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PubMed1985

Effect of adenine, cytidine and guanosine on the expression of the SOS system in Escherichia coli.

Addition of cytidine or guanosine to UV-irradiated cells of a RecA+ strain of Escherichia coli did not produce any effect on the induction of two SOS functions: inhibition of cell division and expression of the umuC gene. Under the same conditions adenine gave a slight increase in the induction of these two responses. In a RecA441 mutant growing at 42 degrees C, both cytidine and guanosine inhibited these SOS functions, whereas adenine produced a large increase in their expression. Moreover, the ATP concentration of the RecA441 mutant at 42 degrees C showed a decrease which occurred earlier in the cells growing in the presence of cytidine or guanosine than in the absence of either compound. Adenine induced an increase of about three times the initial ATP concentration of this mutant at 42 degrees C which dropped quickly after 10 min. Neither cytidine nor guanosine increased the evolution of cellular ATP in UV-irradiated cells of the RecA+ strain, whereas adenine had only a slight positive effect. However, in UV-irradiated RecA+ cells with and without adenine, ATP levels dropped quickly to the initial value after 20 min. These data suggest that the influence of adenine, cytidine and guanosine on the expression of the RecA441 phenotype at 42 degrees C may be due to alteration of the cellular ATP concentration of this mutant.

Adenine↗
PubMed1985

On the mechanism of deoxyribonucleoside toxicity in human T-lymphoblastoid cells. Reversal of growth inhibition by addition of cytidine.

High levels of deoxyadenosine and deoxyguanosine in patients with inherited deficiency of either adenosine deaminase or purine-nucleoside phosphorylase, respectively, are considered to be responsible for the associated immunological disorder. The mechanism involves phosphorylation to the corresponding deoxyribonucleoside triphosphates which subsequently inhibit the CDP-reducing activity of ribonucleotide reductase. Addition of deoxycytidine protects cells from the cytotoxic effects of deoxyadenosine and deoxyguanosine by competition for phosphorylation and by replenishing dCTP, the apparent limiting DNA precursor. Addition of cytidine, but not uridine, led to a reversal of deoxyguanosine and thymidine growth inhibition, comparable to that obtained with deoxycytidine. Analysis of the intracellular nucleotide pools showed that increased levels of cytidine ribonucleotides were sufficient to overcome the inhibitory effects of dGTP and dTTP on CDP reduction, thereby circumventing a depletion of the dCTP pool. A partial reversal of deoxyadenosine toxicity was also obtained with addition of cytidine. In this case little change in the dCTP level was observed, but a decreased dGTP pool appeared to be correlated with growth inhibition. High cytidine ribonucleotide levels partially prevented this effect. The present results may encourage the use of cytidine in combination with deoxycytidine as a pharmacological regime in treatment of immunodeficiency disease associated with increased deoxyribonucleotide levels.

Cell Division↗
PubMed1974

Mutants of group D1 Salmonella carrying the somatic antigen of group A organisms: evidence for the lack of cytidine diphosphate paratose-2-epimerase activity.

The mutant strains of Salmonella durban that possessed O antigen 2, 12 of group A Salmonella were defective in the cytidine diphosphate paratose-2-epimerase activity. The enzyme preparation of the mutant strains catalyzed the conversion of cytidine diphosphate glucose into cytidine diphosphate paratose but not into cytidine diphosphate tyvelose. The defect in the epimerase activity was also confirmed by the use of purified cytidine diphosphate paratose as a substrate. The specificity of dideoxyhexosyl transferase catalyzing the formation of the group-specific determinant is discussed.

Agglutination Tests↗
PubMed2001

Regulation of transcription of the Bacillus subtilis pyrG gene, encoding cytidine triphosphate synthetase.

The B. subtilis pyrG gene, which encodes CTP synthetase, is located far from the pyrimidine biosynthetic operon on the chromosome and is independently regulated. The pyrG promoter and 5' leader were fused to lacZ and integrated into the chromosomes of several B. subtilis strains having mutations in genes of pyrimidine biosynthesis and salvage. These mutations allowed the intracellular pools of cytidine and uridine nucleotides to be manipulated by the composition of the growth medium. These experiments indicated that pyrG expression is repressed by cytidine nucleotides but is largely independent of uridine nucleotides. The start of pyrG transcription was mapped by primer extension to a position 178 nucleotides upstream of the translation initiation codon. A factor-independent termination hairpin lying between the pyrG promoter and its coding region is essential for regulation of pyrG expression. Primer-extended transcripts were equally abundant in repressed and derepressed cells when the primer bound upstream of the terminator, but they were much less abundant in repressed cells when the primer bound downstream of the terminator. Furthermore, deletion of the terminator from pyrG-lacZ fusions integrated into the chromosome yielded elevated levels of expression that was not repressible by cytidine. We suggest that cytidine repression of pyrG expression is mediated by an antitermination mechanism in which antitermination by a putative trans-acting protein is reduced by elevated levels of cytidine nucleotides. Conservation of sequences and secondary structural elements in the pyrG 5' leaders of several other gram-positive bacteria indicates that their pyrG genes are regulated by a similar mechanism.

5' Untranslated Regions↗
PubMed1984

Cytidine deaminase levels in cultured mammalian cell lines measured by the growth tests and enzyme assays.

We developed a test medium for cytidine deaminase in order to examine the distribution of this enzyme in cultured cell lines. The growth of various mammalian cell lines was tested in culture medium containing 2 microM pyrazofurin and 100 microM cytidine. Enzymological assays for the enzyme also were made spectrophotometrically with cell extracts. A good correlation was found between results of cell growth tests and the levels of enzyme activity. Twelve of twenty cell lines were killed in the test medium, but the remaining lines showed good growth. The levels of enzyme activities were lower in the former lines than in the latter. The critical level of enzyme activity required to support cell growth was approximately 30 units per mg protein. These findings indicate that culture medium containing 2 microM pyrazofurin and 100 microM cytidine serves as a test medium for cytidine deaminase. The possibility that the cytidine deaminase may be useful in determining the embryonic origin of cultured cell lines is discussed, based on the growth properties of various cultured cell lines in the test medium.

Amides↗
PubMedDate not supplied

Monospecific antibody against 5-methyl-cytidine for the structural analysis of nucleic acids.

Anti 5-methyl-cytidine antibodies might be useful agents for the detection and localization of 5-methyl-cytidine of nucleic acids, but only if the antibodies recognize this nucleoside with sufficient specificity. A conjugate containing 18 moles of 5-methyl-cytidine per mole of BSA was prepared and antibodies directed against this nucleoside hapten were produced by immunization of rabbits (as determined by gel diffusion in agar containing excessive amounts of the carrier). A slight crossreaction of cytidine-BSA was eliminated by adsorption on the cross-reacting antigen. Further purification of the antibodies was effected by chromatography on DEAE-Sephadex A-50 and a method for the rapid quantitation of the antibodies showed that 12.7% of the IgG protein are monospecific against 5-methyl-cytidine-BSA. Hydrolysis of antibodies with insolubilized papain produced monovalent Fab fragments which were identified by SDS-Disk-electrophoresis. A two stage method for cross linking the immunoproteins to ferritin by glutaraldehyde was used. The isolation of immunoferritin conjugates by Bio-Gel A 1.5 m column chromatography is described. The identification of the effluents was made by glycerin density gradient ultracentrifugation. The results were visualized by electron microscopy after the treatment of immunoferritin conjugates with (methylated and unmethylated) denaturated DNA, fractionation on the glycerine density gradient, and the spreading by a modification of drop technique.

Animals↗
PubMed2006

An overview of cytidine deaminases.

Enzymes that deaminate cytidine to uridine play an important role in a variety of pathways from bacteria to man. Ancestral members of this family were able to deaminate cytidine only in a mononucleotide or nucleoside context. Recently, a family of enzymes has been discovered with the ability to deaminate cytidines on RNA or DNA. The first member of this new family is APOBEC1, which deaminates apolipoprotein B messenger RNA to generate a premature stop codon. APOBEC1 has the conserved active site motif found in Escherichia coli cytidine deaminase. In addition, APOBEC1 has a unique motif containing 2 phenylalanine residues and an insert of 4 amino acid residues across the active site motif. This motif is present in APOBEC family members including activation-induced cytidine deaminase (AID), APOBEC2, and APOBEC3A through APOBEC3G. AID is essential for initiating class-switch recombination, somatic hypermutation, and gene conversion. The APOBEC3 family is unique to primates. APOBEC3G is able to protect cells from human immunodeficiency virus and other viral infections. This function is not unique to APOBEC3G; other APOBEC3 family members also have this ability. Overexpression of enzymes in this family can cause cancer, suggesting that the genes for the APOBEC family of proteins are proto-oncogenes. Recent advances in the understanding of the mechanism of action of this family are summarized in this review.

APOBEC Deaminases↗
PubMedDate not supplied

A homopolymer stretch composed of variable numbers of cytidine residues in the terminal repeats of infectious laryngotracheitis virus.

A homopolymer stretch composed of variable numbers of cytidine residues was found within the inverted terminal repeats of infectious laryngotracheitis virus (ILTV). A polymerase chain reaction procedure was developed to amplify a 750-bp fragment containing this homopolymer stretch. This fragment was then sequenced directly to determine the number of repeated cytidine residues in this homopolymer stretch, which could be used for strain differentiation. By this procedure, vaccine strains of tissue culture origin could be differentiated into two types: type I contains eight repeated cytidine residues, whereas type II contains 10 such residues. Vaccine strains of chicken embryo origin could also be divided into two types: type I contains mainly 11 repeated cytidine residues, whereas type II contains 15-21 such repeats. In comparison, two of the five field isolates examined contain 12-13 repeats; the other three field isolates contain 15-19 repeats, which were similar to the type II chicken-embryo-origin vaccines. The number of repeated cytidine residues described here could serve as a marker for the strain differentiation and epidemiologic study of ILTV.

Animals↗
PubMed1984

Effect of fasting on the metabolism of cytidine nucleotides in the liver of intact and alpha-hexachlorocyclohexane-treated rats.

The utilization of (2-14C)orotic acid for the synthesis of cytidine components of the acid-soluble extract and for the RNA cytosine is decreased in the liver of rats which fasted for 24 or 72 h. The depression of the specific activity of the cytidine components is greater in animals which received alpha-HCH during the 24-hour interval after removal of food than in the control group; by contrast, the specific activity of the cytidine components again increases in rats fasting for 72 h. Analogous changes also occurred in the specific activity of RNA cytosine. Both the (U-14C)cytidine uptake and its utilization for the synthesis of RNA cytosine are enhanced in fasting rats; the administration of alpha-HCH has a potentiating effect. The total content of cytidine components of the acidsoluble extract of 1 g of liver tissue is enhanced 24 h after the animals of the control and experimental group were deprived of food. There are no marked differences in the concentration of the uridine components. Fasting has an additive effect on the increase of cytochrome P-450 level in the alpha-HCH treated rats. Alpha-HCH = alpha-1,2,3,4,5,6-hexachlorocyclohexane.

Animals↗
PubMed1984

Purification and properties of cytidine deaminase from escherichia coli.

A convenient and efficient procedure for the purification of cytidine deaminase (EC 3.5.4.5) from Escherichia coli is reported. The key step involves adsorption of the enzyme from a crude ammonium sulfate fraction onto a cytidine-containing affinity resin, followed by elution with 0.5 M borate buffer. Subsequent chromatography on DEAE-Sepharose results in an overall 1690-fold purification, yielding enzyme with a specific activity of 118 units/mg. Cytidine deaminase has an apparent molecular weight of 54,000 as determined by gel filtration, whereas sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows a band at molecular weight 35,000. Cytidine deaminase is inhibited by 5-(chloromercuri)cytidine with kinetic behavior typical of active-site-directed inactivation, with KD = 0.09 mM and kinact = 1.25 min-1. The enzyme is protected against inactivation in the presence of substrate, and the inhibition is reversed with high concentrations of mercaptoethanol. This suggests that inactivation is the result of a mercaptide formation between the mercury and an active-site thiol.

Borates↗
PubMed1983

Palladium(II) complexes with cytidine-guanosine pair in DMSO.

Solutions containing nucleosides: cytidine and guanosine, and Pd(II) ion in dimethylsulphoxide have been investigated using 1H NMR method. It has been found that the glycylglycinate-palladium(II) complex reacts with cytidine through its N(3) nitrogen atom as the fourth donor for Pd(II) ion, and with guanosine which binds with Pd(II) through N(7) of purine ring. The primary binding site of cytidine-guanosine pair for the glycylglycinate-Pd(II) complex was N(7) of guanosine. However, in the reaction of PdCl2 with the cytidine-guanosine pair, equivalent binding sites were N(1) of guanosine and N(3) of cytidine giving CydN(3)-Pd-N(1)Guo ternary complex.

Binding Sites↗
PubMed1982

The influence of uridine and glutamine on cytidine transport and metabolism in rat brain primary cell culture.

The uptake of labelled cytidine from primary cell cultures from rat embryo brain has been examined in the presence of uridine and glutamine. When uridine and glutamine are incubated with cytidine at a ten-fold higher concentration cytidine uptake is stimulated noticeably but its conversion into cytidine nucleotides is inhibited. When equimolar concentrations of uridine and glutamine are used, both cytidine uptake and metabolism are noticeably increased. The results point to interesting interactions among nucleosides for their transport into living cells and their further utilization.

Animals↗
PubMed1980

Antitumor activity of cytidine dialdehyde and its effects on nucleotide and nucleic acid synthesis.

Cytidine dialdehyde inhibited the growth of leukemia L1210 cells in culture at a 50% inhibitory concentration of 3.5 X 10(-5) M and, when administered i.p. at 200 mg/kg daily for 5 days, increased the mean survival of L1210 tumor-bearing mice by up to 171%. Given by the s.c. or i.v. routes, the compound was ineffective. The ethanol adduct of cytidine dialdehyde, although inactive in cell culture, increased the mean survival of L1210 tumor-bearing mice by up to 225% when administered i.p. but was inactive upon s.c. administration. Exposure of L1210 cells in culture for 25 hr to cytidine dialdehyde at the 50% inhibitory concentration increased the ribonucleoside di- and triphosphate pools, slightly increased deoxyadenosine triphosphate, deoxythymidine triphosphate, and deoxyguanosine triphosphate pools, and caused a pronounced increase in the deoxycytidine triphosphate pool. As determined by the rate of pyrimidine precursor incorporation into nucleic acids, this concentration of drug showed no effect on RNA synthesis but caused a reduction in DNA synthesis to 53% of control. Exposure of L1210 cells for 3 to 6 hr to 10(-4) M cytidine dialdehyde, a concentration which inhibits growth completely, effected an increase in the ribonucleoside di- and triphosphate pools and a rapid decrease of the deoxythymidine triphosphate pool. The deoxycytidine triphosphate and deoxyguanosine triphosphate pools decreased more slowly, and the deoxyadenosine triphosphate pool remained slightly elevated. Analysis of the rate of substrate incorporation into nucleic acids showed that this concentration of drug produced an 80% decrease in RNA synthesis and a 75% decrease in DNA synthesis 3 hr after drug exposure. These results suggest that the mechanism of action of cytidine dialdehyde may be due to its initial interference with DNA synthesis followed by a generalized inhibition of DNA, RNA, and protein synthesis at cytotoxic concentrations.

Animals↗
PubMed1996

Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine.

Genes that confer cellular resistance to cytotoxic agents have potential applications both for marrow protection following cancer chemotherapy and as dominant selectable markers for the selection of genetically modified hematopoietic cell populations in vivo. Cytidine analogues, including cytosine arabinoside (Ara-C), 2',2'-difluorodeoxycytidine (gemcitabine), and other drugs represent a clinically important class of chemotherapeutic agents for which no drug resistance gene has yet been described. Studies were performed to determine whether forced expression of a gene encoding the enzyme cytidine deaminase can confer resistance to cytosine arabinoside (Ara-C) and gemcitabine in vitro. A pooled population of NIH3T3 cells overexpressing cytidine deaminase from a retroviral construct based on the LXSN-vector (LCDSN) demonstrated a 4.5-fold increased resistance to Ara-C based on the 50% inhibitory concentration (ID50) and a 3.7-fold increased resistance to Ara-C based on the 80% inhibitory concentration (ID80) relative to cells transduced with a control vector. In the hemopoietic cell line CCRF-CEM, the same retroviral construct conferred a 2.1-fold increased resistance to Ara-C by ID50 and a 3.0-fold increased resistance to Ara-C by ID80 relative to cells transduced with a control vector. CEM cells transduced with LCDSN were also resistant to gemcitabine (2.4-fold by ID50 and 2.5-fold by ID80). Furthermore, Ara-C-resistance could be completely reversed in LCDSN-transduced CEM cells by a specific inhibitor of cytidine deaminase, tetrahydrouridine (THU). Expression of the transgene was confirmed by RNase-protection assay and by an enzyme activity assay. These results provide the first direct evidence that forced expression of cytidine deaminase confers cellular resistance to Ara-C and gemcitabine.

3T3 Cells↗
PubMed2001

CDP-choline, but not cytidine, protects hippocampal CA1 neurones in the gerbil following transient forebrain ischaemia.

The effects of CDP-choline (citicoline), cytidine monophosphate or cytidine on the number of CA1 hippocampal neurones surviving five-minute forebrain ischaemia have been evaluated in gerbils. The substances tested were given in daily doses equivalent on a molar basis to 500 mg/kg CDP-choline, starting immediately after ischaemia. On day five the brains were perfused, postfixed, cut into 10 microm slices and stained with cresyl violet, and the number of neurones in the CA1 sectors was counted manually under a light microscope at magnification x 400. The results indicate a significant degree of protection provided by citicoline, but no protection by cytidine monophosphate or cytidine. The choline moiety of CDP-choline appears to be essential for the neuroprotective properties of the drug.

Animals↗
PubMed1994

2'-Deoxy-2'-methylene derivatives of adenosine, guanosine, tubercidin, cytidine and uridine as inhibitors of L1210 cell growth in culture.

The 2'-deoxy-2'-methylene derivatives of adenosine (MdAdo), guanosine (MdGuo), tubercidin (MdTu), cytidine (MdCyd) and uridine (MdUrd) were synthesized as mechanism-based inhibitors directed at ribonucleotide reductase. It was shown that MdCyd 5'-diphosphate irreversibly inactivated ribonucleotide reductase from Escherichia coli (Baker et al., J Med Chem 34: 1879-1884, 1991). In studies reported here, MdAdo/EHNA, MdGuo and MdCyd inhibited L1210 cell growth with IC50 values of 3.4, 10.6 and 1.4 microM, respectively. Since MdAdo is a substrate for adenosine deaminase, the presence of EHNA was required to give maximal growth inhibition. 8-Aminoguanosine was not required to maximize the cytotoxic effects of MdGuo. The 2'-deoxy-2'-methylene derivatives of tubercidin and uridine did not inhibit L1210 cell growth at concentrations as high as 50 microM (MdTu) or 100 microM (MdUrd). L1210 cell lines resistant to hydroxyurea (directed at the non-heme iron subunit of ribonucleotide reductase) or deoxyadenosine (directed at the effector binding subunit of ribonucleotide reductase) were not resistant to MdCyd. An L1210 cell line that was highly resistant to dGuo due to the loss of a relatively specific deoxyribonucleoside kinase (Cory et al., J Biol Chem 268: 405-409, 1993) had a 6.6-fold increase in the IC50 value toward MdCyd, but showed only a 2-fold increase in resistance to MdGuo. Another L1210 cell line that was markedly deficient in adenosine kinase activity was highly resistant to MdAdo. Analysis by flow cytometry showed that MdCyd showed the transit of the cells through the G2/M phase of the cell cycle resulting in the buildup of the G2/M population. MdAdo, MdGuo and MdCyd inhibited the incorporation of [14C]cytidine into DNA without an effect on RNA synthesis or total cellular uptake of [14C]cytidine. The conversion of [14C]cytidine to deoxycytidine nucleotides was partially inhibited by MdGuo, but not by MdAdo or MdCyd. These data show that the 2'-deoxy-2'-methylene derivatives of adenosine, guanosine and cytidine are activated via specific nucleoside kinases and that the modes of action of these compounds are not identical.

Animals↗
PubMed1981

Biosynthesis of cytidine nucleotides in rat liver after administration of D-galactosamine.

Following the administration of D-galactosamine the utilization of [2-14C] orotic acid for the synthesis of the cytidine components of the acid-soluble extract and liver RNA cytosine is markedly decreased. The depression of the specific activity of the cytidine components takes place after application of low doses of the drug which do not interfere with the specific activity of the uridine components of the acid-soluble extract or of liver RNA uracil. Simultaneously the administration of [U-14C]cytidine paralleled by its enhanced liver uptake. The total amount of uridine as well as cytidine components of the acid-soluble extract following the administration of D-galactosamine increases; however, the molar ratio of both pyrimidines does not change. The alterations of the cytidine metabolism after the administration of the drug are accompanied by the increased level of microsomal cytochrome P-450.

Animals↗
PubMed2004

Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.

Uridine-cytidine kinase (UCK) catalyzes the phosphorylation of uridine and cytidine and activates pharmacological ribonucleoside analogs. Here we present the crystal structures of human UCK alone and in complexes with a substrate, cytidine, a feedback inhibitor, CTP or UTP, and with phosphorylation products, CMP and ADP, respectively. Free UCK takes an alpha/beta mononucleotide binding fold and exists as a homotetramer with 222 symmetry. Upon inhibitor binding, one loop region was loosened, causing the UCK tetramer to be distorted. Upon cytidine binding, a large induced fit was observed at the uridine/cytidine binding site, which endows UCK with a strict specificity for pyrimidine ribonucleosides. The first UCK structure provided the structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase, which give clues for the design of novel antitumor and antiviral ribonucleoside analogs that inhibit RNA synthesis.

Adenosine Triphosphate↗