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At least 109 records · Page 6Linked to original sources
PubMed2006

Activation-induced cytidine deaminase acts on double-strand breaks in vitro.

Activation-induced cytidine deaminase (AID) is likely responsible for DNA cytidine deamination, although it may also act as an RNA deaminase. It functions on single-stranded DNA, the non-template strand in double-stranded DNA during transcription, or both strands in supercoiled DNA. To ask whether AID is able to deaminate cytidine at DNA breaks, plasmids, containing a SnaBI site (TAC downward arrowGTA) that forms blunt ends after digestion with SnaBI, were generated. If AID deaminates cytidine at the upstream blunt end, the ATG start codon in either of two drug resistance genes will be regenerated after ligation and replication in UDG-null E. coli cells. This study shows that AID targets cytidine at the break. The extent of deamination activity beyond the break is correlated with the base composition in the break region. If the break region is A, T-rich, C > T transitions are extensive. However, when the break region is not A, T-rich, mutations are mainly restricted to the break, similar to findings in vivo. The results indicate that AID has activity on double strand breaks (DSBs). Based on previous and current findings, a somatic hypermutation (SHM) model is proposed, in which collision between the transcription apparatus and the replication fork generates DSBs. After AID acts on break ends, the error-prone DNA repair machinery fixes and creates mutations.

Ampicillin Resistance↗
PubMed1990

Cytidylate cyclase: development of assay and determination of kinetic properties of a cytidine 3',5'-cyclic monophosphate-synthesizing enzyme.

A method is described for the separation of cytidine 3',5'-cyclic monophosphate (cyclic CMP) from cytidine tri-, di- and mono-phosphates and from cytidine 3',5'-cyclic pyrophosphate, cytidine 2'-monophosphate-3',5'-cyclic monophosphate, cytidine 2'-O-aspartyl-3',5'-cyclic monophosphate and cytidine monophosphate, compounds previously shown to be the result of putative cytidylate cyclase activity. This separation, involving elution of a novel bilayer column of QAE-Sephadex and alumina with 0.03 M-HCl, has been incorporated into an assay protocol to determine the enzyme-catalysed conversion of radiolabelled CTP to cyclic CMP. By this assay, cytidylate cyclase activity has been shown to be present in rat lung, spleen, ovary, testes, brain, stomach, liver, heart and kidney preparations; the activity was of a similar order in each tissue and had a sharp pH optimum of 7.0-7.5. The liver preparation had a Vmax. of 1.2 nmol of cyclic CMP formed/min per mg, and a Km of 220 microM-CTP, and although active in the absence of added cations, it was stimulated by Fe2+ and Mn2+ ions. In several of the tissues examined, the cytidylate cyclase activity was inversely proportional to age of the animals.

Aging↗
PubMed2006

Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release.

AIMS: Treatments that increase acetylcholine release from brain slices decrease the synthesis of phosphatidylcholine by, and its levels in, the slices. We examined whether adding cytidine or uridine to the slice medium, which increases the utilization of choline to form phospholipids, also decreases acetylcholine levels and release. METHODS: We incubated rat brain slices with or without cytidine or uridine (both 25-400 microM), and with or without choline (20-40 microM), and measured the spontaneous and potassium-evoked release of acetylcholine. RESULTS: Striatal slices stimulated for 2 h released 2650+/-365 pmol of acetylcholine per mg protein when incubated without choline, or 4600+/-450 pmol/mg protein acetylcholine when incubated with choline (20 microM). Adding cytidine or uridine (both 25-400 microM) to the media failed to affect acetylcholine release whether or not choline was also added, even though the pyrimidines (400 microM) did enhance choline;s utilization to form CDP-choline by 89 or 61%, respectively. The pyrimidines also had no effect on acetylcholine release from hippocampal and cortical slices. Cytidine or uridine also failed to affect acetylcholine levels in striatal slices, nor choline transport into striatal synaptosomes. CONCLUSION: These data show that cytidine and uridine can stimulate brain phosphatide synthesis without diminishing acetylcholine synthesis or release.

Acetylcholine↗
PubMed1984

Activation of phosphoenolpyruvate-dependent protein kinase by cytidine 5'-triphosphate in rat skeletal muscle.

The effects of nucleotides on phosphoenolpyruvate-dependent protein kinase in rat skeletal muscle were examined. Various ribonucleotide triphosphates were tested and the protein kinase reaction was maximally activated by cytidine 5'-triphosphate followed by uridine 5'-triphosphate and guanosine 5'-triphosphate. No activation by adenosine 5'-triphosphate was observed. Cytidine 5'-diphosphate also activated the reaction but to a significantly lesser extent. Cytidine 5'-monophosphate and cyclic cytidine 3',5'-monophosphate showed no effect whereas cytidine was slightly inhibitory.

Adenosine Triphosphate↗
PubMed1984

Characteristics of cytidine aminohydrolase activity in Trypanosoma cruzi and Crithidia fasciculata.

Cytidine deaminase (cytidine aminohydrolase, 3.5.4.5) is present in Crithidia fasciculata (a mosquito parasite) and in Trypanosoma cruzi (a human pathogen). The enzyme from C. fasciculata deaminated both cytidine and deoxycytidine, the affinity for the former being much lower than the latter. Affinities for both substrates are equal for the T. cruzi enzyme. The production of the enzyme in C. fasciculata was significantly stimulated by the addition of a number of pyrimidine nucleosides (cytidine, uridine, 5-bromouridine, thymidine, orotidine) to the culture media. Only cytidine stimulated enzyme production in T. cruzi. The enzyme from both organisms was unstable in air, even in the frozen state. Stabilization was achieved under anaerobic conditions.

Anaerobiosis↗
PubMedDate not supplied

Evolutionary origins of the mammalian apolipoproteinB RNA editing enzyme, apobec-1: structural homology inferred from analysis of a cloned chicken small intestinal cytidine deaminase.

Mammalian apolipoproteinB (apoB) RNA editing is a site-specific deamination reaction that mediates the C to U conversion responsible for apoB48 production in the mammalian small intestine. This process is not detected in chicken apoB RNA. Mammalian apoB RNA editing is mediated by a multicomponent enzyme complex that includes a single catalytic subunit, apobec-1. In order to examine the evolution of apobec-1, we have cloned and characterized an orthologous cytidine deaminase cDNA isolated from chicken small intestine. Northern blot analysis revealed expression restricted to the small intestine, colon and lung but not the liver or other tissues. The cDNA encodes a single 31 kDa protein with features reminiscent of other cytidine deaminases and with approximately 39% overall homology to rat apobec-1. The recombinant protein is a cytidine deaminase with activity on a monomeric substrate that was found to be zinc-dependent. However, no RNA editing activity was detectable towards cytidine nucleotides presented in the context of an optimally configured mammalian apoB RNA template. These studies provide information concerning the evolution of the apoB RNA editing machinery and indicate that a chicken small intestinal cytidine deaminase with homology to apobec-1 demonstrates no activity on an RNA substrate.

APOBEC-1 Deaminase↗
PubMed1999

APOBEC-2, a cardiac- and skeletal muscle-specific member of the cytidine deaminase supergene family.

APOBEC-1, which mediates the editing of apolipoprotein (apo) B mRNA, is the only known member of the C (cytidine)-->U (uridine) editing enzyme subfamily of the cytidine deaminase supergene family. Here we report the cloning of APOBEC-2, another member of the subfamily. Human and mouse APOBEC-2 both contain 224 amino acid residues, and their genes are mapped to syntenic regions of human chromosome 6 (6p21) and mouse chromosome 17. By phylogenetic analysis, APOBEC-2 is shown to be evolutionarily related to APOBEC-1, and analysis of substitution rates indicates that APOBEC-2 is a much better conserved gene than APOBEC-1. APOBEC-2 mRNA and protein are expressed exclusively in heart and skeletal muscle. APOBEC-2 does not display detectable apoB mRNA editing activity. Like other editing enzymes of the cytidine deaminase superfamily, APOBEC-2 has low, but definite, intrinsic cytidine deaminase activity. The identification of APOBEC-2 indicates that APOBEC-1 is not the only member of the C-->U editing enzyme subfamily, which, like the A (adenosine)-->I (inosine) subfamily of editing enzymes, must encompass at least two and possibly more different deaminase enzymes. It suggests that the C-->U editing affecting apoB mRNA and other RNAs is not an isolated event mediated by a single enzyme but involves multiple related proteins that have evolved from a primordial gene closely related to the housekeeping enzyme cytidine deaminase.

APOBEC Deaminases↗
PubMed1978

Increased transport of (G-14C) cytidine into rat liver after administration of alpha-hexachlorocyclohexane.

The transport of cytidine into liver over a wide dose range (0.003--100mumol per animal) proceeds as an nonsaturabel process. After the administration of alpha-hexachlorocyclohexane (alpha-HCH)1 the transport of (G-14C) cytidine is markedly activated if the concentration of nucleoside administered is low; the differences between the control and experimental group disappear after the administration of higher doses of the nucleoside. The incorporation of (G-14C) cytidine into RNA cytosine is enhanced after the administration of alpha-HCH. The degree of utilization of labeled cytidine for the RNA synthesis decreases in proportion to the logarithm of its dose, both in the control and in the experimental group. Increased transport of (G-14C)cytidine is observable even between the 4th and 6th day after the administration of a single dose of alpha-HCH.

Animals↗
PubMedDate not supplied

Pyrimidine nucleotide synthesis from exogenous cytidine in the isolated rat heart.

The rate of incorporation of exogenous cytidine into the pyrimidine nucleotides of isolated perfused rat hearts bears a Michaelis-Menten kinetic relationship to the extracellular concentration of the precursor, with an apparent Km of 10 microM and a maximal rate of incorporation of about 60 nmol per gram (ww) per 30 minutes. The myocardial cytosine nucleotide content was significantly increased by a 30 minute supply of 15 microM cytidine and more than doubled after a 2 hour administration period of 50 microM cytidine. In the latter case, the rate of cytidine incorporation fell by 30% (with respect to the initial uptake) during the last 30 minutes of administration. These results suggest that the uptake of cytidine can play an important part in the myocardial cytosine nucleotide metabolism under physiological conditions.

Animals↗
PubMed1996

Synthesis and antiproliferative activity of cytidine-5'-alkylphosphonophosphates and structurally related compounds.

The chemical synthesis of cytidine-5'-alkyl- and cytidine-5'-alkyl (acyl)deoxyglycerophosphonophosphates is reported. The compounds obtained represent a novel class of cytostatically active agents based on phospholipids, which inhibit the growth of various tumor cell lines in vitro. They are phosphono analogs of the cytidine-5'-diphosphate-diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety and a phospholipase C-resistant P-C bond. The antiproliferative efficacy of the cytidine-5'-alkylphosphonophosphates strongly depends on the alkyl chain length. The cytidine-5'-hexadecylphosphonophosphate was found to be the most effective compound tested in this study. Its cytostatic effect was distinctly higher than that of the alkyl(acyl) deoxyglycero derivatives and of the corresponding diphosphates. The structure of the new compounds were confirmed by fast atom bombardment mass spectrometry (FAB). The FAB fragmentation pattern is discussed.

Animals↗
PubMed2006

Uridine and cytidine in the brain: their transport and utilization.

The pyrimidines cytidine (as CTP) and uridine (which is converted to UTP and then CTP) contribute to brain phosphatidylcholine and phosphatidylethanolamine synthesis via the Kennedy pathway. Their uptake into brain from the circulation is initiated by nucleoside transporters located at the blood-brain barrier (BBB), and the rate at which uptake occurs is a major factor determining phosphatide synthesis. Two such transporters have been described: a low-affinity equilibrative system and a high-affinity concentrative system. It is unlikely that the low-affinity transporter contributes to brain uridine or cytidine uptake except when plasma concentrations of these compounds are increased several-fold experimentally. CNT2 proteins, the high-affinity transporters for purines like adenosine as well as for uridine, have been found in cells comprising the BBB of rats. However, to date, no comparable high-affinity carrier protein for cytidine, such as CNT1, has been detected at this location. Thus, uridine may be more available to brain than cytidine and may be the major precursor in brain for both the salvage pathway of pyrimidine nucleotides and the Kennedy pathway of phosphatide synthesis. This recognition may bear on the effects of cytidine or uridine sources in neurodegenerative diseases.

Animals↗
PubMed1988

Synthesis of pyrimidine nucleotides in rat myocardium: potential role of blood cytidine.

Plasma contains micromolar concentrations of pyrimidine bases and nucleosides: uracil 1.9 +/- 0.1 (n = 29), cytosine 1.1 +/- 0.01 (n = 29), uridine 1.2 +/- 0.1 (n = 56) and cytidine 5.4 +/- 0.1 (n = 59) (means +/- S.E.M.). Accordingly, we postulated that these compounds could be used as the main precursors for myocardial pyrimidine nucleotide synthesis. The kinetics of the incorporation of blood plasma bases and nucleosides into myocardial nucleotides was studied by in vivo radio-isotopic studies in rats. The clearance of the radiolabelled compounds in blood plasma and the incorporation of radiolabelled precursors into liver nucleotides was also investigated. The results can be summarized as follows: (1) The pyrimidine radioactive bases were only very slightly incorporated into heart nucleotides 1 h after injection: thus 1 h after injection any incorporation of radiolabelled cytosine into nucleotides remained undetectable and for radioactive uracil the ratio of the specific radioactivity of uracil nucleotides to that of plasma uracil remained below 0.7%. (2) Radiolabelled plasma uridine was subject to a far more rapid catabolism than radiolabelled plasma cytidine. (3) The labelling of myocardial uracil nucleotides from plasma uridine was very slight. Their specific radioactivity represented less than 16% of plasma uridine specific radioactivity. (4) When the tracer was cytidine the specific radioactivity of cytosine nucleotides reached that of precursor within 30 min after injection and uracil nucleotides were also labeled (10% of cytidine nucleotides specific radioactivity). These results, and other previous data, suggest the possibility that the pyrimidine nucleotide synthesis in the rat heart may be largely achieved via the phosphorylation of blood plasma cytidine.

Animals↗
PubMed1996

Reaction of mucochloric and mucobromic acids with adenosine and cytidine: formation of chloro- and bromopropenal derivatives.

Mucochloric (MCA) and mucobromic acid (MBA)--bacterial mutagens and water disinfection byproducts--were reacted with adenosine, cytidine, and guanosine in N,N-dimethylformamide (DMF). In the MCA reaction with adenosine and cytidine and in the MBA reaction with adenosine one major product was formed. In the reactions of MBA with cytidine and in the reactions of MCA and MBA with guanosine only trace levels of products could be detected, and these were not further characterized. The products from the adenosine and cytidine reactions were isolated by preparative chromatography on octadecylsilane columns and structurally characterized by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The products were identified as 3-(N6-adenosinyl)-2-chloro-2-propenal (MClA), 3-(N6-adenosinyl)-2-bromo-2-propenal (MBrA), and 3-(N4-cytidinyl)-2-chloro-2-propenal (MClC). The yields of MClA, MBrA, and MClC were 19, 4 and 7 mol %, respectively. These halopropenal derivatives were formed also in reactions carried out in aqueous solutions at pH 7.4 and 37 degrees C at low yields, about 5 x 10(-3)%. The mechanism of formation of the halopropenal derivatives and of the previously identified etheno and ethenocarbaldehyde derivatives was elucidated by reacting 13C-3 labeled MCA with adenosine in DMF and in water. The location of the labeled carbon in the products was determined from the 13 C NMR spectra. It was concluded that the halopropenal derivatives were formed by mechanisms that differ completely from the one responsible for the formation of the propenal adducts (M1A and M1C) previously reported to be formed in reactions of malonaldehyde with adenosine and cytidine.

Adenosine↗
PubMed1999

A prokaryotic-type cytidine deaminase from Arabidopsis thaliana gene expression and functional characterization.

The gene and cDNA of an Arabidopsis thaliana cytidine deaminase (CDA) were cloned and sequenced. The gene, At-cda1, is located on chromosome 2 and is expressed in all plant tissues tested, although with quantitative differences. Expression analysis suggest that At-cda1 probably codes for the housekeeping cytidine deaminase of Arabidopsis. The gene was functionally expressed in Escherichia coli and the protein, At-CDA1, shows similar enzymatic and substrate specificities as conventional cytidine deaminases: it deaminates cytidine and deoxycytidine and is competitively inhibited by cytosine-containing compounds. Because the protein shows no affinity to RNA, it is not likely to be involved in RNA-editing by C-to-U deamination. When compared to cytidine deaminases from other organisms, it becomes clear that At-CDA1 is related, both in sequence and structure, to the CDA of E. coli and other gram-negative bacteria. The eubacterial nature of the Arabidopsis CDA suggests that it is an additional example of a plant gene of endosymbiotic origin.

Amino Acid Sequence↗
PubMed1983

Light- and cytidine-dependent phosphatidylinositol synthesis in photoreceptor cells of the rat.

Incorporation of [3H]inositol into phosphatidylinositol (Pl) in isolated rat retinas is enhanced by light and by the addition of cytidine to the incubation media. In retinas preincubated with [3H]inositol in dark, [3H]inositol was chased into Pl in light by addition of unlabeled cytidine and was chased out of Pl in light by addition of unlabeled cytidine plus inositol. Autoradiograms of retinas show a heavy density of silver grains over photoreceptor cell inner segments (with chase-in) and a loss of labeling (with chase-out). Exogenous cytidine and inositol were shown to enhance not only the turnover of Pl within photoreceptor cells but the synthesis of Pl as well; in media supplemented with these precursors, approximately 50% of [14C]glycerol and 25% of [32Pi]incorporated into lipid in light were associated with Pl. These results suggest that availability of both cytidine and inositol may play a role in the light-dependent changes in Pl metabolism within photoreceptor cells.

Animals↗
PubMed2005

GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia.

Down syndrome children with acute megakaryocytic leukemia (AMkL) have higher cure rates than non-Down syndrome acute myeloid leukemia (AML) patients treated with cytosine arabinoside (ara-C). Megakaryoblasts from Down syndrome AML patients are more sensitive in vitro to ara-C than cells from non-Down syndrome AML patients. Somatic mutations in the GATA1 transcription factor have been detected exclusively and almost uniformly in Down syndrome AMkL patients, suggesting a potential linkage to the chemotherapy sensitivity of Down syndrome megakaryoblasts. Stable transfection of wild-type GATA1 cDNA into the Down syndrome AMkL cell line CMK resulted in decreased (8- to 17-fold) ara-C sensitivity and a threefold-lower generation of the active ara-C metabolite ara-CTP compared with that for mock-transfected CMK cells. High intracellular levels of uridine arabinoside (ara-U) (an inactive ara-C catabolite generated by cytidine deaminase) and cytidine deaminase transcripts were detected in GATA1-transfected CMK sublines, whereas no ara-U was detected in mock-transfected cells. Cytidine deaminase transcripts were a median 5.1-fold (P = .002) lower in Down syndrome megakaryoblasts (n = 16) than in blast cells from non-Down syndrome patients (n = 56). These results suggest that GATA1 transcriptionally upregulates cytidine deaminase and that the presence or absence of GATA1 mutations in AML blasts likely confers differences in ara-C sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.

Antimetabolites, Antineoplastic↗
PubMed1974

Transport of nucleosides in Bacillus subtilis: characteristics of cytidine-uptake.

In Bacillus subtilis SMYW cytidine and uridine are transported by a common system. Transport of these substances requires metabolic energy. After 60 sec of (3)II-cytidine-uptake practically all accumulated radioactivity was found in phosphorylated products. Addition of ribonucleosides with inhibitory effect upon cytidine-uptake resulted in competitive type of inhibition while interference with deoxyribonucleosides was of hyperbolic competitive type. Adenosine possesses a high affinity to cytidine-transporting site but requires different system(s) for its own transport. Guanosine, adenine, cytosine and 5-nucleotides do not interfere with cytidine-uptake.

Bacillus subtilis↗
PubMed1996

Transfection of murine fibroblast cells with human cytidine deaminase cDNA confers resistance to cytosine arabinoside.

One of the major limitations in the use of cytosine arabinoside (Ara-C) in cancer chemotherapy is the hematopoietic toxicity produced by this nucleoside analog. One approach to overcome this problem would be to insert a gene for drug resistance to Ara-C in normal hematopoietic cells to protect them from drug toxicity. An interesting candidate gene for this aim is cytidine deaminase which catalyzes the deamination of Arac-C, resulting in a significant loss of its antineoplastic activity. We have ligated the human cDNA for cytidine deaminase into the plasmid vector pMFG. Transfection of NIH 3T3-derived GP + E86 murine fibroblasts cells with this vector resulted in a marked increase (> 50-fold) in the expression of cytidine deaminase. In addition, the transfected cells showed resistance to the cytotoxic action and to the inhibition of DNA synthesis produced by Ara-C. Northern and Western blot analysis of the transfected cells showed increased expression of mRNA for cytidine deaminase and increased immunologically detectable enzyme. The ability to confer drug resistance to Ara-C through gene transfer of cytidine deaminase may have the potential as a selectable marker and for the protection of the bone marrow from the toxicity produced by this analog so as to increase its effectiveness in cancer chemotherapy.

3T3 Cells↗