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PubMed1972

Induction of phenylalanine ammonia lyase and pisatin by photosensitive psoralen compounds.

The psoralen compounds, xanthotoxin and 4,5', 8-trimethylpsoralen, when activated, increased phenylalanine ammonia lyase (PAL) activity and the synthesis of pisatin in excised pea pods. Pods presoaked 1 hr with 4,5',8-trimethylpsoralen and then irradiated 4 minutes with 366 nanometer ultraviolet light had twice as much PAL activity 3 hours after irradiation and 12 times as much PAL activity 20 hours after irradiation as the pods of the water-treated control. Increases in PAL activity and pisatin synthesis were not obtained with 4,5',8-trimethylpsoralen, xanthotoxin, or 366 nanometer light treatment alone. 4,5',8-Trimethylpsoralen in combination with the irradiation treatment (366 nanometers) enhanced the rate at which l-leucine is incorporated into various fractions of soluble proteins in excised pods 8 hours after treatment. This treatment decreased the rate at which orotic acid is incorporated into RNA. The increase in PAL activity induced by irradiated psoralens was prevented when 6-methylpurine (0.5 milligram per milliliter) or cycloheximide (10 micrograms per milliliter) was applied immediately following the irradiation period. Possible functions of psoralen compounds in plants are discussed.

Journal Article↗
PubMed1978

Pyrimidine Metabolism in Lemna minor: I. Functional Compartmentation of Chloroplast Pyrimidine Metabolism in a Higher Plant.

Cytidine deoxyriboside (Cdr), uridine deoxyriboside (Udr), and guanosine deoxyriboside (Gdr), induce quantitative bleaching of the fronds of Lemna minor (duckweed) during growth in continuous light on photoheterotrophic medium. Cdr-induced bleaching is not accompanied by a reduction in frond multiplication rate, but Udr- and Gdr-induced bleaching is. Bleaching by Cdr is fully prevented by thymidine (Tdr), cytidine (Cr), or uridine (Ur), but not by orotic acid (OA) which itself inhibits growth. Bleaching by Udr is not antagonized by Tdr, Cdr, Cr, Ur, or OA. The ability of Cdr to induce phenocopies of chlorophyll-deficient mutants in the absence of effect on growth rate is interpreted as indicating a functional compartmentation of pyrimidine metabolism between chloroplast and whole cell. On the assumption that Cdr induces bleaching by regulating the biosynthesis of deoxynucleoside triphosphates, and in analogy with the antagonism of fluorodeoxyuridine effects on growth by Tdr, Cr, or Ur, the suggestion is made that deoxycytidine is converted to thymidylate by a step other than that utilizing thymidylate synthetase.

Journal Article↗
PubMed2005

Comparative genome hybridization reveals widespread aneuploidy in Candida albicans laboratory strains.

Clinical strains of Candida albicans are highly tolerant of aneuploidies and other genome rearrangements. We have used comparative genome hybridization (CGH), in an array format, to analyse the copy number of over 6000 open reading frames (ORFs) in the genomic DNA of C. albicans laboratory strains carrying one (CAI-4) to three (BWP17) auxotrophies. We find that during disruption of the HIS1 locus all genes telomeric to HIS1 were deleted and telomeric repeats were added to a 9 nt sequence within the transforming DNA. This deletion occurred in approximately 10% of transformants analysed and was stably maintained through two additional rounds of transformation and counterselection of the transformation marker. In one example, the deletion was repaired, apparently via break-induced replication. Furthermore, all CAI-4 strains tested were trisomic for chromosome 2 although this trisomy appears to be unstable, as it is not detected in strains subsequently derived from CAI-4. Our data indicate CGH arrays can be used to detect monosomies and trisomies, to predict the sites of chromosome breaks, and to identify chromosomal aberrations that have not been detected with other approaches in C. albicans strains. Furthermore, they highlight the high level of genome instability in C. albicans laboratory strains exposed to the stress of transformation and counterselection on 5-fluoro-orotic acid.

Aneuploidy↗
PubMed1984

Partial ornithine transcarbamylase deficiency associated with recurrent hyperammonemia, lethargy and depressed sensorium.

A 6-year-old boy presented with recurrent coma associated with hyperammonemia and infection is reported. A liver biopsy revealed decreased ornithine transcarbamylase (OTC) activity (16% of normal). The enzymatic abnormality in the child is supported by the finding of elevated orotic acid excretion in his mother following a protein load, compatible with an X-linked pattern of inheritance. Since initiation of a dietary arginine supplement, the child has not had recurrent episodes of hyperammonemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed1975

Character of the stimulatory response of uridine kinase in rat livers to cycloheximide treatment.

Administration of cycloheximde to adult rats resulted in the enhancement of uridine kinase activity in the liver. The increase of enzyme activity was not affected by adrenal secretion or uptake of food. Actinomycin D, hydroxyurea and puromycin injected simultaneously with cycloheximide depressed the increase of enzyme activity. On the contrary, administration of 5-azacytidine following cycloheximide resulted in further enhancement of uridine kinase. While the half-time of template RNA for uridine kinase in control rat livers was 24 h, for cycloheximide-stimulated enzyme it was about 11 h. At higher dose levels cycloheximide leads to an increased incorporation of both uridine and orotic acid into liver RNA; however, this effect was not observed in the starved animals. The mechanism of action of cycloheximide is briefly mentioned.

Animals↗
PubMed1982

Enhancement of intracellular 5-phosphoribosyl 1-pyrophosphate levels as a major factor in the 6-azauridine-induced stimulation of carbamoyl phosphate synthesis in mouse spleen slices.

Brief exposure to 6-azauridine stimulates the production of carbamoyl phosphate for de novo pyrimidine biosynthesis in vitro in slices of haematopoietic spleen from anaemic mice (preceding paper). In studies of the underlying mechanism for this response we turned our attention to changes in the level of substrates and effectors for carbamoyl-phosphate synthetase II. Intermediates of the orotic acid pathway and 6-azauridine had little effect on the synthetase activity in vitro. 6-Azauridine 5'-monophosphate (6-AzaUMP) stimulated synthetase II, possibly in an allosteric manner. However, in view of the potency as an activator and the tissue levels, 6-azaUMP may be only partially responsible for the stimulation. Adenine nucleotide levels in the tissue showed only minor changes after brief exposure (15 min) to 6-azauridine. The level of UTP and UDP, potent inhibitors for synthetase II, showed no significant change. The level of 5-phosphoribosyl 1-pyrophosphate (PPRibP), a potent positive effector for the synthetase II, showed a more than 1.5-fold increase after 15 min. The relative importance of these factors was evaluated by assay of the synthetase, partially purified from mouse spleen, under simulated conditions in vitro. The results indicated that the enhanced level of PPRibP played a major role in increasing the production of carbamoyl phosphate. In Ehrlich ascites cells in vitro, where 6-azauridine did not increase carbamoyl phosphate production, the basal PPRibP level was high (range over 0.1 mM) and the changes in the level, brought about by the analogue, were relatively small.

Animals↗
PubMed1993

Metabolic characteristics of rat liver cytosolic 5SRNA.

5SRNA were purified from the cytosol, ribosomes, nucleoli and nucleoplasm of rat liver. The 5'-terminal and 3'-terminal sequences of these 5SRNA species were shown to be the same. The time course of changes in specific activities of these 5SRNA in rat liver, 20 min to 16 h after intraperitoneal injection of [14C]orotic acid, were investigated. The specific activity of cytosolic 5SRNA increased almost linearly for 3 h, without a lag, to a high value, then decreased rapidly. The specific activity of cytosolic 5SRNA was much higher than the specific activities of 5SRNA from the other cellular components over 45 min to 6 h after intraperitoneal injection, although at 20 min the specific activity was similar to that of nucleoplasmic 5SRNA. Thus, cytosolic 5SRNA of rat liver is characterized by a high rate of turnover, which was shown to be comparable to that of heterogeneous nuclear RNA. The specific activity of 5SRNA, 45 min to 6 h after intraperitoneal injection, was as follows; cytosolic > nucleoplasmic > nucleolar > ribosomal 5SRNA. The specific activity of nucleoplasmic RNA that migrated slightly slower than nucleoplasmic 5SRNA on PAGE was much higher than that of cytosolic 5SRNA or nucleoplasmic 5SRNA, and so may be the precursor of nucleoplasmic 5SRNA. Together, these results indicate that cytosolic 5SRNA is transferred from the nuclei to the cytosol immediately after maturation of the precursor of nucleoplasmic 5SRNA without entering the nucleoplasmic pool of 5SRNA.

Animals↗
PubMed1964

THE DEMONSTRATION OF THE SITE OF ACTION OF THE ANTIMETABOLITE DRUG 6-AZAURIDINE BY THE USE OF LEUCOCYTE CULTURES.

The ability of the lymphocyte cultured in vitro to transform and synthesize deoxyribonucleic has been utilized to locate the site of action of a new antimetabolite 6-azauridine which acts by inhibiting nucleic acid synthesis. The exact site can be demonstrated by incorporating into the cultures nucleotides occurring distal and proximal to the presumed site of action of 6-azauridine.

Antimetabolites↗
PubMed2002

Flumazenil responsive ornithine transcarbamylase deficiency encephalopathy: clinical and radiographic features.

A 22-year-old woman with a negative urine drug screen and somnolence rapidly reversed by intravenous flumazenil was found to have elevated ammonia levels and punctate calcifications of the subcortical frontal white matter. Abnormally high levels of orotic acid were found in serum and urine, confirming the diagnosis of ornithine transcarbamylase deficiency. Although computed tomography findings are non-specific, young patients with unexplained hyperammonemic states of somnolence reversed by flumazenil should be screened for this X-linked recessive metabolic disorder.

Adult↗
PubMed1996

Disruption of phospholipase B gene, PLB1, increases the survival of baker's yeast Torulaspora delbrueckii.

An uracil auxotrophic mutant of baker's yeast Torulaspora delbrueckii, which is resistant to 5-fluoro-orotic acid, was complemented by transformation with YEp24 which harbors 2 microns origin and URA3 derived from Saccharomyces cerevisiae. The phospholipase B in T. delbrueckii cells is active in both acidic and alkaline conditions. However, activity of phospholipase B gene (PLB1) in cells of disruption mutant (plb1:: URA3) was lost in both conditions, which indicates that all phospholipase B activity is encoded by a single gene (or a single polypeptide) in these yeast cells. Over-expression of PLB1 with YEp plasmid vector in T. delbrueckii cells showed approximately 2.5-fold increase in phospholipase B activity, comparing with that in wild-type cells. Cells of plb1 delta mutant showed increased survival when cells of plb1 delta mutant and wild-type strain were incubated in water at 30 degrees C. Cells of PLB1-over-expressed strain died rapidly even during the cultivation period, indicating that phospholipase B activity may be a determinant for the survival of this yeast.

Bread↗
PubMed1987

The transport of pyrimidines into tissue rings cut from rat small intestine.

1. At low concentrations (0.1 mM) the transport of uracil, 5-fluorouracil and thymine into jejunal tissue rings is an active process. 2. The transport of 5-fluorouracil into tissue rings cut from the duodenum and jejunum was greater than the transport into rings cut from the ileum. This difference was abolished by starving the rats for 48 h before the experiment. 3. The active transport can be abolished by replacing the Na+ in the incubation medium with either K+ or mannitol, or by increasing the concentration of the pyrimidine to 1.0 mM. 4. The accumulation of uracil or 5-fluorouracil into the jejunal rings was identical when determined by radioactive tracer or by high-performance liquid chromatography. 5. The apparent Michaelis constant (Km) for 5-fluorouracil transport into jejunal rings was 0.074 mM in the standard Na+ bicarbonate Krebs-Ringer solution and 0.394 mM in the K+-substituted bicarbonate Krebs-Ringer solution. 6. Both thymine and uracil inhibited the transport of 5-fluorouracil into jejunal tissue rings: however, cytosine and orotic acid did not.

Animals↗
PubMed1987

Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth.

Several of the new 4-quinolones significantly increase the incorporation of [3H]thymidine into the DNA of mitogen-stimulated human lymphocytes. This study suggests that ciprofloxacin inhibits de novo pyrimidine biosynthesis, thereby resulting in a compensatory increase in the uptake of pyrimidine precursors through salvage pathways, and that additional effects may affect eucaryotic cell growth. Incorporation of deoxyuridine, uridine, and orotic acid as well as thymidine was increased in the presence of ciprofloxacin, one of the antibacterially most active of the new 4-quinolones. In contrast, the uptake was decreased in very high concentrations of the drug. Culture in HAT (hypoxanthine, aminopterine, thymidine) medium, which blocks de novo thymidylate synthesis, abrogated the increase in [3H]thymidine incorporation induced by ciprofloxacin. Ciprofloxacin also failed to increase the uptake of [14C]hypoxanthine or leucine, indicating a selective effect on pyrimidine and not on purine nucleotide biosynthesis. N-(Phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine nucleotide biosynthesis, also increased [3H]thymidine incorporation in phytohemagglutinin-stimulated lymphocytes in a fashion similar to ciprofloxacin. The growth of several cell lines was partially inhibited by ciprofloxacin at 20 micrograms/ml and completely inhibited at 80 to 160 micrograms/ml. Growth inhibition by ciprofloxacin could not be restored by the addition of uridine to the medium. Chromosome breaks, gene amplification, or other genetic alterations could not be detected in human lymphocytes incubated with up to 25 micrograms of ciprofloxacin per ml.

Animals↗
PubMed2000

Factors affecting exocellular polysaccharide production by Lactobacillus delbrueckii subsp. bulgaricus grown in a chemically defined medium.

We developed a chemically defined medium (CDM) containing lactose or glucose as the carbon source that supports growth and exopolysaccharide (EPS) production of two strains of Lactobacillus delbrueckii subsp. bulgaricus. The factors found to affect EPS production in this medium were oxygen, pH, temperature, and medium constituents, such as orotic acid and the carbon source. EPS production was greatest during the stationary phase. Composition analysis of EPS isolated at different growth phases and produced under different fermentation conditions (varying carbon source or pH) revealed that the component sugars were the same. The EPS from strain L. delbrueckii subsp. bulgaricus CNRZ 1187 contained galactose and glucose, and that of strain L. delbrueckii subsp. bulgaricus CNRZ 416 contained galactose, glucose, and rhamnose. However, the relative proportions of the individual monosaccharides differed, suggesting that repeating unit structures can vary according to specific medium alterations. Under pH-controlled fermentation conditions, L. delbrueckii subsp. bulgaricus strains produced as much EPS in the CDM as in milk. Furthermore, the relative proportions of individual monosaccharides of EPS produced in pH-controlled CDM or in milk were very similar. The CDM we developed may be a useful model and an alternative to milk in studies of EPS production.

Culture Media↗
PubMed1981

Characterization of hemadsorption-negative mutants of Mycoplasma pneumoniae.

Previously isolated mutants of Mycoplasma pneumoniae incapable of hemadsorption were characterized with respect to specific protein content, tracheal ring attachment capability, and virulence for both in vitro and in vivo model systems. Two-dimensional gel electrophoresis revealed both quantitative and qualitative differences between the protein complements of two different mutant strains and that of the virulent parent strain. Studies of mycoplasma attachment to hamster tracheal rings in vitro demonstrated that only one of these mutant strains still possessed the ability to attach to the respiratory epithelium via neuraminidase-sensitive receptors. Measurement of [3H]orotic acid uptake in mycoplasma-infected tracheal rings indicated that infection with the hemadsorption-negative mutants resulted in only slight reductions of ribonucleic acid synthesis, similar to levels observed for tracheal rings infected with an avirulent strain of M. pneumoniae. The virulence potential of the two mutant strains was further investigated by utilizing the hamster model system. Both mutant strains were rapidly cleared from the lungs of infected animals and produced little or no microscopic pneumonia.

Animals↗
PubMed1971

Regulation and mechanism of phosphoribosylpyrophosphate synthetase: repression by end products.

Phosphoribosylpyrophosphate (PRPP) synthetase participates in the biosynthesis in bacteria of purine nucleotides, pyrimidine nucleotides, tryptophan, and histidine. The regulation of the synthesis of PRPP synthetase in Salmonella typhimurium was studied. Addition of end products to the growth medium, singly or in combination, resulted in small decreases in the specific activity of PRPP synthetase, but levels of the enzyme were never decreased to less than half of those found when the bacteria were grown on minimal medium. Growth of the bacteria on several different carbon sources or starvation for phosphate had little effect on the specific activity of PRPP synthetase. Over-production of histidine in a histidine regulatory mutant, which would be expected to result in a depletion of intracellular PRPP pools, did not alter PRPP synthetase specific activity. PRPP synthetase levels were examined in auxotrophic strains of S. typhimurium that had been starved for the end products of PRPP. In each case derepression of an enzyme in the biosynthetic pathway for the limiting end product was demonstrated. However, only alterations in the levels of pyrimidine bases in the culture medium brought about derepression and repression of PRPP synthetase. Excess pyrimidines do not completely repress the enzyme. Deprivation of exponentially growing cells for pyrimidines by growth of an auxotrophic mutant on media containing orotic acid, which enters the cells slowly, resulted in a 10-fold derepression of PRPP synthetase. Derepression of PRPP synthetase during uracil starvation was prevented by chloramphenicol. The PRPP synthetase activities of extracts from repressed and derepressed cells responded in identical fashion to heat inactivation, cellulose acetate electrophoresis at several pH values, and in kinetic experiments.

Adenine↗
PubMed1987

Genetic analysis of the 5-azacytidine sensitivity of Escherichia coli K-12.

DNA containing 5-azacytidine (5-azaC) has been shown to form stable detergent-resistant complexes with cytosine methylases. We reasoned that if 5-azaC treatment causes protein-DNA cross-links in vivo, then mutations in DNA repair and recombination genes may increase the sensitivity of a cell to 5-azaC. We found that although recA (defective) and lexA (induction-negative) mutants of Escherichia coli were very sensitive to the drug, mutations in uvrA and ung genes had little effect on cell lethality. The sensitivity of recA strains to 5-azaC was dose dependent and was enhanced by the overproduction of a DNA cytosine methylase in the cell. Unexpectedly, a strain of E. coli carrying a recA mutation and a deletion of the DNA cytosine methylase gene (dcm) was found to be significantly sensitive to 5-azaC. Study of mutations in the pyrimidine salvage pathway of E. coli suggests that direct phosphorylation of 5-azaC, rather than phosphorylation of its degradation products, is largely responsible for the lethal effects of the drug. The addition of uracil to the growth medium has little effect on cell lethality of recA mutants, but it partially reversed the inhibition of cell growth caused by 5-azaC. This reversal of the bacteriostatic effects of the drug could not be achieved by adding cytosine or orotic acid to the growth medium and required the presence of functional UMP-pyrophosphorylase (gene upp) in the cell.

Azacitidine↗