown to be a sequence-specific DNA-binding protein that does not require, at least not in vitro, any pyrimidine cofactor to bind to the DNA. Mobility-shift and DNase I footprinting experiments have revealed a specific binding of purified CarP (PepA) to two sites in each one of the control regions of the E. coli and Salmonella typhimurium carAB operons and to a single site in the carP (pepA) control region. We propose that integration host factor and CarP/PepA-induced structural modifications in the carAB control region cause conformational changes required to assemble a pyrimidine-specific nucleo-protein regulatory complex.

Amino Acid Sequence↗

PubMed1986

The repair of pyrimidine dimers via a DNA-glycosylase mechanism.

The "UV endonuclease" isolated either from M. luteus or bacteriophage T4 infected E. coli (the denV gene product) consists of two enzymatic activities on a single polypeptide chain: a pyrimidine dimer-DNA glycosylase and an AP endonuclease. The repair of pyrimidine dimers by this enzyme is initiated by the cleavage of the N-glycosylic bond of the 5' pyrimidine of the dimer that leaves the cyclobutane dimer still attached to the DNA through the N-glycosylic bond of the 3' pyrimidine of the dimer. This reaction results in the formation of an apyrimidinic site in the DNA. The second step in this repair pathway is the endonucleolytic cleavage of the DNA 3' to the AP site by the associated AP endonuclease. As a result, the nicked DNA contains DNA damage on both sides of the incision site: an apyrimidinic moiety on the 3' end and a thymine-thymidylate dimer on the 5' end. The enzymes prefer double stranded DNA over single stranded DNA, and thymine over cytosine at the 5' position of the dimer. The AP endonuclease activity prefers the AP site created by the pyrimidine dimer-DNA glycosylase on UV irradiated DNA over either apurinic or apyrimidinic DNA. This repair mechanism appears to be operative in vivo since DNA intermediates containing thymine-thymidylate dimer sites have been detected in UV irradiated T4 infected E. coli and in UV irradiated M. luteus. The cloned denV gene partially complements the UV repair deficient uvr A, B, C strains of E. coli.

Cloning, Molecular↗

PubMed1987

Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis.

The effect of high concentrations of exogenous dCyd on the growth inhibitory properties of several inhibitors of de novo pyrimidine biosynthesis (dThd, 3-DAU, PALA, PF) was examined in three cultured human leukemic cell lines (HL-60, K-562, KG-1), and a dCyd kinase-deficient, Ara-C-resistant variant (HL-60/Ara-C). In the presence of dCyd concentrations (10(-3) M), far exceeding normal human plasma levels (0.5 to 4.0 X 10(6) M), substantial but partial reversal of pyrimidine antagonist-mediated growth inhibition and restoration of intracellular dCTP levels was noted in all cell types except HL-60/Ara-C. When high concentrations of dCyd (10(-3) M) were combined with low levels of uridine or cytidine (10(-5) M), full restoration of growth was observed in sensitive cell lines. When exposed to supraphysiologic concentrations of dCyd, HL-60/Ara-C cells were more sensitive to the growth inhibitory effects of pyrimidine antagonists than parent HL-60 cells; this phenomenon was maximal at 10(-4) M dCyd and was not observed in the presence of dCyd concentrations of 10(-6) M or lower. These studies suggest that in the presence of low concentrations of uridine or cytidine, perturbations in intracellular dCTP pools may play a critical role in determining the in vitro antiproliferative response of human leukemic myeloid cells to diverse inhibitors of de novo pyrimidine biosynthesis. They also raise the possibility that modulation of exogenous dCyd concentrations may improve the therapeutic efficacy of pyrimidine antagonists toward certain salvage pathway-deficient, drug-resistant leukemic cells.

3-Deazauridine↗

PubMed1994

Control of the pyrimidine biosynthetic pathway in Pseudomonas pseudoalcaligenes.

The five de novo enzyme activities unique to the pyrimidine biosynthetic pathway were found to be present in Pseudomonas pseudoalcaligenes ATCC 17440. A mutant strain with 31-fold reduced orotate phosphoribosyltransferase (encoded by pyrE) activity was isolated that exhibited a pyrimidine requirement for uracil or cytosine. Uptake of the nucleosides uridine or cytidine by wild-type or mutant cells was not detectable; explaining the inability of the mutant strain to utilize either nucleoside to satisfy its pyrimidine requirement. When the wild-type strain was grown in the presence of uracil, the activities of the five de novo enzymes were depressed. Pyrimidine limitation of the mutant strain led to the increase in aspartate transcarbamoylase and dihydroorotate dehydrogenase activities by more than 3-fold, and dihydroorotase and orotidine 5'-monophosphate decarboxylase activities about 1.5-fold, as compared to growth with excess uracil. It appeared that the syntheses of the de novo enzymes were regulated by pyrimidines. In vitro regulation of aspartate transcarbamoylase activity in P. pseudoalcaligenes ATCC 17440 was investigated using saturating substrate concentrations; transcarbamoylase activity was inhibited by Pi, PPi, uridine ribonucleotides, ADP, ATP, GDP, GTP, CDP, and CTP.

Aspartate Carbamoyltransferase↗

PubMed1990

Regulation of pyrimidine biosynthesis in Pseudomonas cepacia.

Pyrimidine biosynthesis was investigated in Pseudomonas cepacia ATCC 17759. The presence of the de novo pyrimidine biosynthetic pathway enzyme activities was confirmed in this strain. Following transposon mutagenesis of the wild-type cells, a mutant strain deficient for orotidine 5'-monophosphate decarboxylase activity (pyrF) was isolated. Uracil, cytosine or uridine supported the growth of this mutant. Uracil addition to minimal medium cultures of the wild-type strain diminished the levels of the de novo pyrimidine biosynthetic enzyme activities, while pyrimidine limitation of the mutant cells increased those de novo enzyme activities measured. It was concluded that regulation of pyrimidine biosynthesis at the level of enzyme synthesis in P. cepacia was present. Aspartate transcarbamoylase activity was found to be regulated in the wild-type cells. Its activity was shown to be controlled in vitro by inorganic pyrophosphate, adenosine 5'-triphosphate and uridine 5'-phosphate.

Aspartate Carbamoyltransferase↗

PubMed1983

Identification of a trans-acting regulatory factor involved in the control of the pyrimidine pathway in E. coli.

A pyrimidine auxotroph of Escherichia coli was isolated which contained a defect in its ability to synthesize both oroate phosphoribosyl transferase, the product of the gene pyrE, and orotidine monophosphate decarboxylase, product of the gene pyrF. A single location on the E. coli linkage map was found to be responsible for the loss of both enzyme activities. This gene was located near cysE at 80.55 min by a combination of Hfr crosses and P1 transductions. The pyrimidine requirement was also corrected by episome F'140 which was found not to carry any pyrimidine structural genes. These data confirm the existence of a new gene, pyrS, unlinked to any previously mapped pyrimidine structural gene, responsible for partial control of pyrimidine biosynthesis. A spontaneous revertant of the mutant strain was also identified which displayed constitutive levels of aspartate transcarbamylase, dihydroorotase, dihydroorotate dehydrogenase, orotidine monophosphate decarboxylase, and limited levels of orotate phosphoribosyl transferase. A model is proposed in which the pyrS gene product is an activator protein, necessary for the transcription of the pyrE and pyrF genes. This activator protein is nonfunctional in the original mutant strain, and partially functional in the revertant strain. The data presented here cannot rule out an alternative mechanism involving a repressor.

Escherichia coli↗

PubMed1990

Expression of key enzymes of purine and pyrimidine metabolism in a hepatocyte-derived cell line at different phases of the growth cycle.

The effect of growth phase on enzymatic activities of the de novo and salvage pathways for purine and pyrimidine nucleotide synthesis was studied in a hepatocyte-derived cell line from the rat. The cells were in lag phase after plating for 36 h; log phase started at 48 h and persisted up to 120 h of culture. Then the cells stopped growing and entered into plateau phase (144 h). In non-proliferating cells (144 h of culture) the basal activities of the enzymes of purine de novo biosynthesis were 1.7- to 6.8-fold higher than in normal rat liver, those of pyrimidine de novo synthesis showed 0.6- to 30-fold increase in activity. The purine salvage enzymes were unchanged, and the pyrimidine salvage enzymes were 3.1- to 7.4-fold higher compared to normal liver. During the growth cycle all enzymes except the purine salvage enzymes, which did not change, showed a peak in activity at 72 h of culture (log phase). The increase in activity in log phase compared to plateau phase was 1.3- to 2.4-fold for purine de novo synthetic enzymes, 1.1- to 2.4-fold for pyrimidine de novo enzymes, and 1.4- to 4.7-fold for pyrimidine salvage enzymes. The specific activities of the enzymes in exponentially growing cells were comparable either to that in 24-h regenerating liver, or to that in hepatomas of low or medium growth rate. It was concluded that the enzymatic pattern and metabolic state of the cells shared some features with regenerating liver, others with tumors, although they were not tumorigenic after transplantation into athymic nude mice.

Animals↗

PubMed2004

Pathways of pyrimidine salvage in Streptomyces.

Using 5-fluoropyrimidine analogues, high-performance liquid chromatography (HPLC), and the feeding of pyrimidine compounds to pyrimidine auxotrophs, the pathways for salvage of exogenous pyrimidine nucleosides and bases in Streptomyces were established. Selection for resistance to the analogues resulted in the isolation of strains of S. griseus lacking the following enzyme activities: uracil phosphoribosyltransferase (upp) and cytidine deaminase (cdd). The conversion of substrates in the pathway was followed using reverse-phase HPLC. The strains deficient in salvage enzymes were also verified by this method. In addition, feeding of exogenous pyrimidines to strains lacking the biosynthetic pathway confirmed the salvage pathway. Data from the analogue, HPLC, and feeding experiments showed that Streptomyces recycles the pyrimidine base uracil, as well as the nucleosides uridine and cytidine. Cytosine is not recycled due to a lack of cytosine deaminase.

Chromatography, High Pressure Liquid↗

PubMed1979

Nucleoside deoxyribosyltransferase-II from Lactobacillus helveticus Substrate specificity studied. Pyrimidine bases as acceptors.

The nucleoside deoxyribosyltransferase (nucleoside:purine (pyrimidine) deoxyribosyltransferase, EC 2.4.2.6) fraction catalyzing specifically the transfer of the deoxyribosyl moiety from a purine (or a pyrimidine) to a pyrimidine (or a purine) exhibits a broad specificity for the acceptor base. With a pyrimidine base as the acceptor a -OH or -SH group adjacent to the N-1 atom is essential. A substituent on position 6 hinders the reaction. On positions 4 and 5 various substituent were found to influence the reaction rate and some of them give non-competent substrates. A few anomalous cases are also discussed in relation with the role of N-3. Deoxyribonucleosides can also be obtained with non-pyrimidine rings.

Catalysis↗

PubMed1977

Structure of animal mitochondrial DNA (base composition, pyrimidine clusters, character of methylation).

Base composition, content of pyrimidine isopliths and methylation degree of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) from various vertebrates and protozoon Crithidia oncopelti have been studied. mtDNAs from mammals (ox, rat) do not differ in fact in the G + C content from the respective nDNA. The G + C content in mtDNA from fishes (sheat-fish) and birds (duck, chicken) is 1.5--2.5 mol % higher than in the respective nDNA. Kinetoplast DNA (kDNA) from Crithidia oncopelti (G + C = 42.9 mol %) differs significantly in base composition from nDNA (G + C 51.3 mol%). All the mtDNA and kDNA studied differ from the respective nDNA by a lower degree of pyrimidine clustering. The amount of mono- and dipyrimidine fragments in mtDNA is more than 30 mol %, whereas in nDNA it does not exceed 23 mol %. The quantity of long pyrimidine clusters (hexa- and others) is 2--4 times lower in mtDNA than in nDNA. The lower degree of clustering of pyrimidine nucleotides seems to be a specific feature of all the mtDNA studied. This may be indicative of common traits in the organization and origin of mtDNA. All mtDNA of vertebrates contain 5-methylcytosine as "minor" base (1.5--3.15 mol %) and surpass by 1.5--2 times the respective nDNA in the methylation degree. It has been found that in animals mtDNA is species specific as far as the 5-methylcytosine content is concerned. mtDNA of beef heart differs significantly from nDNA in the mode of 5-methylcytosine distribution in pyrimidine isopliths, which may indicate that methylation specificity of nuclear and mitochondrial DNA is not the same. In mitochondria and nuclei of rat liver certain DNA-methylase activity has been detected, which provides in vitro the methylation of cytosine residues both in homologbous DNA and various heterologous DNAs. Specificity of methylation in vitro of cytosine residues in one and the same heterologous DNA from Escherichia coli B with nuclear and mitochondrial enzymes is different. Mitochondrial enzyme methylates cytosine residues chiefly in mono-, whereas nuclear enzyme, in di- and tripyrimidine fragments.

Animals↗

PubMed1989

Pyrrolo[2,3-d]pyrimidines as inhibitors of cAMP-phosphodiesterase. Structure-activity relationship.

The effects of pyrrolo[2,3-d]pyrimidine compounds (7-desazapurines) on cAMP hydrolyzing, calmodulin dependent and calmodulin independent phosphodiesterase were studied. Phosphodiesterase inhibition depended on the chemical nature of substituents attached to the pyrrolo-pyrimidine-nucleus at positions 2, 4, 5, 6 and 7. Among a total of 28 compounds tested, the 4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dicarbaldehyde (9) was the most potent inhibitor of phosphodiesterase activity (IC50 = 16 microM). In addition to the 5,6-disubstitution, position 2 of the pyrrolo-pyrimidine derivatives had to be unsubstituted and position 4 had to bear an amino-group for an optimal inhibitory effect. Calmodulin dependent and calmodulin independent isozymes were affected to the same extent. Inhibition of PDE activity was reversible upon removal of the pyrrolo-pyrimidine derivative 9 and non-competitive with respect to cAMP (Ki = 27 microM).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1975

Radiation-sensitive pyrimidine auxotrophs of Ustilago maydis. I. Isolation and characterization of mutants.

The relationship between UV sensitivity and pyrimidine auxotrophy has been examined. Fourteen pyrimidine-requiring mutants have been classified on the basis of genetic complementation and utilization of biosynthetic intermediates and have been assigned to at least four loci. All the mutants studied were sensitive to UV, although the degree of sensitivity varied both between loci and amongst alleles at the same locus. A double mutant strain carrying pyrimidine mutants at two loci was only as sensitive to UV as the more sensitive of the singles. This suggests that both mutants are deficient in the same repair mechanism. Suppressor mutations which restored endogenous pyrimidine biosynthesis were isolated. These suppressors restored UV resistance in the presence of the original mutation. The results indicate that the UV sensitivity of these mutants is a direct result of pyrimidine auxotrophy and not to any secondary properties of the mutants.

Alleles↗

PubMed1991

Pyrimidine catabolism in Pseudomonas aeruginosa.

Pyrimidine catabolism in Pseudomonas aeruginosa was investigated. It was found that the pyrimidine bases uracil and thymidine as well as their respective reductive catabolic products could be utilized as sole sources of nitrogen. Reductive degradation of the pyrimidine bases was noted. The reductive catabolic pathway enzymes dihydropyrimidine dehydrogenase, dihydropyrimidinase and N-carbamoyl-beta-alanine amidohydrolase were all detected in minimal medium grown cells. Induction of pyrimidine catabolism by uracil was observed in this pseudomonad. Pyrimidine degradation in P. aeruginosa was not subject to catabolite repression.

Amidohydrolases↗

PubMed1991

Evidence for defective repair of cyclobutane pyrimidine dimers with normal repair of other DNA photoproducts in a transcriptionally active gene transfected into Cockayne syndrome cells.

Cockayne syndrome (CS) and xeroderma pigmentosum (XP), autosomal recessive diseases with clinical and cellular hypersensitivity to UV radiation, differ in ability to repair UV DNA photoproducts in their overall genome: normal repair in CS, defective repair in XP. In order to characterize a DNA repair defect in an active gene in CS, we measured the capacity of cells from patients with CS and XP to reactivate 2 major types of UV-induced DNA damage, photoreactivatable (i.e., cyclobutane pyrimidine dimers) and non-photoreactivatable (primarily pyrimidine-(6-4)pyrimidone photoproducts), in the actively transcribing chloramphenicol acetyltransferase (cat) gene of the plasmid expression vector pRSV-cat. Epstein-Barr virus-transformed lymphoblast lines from 4 normal persons and from 3 patients with CS and from two with XP were transiently transfected with the plasmid, and the cat activity in cell extracts was determined. When the cells were transfected with UV-irradiated plasmid, expression was abnormally decreased in both the CS and XP cells. When the cyclobutane pyrimidine dimers in the UV-irradiated plasmid were removed by photoreactivation prior to transfection, cat expression in the CS, but not in the XP, lines reached normal levels. These data imply that both the XP and CS cells are unable to repair normally the cyclobutane pyrimidine dimer photoproducts which block transcription of cat. However, the CS, but not XP, cells can repair normally the other UV-induced photoproducts which block transcription. The ability of CS, but not XP, cells to repair these non-dimer photoproducts indicates that the active gene repair mechanism treats the cyclobutane pyrimidine dimer differently from the non-dimer photoproducts.

Cell Line↗

PubMed2005

Synthesis, anti-inflammatory and analgesic activities evaluation of some mono, bi and tricyclic pyrimidine derivatives.

3-Aminobenzonitrile and 2-amino-4-phenyl thiazole on condensation with 4-isothiocyanato-4-methyl pentane-2-one gave condensed monocyclic pyrimidine derivatives 1 and 2, 3, respectively. Condensation of 3-aminopropyl imidazole with 3-isothiocyantobutanal gave condensed monocyclic pyrimidine derivative 4. Bicyclic pyrimidine derivatives 5a and 5b have been synthesized by the condensation of diaminomaleonitrile with 4-isothiocyanto-4-methylpentane-2-one and 3-isothiocyanatobutanal, respectively. Condensation of 4-isothiocyanato-4-methyl pentane-2-one with 2,3-diaminopropionic acid hydrochloride yielded another bicyclic compound 7. 4-Isothiocyanato-4-methyl pentane-2-one, 3-isothiocyanatobutanal and 4-isothiocyanatobutan-2-one on condensation with 2-amino-4-nitro phenol gave tricyclic pyrimidine derivatives 8a, 8b and 8c, respectively. Structures of all the synthesized pyrimidine derivatives are supported by correct IR, 1H NMR and mass spectral data. The anti-inflammatory activity evaluation was carried out using carrageenin-induced paw oedema assay, and compounds 1, 3 and 5b exhibited good anti-inflammatory activity, that is, 27.9, 34.5 and 34.3% at 50 mg/kg po, respectively. Analgesic activity evaluation was carried out using phenylquinone writhing assay and compounds 5a, 5b and 8b showed good analgesic activity, that is, 50, 70 and 50% at 50 mg/kg po, respectively.

Analgesics↗