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PubMed2000

Choline plus cytidine stimulate phospholipid production, and the expression and secretion of amyloid precursor protein in rat PC12 cells.

The amyloid precursor protein (APP) is a transmembrane protein anchored in the membrane lipid bilayer. Choline and cytidine are major precursors of cell membranes, and are regulatory elements in membrane biosynthesis. We examined the levels of cellular APP holoprotein and secreted APPs when rat PC12 cells are stimulated to undergo increase in membrane phospholipids by choline+cytidine (2+2, 5+5, 10+10 or 50+50 microM) treatment. We now show that as phospholipids levels are increased by supplemental choline and cytidine treatment, the levels of cell-associated APP also rise stoichiometrically; these treatments also caused major (up to 6. 8-fold) increases in the amounts of secreted APP released into the cell medium, and also stimulated increased process formation. These results show that choline plus cytidine increase both phospholipid levels, and the expression and secretion in PC12 cells. It appears that agents that stimulate cellular membrane biosynthesis may be used to stimulate the secretion of neurotrophic APPs and neurite formation in neurodegenerative disorders such as Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Molecular recognition of 7-(2-octadecyloxycarbonylethyl)guanine to cytidine at the air/water interface and LB film studied by Fourier transform infrared spectroscopy.

Monolayer behavior of a nucleolipid amphiphile, 7-(2-octadecyloxycarbonylethyl)guanine (ODCG), on aqueous cytidine solution was investigated by means of surface-molecular area (pi-A) isotherms. It indicates that molecular recognition by hydrogen bonding is present between ODCG monolayer and the cytidine in subphase. The Fourier transform infrared (FTIR) transmission spectroscopic result indicates that the cytidine molecules in the subphase can be transferred onto solid substrates by Langmuir-Blodgett (LB) technique as a result of the formation of Watson-Crick base-pairing at the air/water interface. Investigation by rotating polarized FTIR transmission also suggests that the headgroup recognition of this amphiphile to the dissolved cytidine influence the orientation of the tailchains.

Cytidine↗
PubMed2000

Temperature effects on the catalytic efficiency, rate enhancement, and transition state affinity of cytidine deaminase, and the thermodynamic consequences for catalysis of removing a substrate "anchor".

To obtain a clearer understanding of the forces involved in transition state stabilization by Escherichia coli cytidine deaminase, we investigated the thermodynamic changes that accompany substrate binding in the ground state and transition state for substrate hydrolysis. Viscosity studies indicate that the action of cytidine deaminase is not diffusion-limited. Thus, K(m) appears to be a true dissociation constant, and k(cat) describes the chemical reaction of the ES complex, not product release. Enzyme-substrate association is accompanied by a loss of entropy and a somewhat greater release of enthalpy. As the ES complex proceeds to the transition state (ES), there is little further change in entropy, but heat is taken up that almost matches the heat that was released with ES formation. As a result, k(cat)/K(m) (describing the overall conversion of the free substrate to ES is almost invariant with changing temperature. The free energy barrier for the enzyme-catalyzed reaction (k(cat)/K(m)) is much lower than that for the spontaneous reaction (k(non)) (DeltaDeltaG = -21.8 kcal/mol at 25 degrees C). This difference, which also describes the virtual binding affinity of the enzyme for the activated substrate in the transition state (S), is almost entirely enthalpic in origin (DeltaDeltaH = -20.2 kcal/mol), compatible with the formation of hydrogen bonds that stabilize the ES complex. Thus, the transition state affinity of cytidine deaminase increases rapidly with decreasing temperature. When a hydrogen bond between Glu-91 and the 3'-hydroxyl moiety of cytidine is disrupted by truncation of either group, k(cat)/K(m) and transition state affinity are each reduced by a factor of 10(4). This effect of mutation is entirely enthalpic in origin (DeltaDeltaH approximately 7.9 kcal/mol), somewhat offset by a favorable change in the entropy of transition state binding. This increase in entropy is attributed to a loss of constraints on the relative motions of the activated substrate within the ES complex. In an Appendix, some objections to the conventional scheme for transition state binding are discussed.

Catalysis↗
PubMed1985

Cytidine deaminase from Escherichia coli B. Purification and enzymatic and molecular properties.

Cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5) from Escherichia coli has been purified to homogeneity through a rapid and efficient two-step procedure consisting of anion-exchange chromatography followed by preparative electrophoresis. The final preparation is homogeneous, as judged by a single band obtained by disc gel electrophoresis performed in the absence and presence of denaturing agents. The native protein molecular weight determined by gel filtration is 56 000. Sodium dodecyl sulfate disc gel electrophoresis experiments conducted upon previous incubation of the enzyme with dimethyl suberimidate suggest an oligomeric structure of two identical subunits of 33 000 molecular weight. The absorption spectrum of the protein reveals a maximum at 277 nm and a minimum at 255 nm. The isoelectric point is at pH 4.35. Amino acid analysis indicates an excess of acidic amino acid residues as well as six half-cystine residues. No interchain disulfide groups have been evidenced. According to Cleland's nomenclature, kinetic analysis shows a rapid-equilibrium random Uni-Bi mechanism. Cytidine deaminase is competitively inhibited by various nucleosides. Km values for cytidine, deoxycytidine, and 5-methylcytidine are 1.8 X 10(-4), 0.9 X 10(-4), and 12.5 X 10(-4) M, respectively.

Amino Acids↗
PubMed1987

Mechanism of hydroxylamine mutagenesis: tautomeric shifts and proton exchange between the promutagen N6-methoxyadenosine and cytidine.

Whereas the amino, but not imino, tautomer of the promutagen N6-methoxyadenosine (OMe6A) forms planar associates (base pairs) with the potentially complementary uridine [Stolarski, R., Kierdaszuk, B., Hagberg, C.-E., & Shugar, D. (1984) Biochemistry 23, 2906-2913], it has now been found, with the aid of 1H NMR spectroscopic techniques, that only the imino tautomer of OMe6A base pairs with the potentially complementary cytidine. The association constant for such heteroassociates is more than an order of magnitude higher than that for autoassociates of OMe6A. The formation of heteroassociates is accompanied by a marked shift in tautomeric equilibrium of OMe6A, with an increase in the population of the amino form from 18% to as high as 44% and a corresponding decrease in the population of the imino species. Furthermore, the presence of cytidine in a solution of OMe6A appreciably enhances the rate of tautomeric exchange between the two tautomeric forms. Formation of planar heteroassociates between cytidine and the imino form of OMe6A is also accompanied by proton exchange between the cytidine NH2 and the N6-H of the amino form of OMe6A. The rate constants for this exchange and for tautomeric exchange, determined by the saturation transfer technique, have been measured at various concentrations and temperatures. A model is advanced for proton exchange that takes into account the interdependence of tautomeric exchange and proton exchange, as well as the role of auto- and heteroassociates. The relevance of these results to the molecular basis of hydroxylamine and methoxyamine mutagenesis and to the phenomenon of proton exchange in other systems is briefly discussed.

Adenosine↗
PubMed1975

On the interaction of 3,4,5,6-tetrahydrouridine with human liver cytidine deaminase.

In contrast to the rapid inhibition of bacterial cytidine deaminase by 3,4,5,6-tetrahydrouridine, the onset of inhibition of the enzyme from human liver was found to be relatively slow. Inhibition was found to be reversible, and the corrected rate constants for binding (kon = 2.4 x 10(4) M-1 sec-1) and release (koff = 5.6 x 10(-4) sec-1) were in reasonable agreement with a Ki value (2.9 x 10(-8) M) measured separately under steady-state conditions, which was several orders of magnitude lower than estimates previously reported in the literature. Rates of binding and release of this potential transition state analogue were not appreciably affected by the substitution of deuterium oxide for solvent water. The slow onset of inhibition, which was also observed for cytidine deaminase from HeLa cells, suggests that structural reorganization precedes the formation of a stable enzyme-inhibitor complex. 6-Azacytidine, which favors a "high-anti" configuration at the glycosidic bond, was found to be active as a substrate for cytidine deaminase, with a turnover number exceeding that of cytidine. 2,2'-Anhydro-1-beta-D-arabinofuranosylcytosine, which is restricted to the "syn" configuration, was found to be without activity as a substrate or an inhibitor.

Azacitidine↗
PubMed2005

Reaction of glyoxal with 2'-deoxyguanosine, 2'-deoxyadenosine, 2'-deoxycytidine, cytidine, thymidine, and calf thymus DNA: identification of DNA adducts.

Glyoxal (ethanedial) is an increasingly used industrial chemical that has been found to be mutagenic in bacteria and mammalian cells. In this study, the reactions of glyoxal with 2'-deoxyguanosine, 2'-deoxyadenosine, 2'-deoxycytidine, cytidine, thymidine, and calf thymus DNA have been studied in aqueous buffered solutions. The nucleoside adducts were isolated by reversed-phase liquid chromatography and characterized by their UV absorbance and 1H and 13C NMR spectroscopic and mass spectrometric features. The reaction with 2'-deoxyguanosine gave one adduct, the previously known 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7-trihydro-6,7-dihydroxyimidazo[1,2-a]purine-9-one adduct. The reaction of 2'-deoxyadenosine with glyoxal resulted in the formation of a previously not reported N6-(hydroxyacetyl)-2'-deoxyadenosine adduct. In the reaction of glyoxal with 2'-deoxycytidine and cytidine at neutral conditions and 37 degrees C, 5-hydroxyacetyl pyrimidine derivatives were obtained. When the cytidine reaction was performed at pH 4.5 and 50 degrees C, the 5-hydroxyacetyl derivative of uridine was formed through deamination of cytidine-glyoxal. Adducts in the thymidine reaction could not be detected. In the reaction of glyoxal with calf thymus DNA, the 2'-deoxyguanosine-glyoxal and 2'-deoxyadenosine-glyoxal adducts were obtained, the former being the major adduct.

Cytidine↗
PubMed2004

Characterization of the adducts formed in the reactions of glycidamide with thymidine and cytidine.

Glycidamide (GA) is a mutagenic epoxide metabolite of acrylamide (AM), a high production chemical with many industrial uses. Moreover, recent findings have shown that AM is formed in starchy foods cooked at high temperatures. This has refocused the attention on this chemical and its metabolite and on their possible mutagenicity and carcinogenicity. In this study, we have reacted GA with cytidine and thymidine in aqueous-buffered solutions. The adducts from the nucleosides have been isolated by reversed phase HPLC and characterized by their UV absorbance and 1H and 13C NMR spectroscopic and mass spectrometric features. The reaction with thymidine yielded one adduct, N3-(2-carbamoyl-2-hydroxyethyl)thymidine (N3-GA-dThd), while the reaction with cytidine yielded three adducts. Two adducts were identified as a diastereomeric pair of N3-(2-carboxy-2-hydroxyethyl)cytidine (N3-GA-Cyd-1 and N3-GA-Cyd-2). The third adduct from the cytidine reaction was identified as N3-(2-carboxy-2-hydroxyethyl)uridine (N3-GA-Urd).

Chromatography, High Pressure Liquid↗
PubMed1991

Site-specific creation of uridine from cytidine in apolipoprotein B mRNA editing.

Human apolipoprotein (apo) B mRNA is edited in a tissue specific reaction, to convert glutamine codon 2153 (CAA) to a stop translation codon. The RNA editing product templates and hybridises as uridine, but the chemical nature of this reaction and the physical identity of the product are unknown. After editing in vitro of [32P] labelled RNA, we are able to demonstrate the production of uridine from cytidine; [alpha 32P] cytidine triphosphate incorporated into RNA gave rise to [32P] uridine monophosphate after editing in vitro, hydrolysis with nuclease P1 and thin layer chromatography using two separation systems. By cleaving the RNA into ribonuclease T1 fragments, we show that uridine is produced only at the authentic editing site and is produced in quantities that parallel an independent primer extension assay for editing. We conclude that apo B mRNA editing specifically creates a uridine from a cytidine. These observations are inconsistent with the incorporation of a uridine nucleotide by any polymerase, which would replace the alpha-phosphate and so rule out a model of endonucleolytic excision and repair as the mechanism for the production of uridine. Although transamination and transglycosylation remain to be formally excluded as reaction mechanisms our results argue strongly in favour of the apo B mRNA editing enzyme as a site-specific cytidine deaminase.

Apolipoproteins B↗
PubMed1995

Electrostatic properties of beta-cytidine and cytosine monohydrate from Bragg diffraction.

The charge-density distribution in the crystal structure of the nucleoside beta-cytidine at 123 K has been determined from X-ray diffraction data (Ag K alpha, lambda = 0.5608 A) using all 7233 reflections with sin theta/lambda < or = 1.14 A-1. Maps of electrostatic potential for the cytosine base in cytidine are similar to those derived from previous charge-density studies of cytosine monohydrate and 1-beta-D-arabinosyl-cytosine, after taking chemical differences into account. These results were obtained from pseudoatom multipole refinements including kappa as a variable to describe the expansion or contraction of the spherical valence shell for each atom type. A new structure refinement of this type has also been carried out for cytosine monohydrate. A survey of kappa values for hydrogen indicates that this is a variable which is not well determined experimentally. Variations in kappa H are relayed into the population parameters obtained for other pseudoatoms and can have a small but significant effect on molecular properties, such as the dipole moment. Assuming an average theoretical value of kappa H = 1.24, the molecular dipole moments calculated from the monopole and dipole pseudoatom population parameters are 17 (4) and 8.2 (15) Debye for cytidine nucleoside and cytosine in the monohydrate, respectively. Systems of atomic point charges are presented for cytidine, cytosine and water. These are generally satisfactory in reproducing the experimentally determined molecular electrostatic potentials and dipole moments.

Chemical Phenomena↗
PubMed1985

Cytidine deaminase--a marker for pre-eclampsia?

Cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5) was measured in blood collected for routine antenatal monitoring from 590 unselected pregnant women. The enzyme measurements were made without prior knowledge of the clinical condition of the patients. Increased activity of cytidine deaminase was found in 42.9% of patients with severe pre-eclampsia, 9.1% of patients with mild pre-eclampsia and in 8.6% of normal pregnancies. These results show a poor correlation of elevated cytidine deaminase activity with pre-eclampsia and a significant false positive elevation of the enzyme activity in normal pregnancies.

Cytidine Deaminase↗
PubMed1995

A 3-deazauracil-resistant mutant of Bacillus subtilis with increased production of cytidine.

Bacillus subtilis No. 344 is a cytidine-producing mutant strain derived from wild type strain No. 122. When 3-deazauracil-resistant mutants were derived from strain No. 344, some of the mutants had higher productivities of cytidine. Among them, strain No. 428 accumulated 14.2 mg/ml cytidine in the culture. Cytidine 5'-triphosphate (CTP) synthetase from strain No. 428 changed to be free from feedback inhibition by CTP, compared with the enzyme from strain No. 344.

Bacillus subtilis↗
PubMed2002

Serum adenosine deaminase and cytidine deaminase activities in patients with systemic lupus erythematosus.

We evaluated serum total adenosine deaminase, its isoenzymes adenosine deaminase-1 and adenosine deaminase-2, and cytidine deaminase activities in 24 patients with active systemic lupus erythematosus, and in 26 healthy control subjects, and found the means +/- SD values to be 21.38 +/- 5.96 IU/l, 3.74 +/- 2.12 IU/l, 17.72 +/- 5.02 IU/l and 17.89 +/- 4.62 IU/l, respectively in the patients, and 14.97+/- 4.71 IU/l, 4.01 +/- 1.35 IU/l, 10.91 +/- 3.91 IU/l and 7.39 +/- 3.97 IU/l, respectively in the control subjects. When compared to the healthy controls, serum total adenosine deaminase, adenosine deaminase-2 and cytidine deaminase levels were significantly higher (p<0.001) in systemic lupus erythematosus patients, but the decrease of adenosine deaminase-1 level was not statistically significant (p>0.05). The increased adenosine deaminase-2 may be of macrophage origin. It closely correlated with clinical signs of active systemic lupus erythematosus. The membranes of polymorphonuclear neutrophils may be damaged, and cytidine deaminase may be released into serum. In conclusion, serum total adenosine deaminase, adenosine deaminase-2 and cytidine deaminase activities may serve as useful indicators for evaluating disease activity in patients with active systemic lupus erythematosus.

Adenosine Deaminase↗
PubMed1987

[Effect of D-galactosamine on nucleotides in the rat heart. Effects of cytidine and uridine administration].

The treatment of rats by galactosamine (2 mmol/kg i.p.), which dramatically alters the metabolism of pyrimidine nucleotides in the liver, has been used to investigate the dynamics of pyrimidine nucleotides in the rat heart. Six hours after administration of the drug, the UTP and UDPG myocardial contents were decreased by respectively 40 and 52% while the sum of uracil nucleotides was increased by 66% and that of cytosine nucleotides by 15%. When administered 5 h after galactosamine treatment, cytidine (750 nmol/rat i.v.) induced a further increase in cytosine nucleotides (46% above control value 1 h later) without however effect on uracil nucleotides. On the other hand, the administration of uridine (250 nmol/rat, i.v. 5 h after galactosamine), while restoring UTP, UDPG and the pool of uracil nucleotides, provoked a decrease in cytosine nucleotide level (-17%). In the absence of galactosamine treatment, the administration of uridine and cytidine did not induce changes in nucleotide levels despite a rise in blood cytidine concentration. All these observations support the hypothesis that: 1. the pathway for cytosine nucleotide synthesis predominant in the heart is that utilizing preformed exogenous cytidine and 2. this pathway is mainly controlled by the intracellular concentration of UTP rather than that of CTP.

Adenine Nucleotides↗
PubMed1999

Catabolism of the methyl derivatives of adenosine and cytidine in staphylococci.

Products of 1-methyladenosine, 2'-O-methyladenosine, 2'-O-methylcytidine, and 5-methylcytidine catabolism by resting cells of Staphylococcus aureus and Staphylococcus intermedius were chromatographically separated. The methyl group in 1-methyladenosine protected the adenosine derivative from deamination by S. intermedius but it did not protect N-glycosidic bond from cleavage by S. intermedius and S. aureus. The methyl group in 2'-O-methyladenosine and 2'-O-methylcytidine protected the N-glycosidic bond from cleavage by S. aureus and S. intermedius but it did not protect the adenosine and cytidine derivatives from deamination by S. intermedius. 5-Methylcytidine was converted by the common route in which 5-methylcytidine was first deaminated to ribothymidine which was cleaved to yield thymine. S. intermedius deaminated the purine and pyrimidine ribonucleosides adenosine, 2'-O-methyladenosine, cytidine, and 5-methylcytidine. Pyrimidine ribonucleosides (cytidine, 5-methyl-cytidine) were deaminated only slowly and purine ribonucleosides (adenosine, 2'-O-methyladenosine) not at all by S. aureus.

Adenosine↗
PubMed1979

Isolation and characterization of cultured mouse T-lymphoma cells deficient in uridine-cytidine kinase.

Two clones were isolated from mutagenized mouse T-lymphoma cells (S49) which are over 90% deficient in uridine-cytidine kinase. The first clone, AU-200-1, was isolated in two steps by virtue of its resistance to 6-azauridine; whereas the second clone, FU3-70G, was isolated in three steps after exposure to three increasing concentrations of 5-fluorouracil. Extracts of both the AU-200-1 and the FU3-70G cell lines lacked over 90% of the capacity of those from wild type cells to phosphorylate either uridine or cytidine. Furthermore, the uptake of radioactive uridine and cytidine from the medium by intact AU-200-1 and FU3-70G cells was less than 5% of that found for intact wild type cells. By growth rate experiments, these uridine-cytidine kinase-deficient cell lines have altered sensitivities to the toxic pyrimidine analogs, 6-azauridine, 5-fluorouracil, and 5-fluorouridine and thus have been useful in elucidating the biochemical determinants involved in the metabolism of these compounds.

Animals↗
PubMed1987

Synthesis of pyrimidine nucleotides in the heart: uridine and cytidine kinase activity.

These experiments were designed to determine through the study of uridine and cytidine kinase activity, the precise mechanisms of plasma nucleoside salvage leading to pyrimidine nucleotide synthesis in the rat heart. The kinetic parameters were: Km = 10 microM, V = 4 nmol g-1 min-1 for cytidine kinase activity and Km = 43 microM and V = 18 nmol g-1 min-1 for uridine kinase activity. Competing activity as concerns the two nucleosides was shown to occur, suggesting that in the rat myocardium as in other cells, one and the same enzyme phosphorylates both uridine and cytidine. UTP and CTP were shown to exert a potent inhibitory action on nucleoside phosphorylation; two factors thus exert a joint influence on the control of pyrimidine nucleotide synthesis in the rat heart: the extracellular concentration of precursor and the intracellular level of UTP and CTP. The kinetic parameters for kinase activities are discussed, taking into account the actual concentration of plasmatic nucleosides. Comparison of these data with respectively those for incorporation of nucleosides into the pyrimidine nucleotides of isolated rat heart and with nucleotide turnover rates in vivo suggests that, under physiological conditions, the utilization of plasma cytidine is crucial to the synthesis of myocardial pyrimidine synthesis.

Animals↗
PubMed1977

Uridine and cytidine transport in Escherichia coli B and transport-deficient mutants.

Three mutants of Escherichia coli B which are defective in components of the transport system for uridine and uracil were isolated and utilized to study the mechanism of uridine transport. Mutant U- was isolated from a culture resistant to 77 micronM 5-fluorouracil. Mutant U-UR-, isolated from a culture of mutant U-, is resistant to 770 micronM 5-fluorouracil and 750 micronM adenosine. Mutant NUC- is resistant to 80 micronM showdomycin and has been reported previously. The characteristics of uridine transport by E. coli B and the mutants provide data supporting the following conclusions. The transport of adenosine, deoxyadenosine, guanosine, deoxyguanosine, adenine, or guanine by mutant U- and mutant U-UR- is identical with that in the parental strain. Uridine is transported by E. coli B as intact uridine. In addition, extracellular uridine is also rapidly cleaved to uracil and the ribose moiety. The latter is transported into the cells, whereas uracil appears in the medium and is transported by a separate uracil transport system. The entry of the ribose moiety of uridine is fast relative to the uracil and uridine transport processes. The Km values and the inhibitory effects of heterologous nucleosides for the transport of uridine and the ribose moiety of uridine are similar. Studies of cytidine uptake in the parental and mutant strains provide evidence that cytidine is transported by two independent systems, one of which is the same as that involved in the transport of intact uridine. Uridine inhibits but is not transported by the other system for cytidine transport. Evidence for the above conclusions was based on comparisons of the characteristics of [2-14C]uridine, [U-14C]uridine, and [2-14C]cytidine transport using E. coli B and the three transport mutants under conditions which measure initial rates. The nature of the inhibitory effects of heterologous nucleosides on the uridine transport processes and identification of extracellular components from radioactive uridine provides supportive data for the conclusions.

Adenosine↗