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At least 109 records · Page 6Linked to original sources
PubMed1987

Ribonucleoside uptake and phosphorylation during fertilization and early development of the sea-urchin, Strongylocentrotus purpuratus.

Uptake of the four ribonucleosides normally present in RNA increases nearly 50-fold shortly after fertilization in eggs of the sea-urchin, Strongylocentrotus purpuratus. Uridine, adenosine and cytidine are phosphorylated (greater than 95%) to their mono-, di- and triphosphates immediately after transport into the fertilized egg. Although guanosine is transported to an extent equal to the other three ribonucleosides, less than 12% of its phosphorylated after transport. In vitro nucleoside and nucleotide kinase assays of unfertilized egg homogenates indicate that the uridine, adenosine and cytidine kinases as well as the uridylate, adenylate, cytidylate and guanylate kinases are present in the egg prior to fertilization. Substrate competition measurements indicate that adenosine phosphorylation is catalyzed by a monospecific enzyme, while uridine and cytidine phosphorylations are catalyzed by a common kinase. Guanosine kinase activity was not detectable in unfertilized egg homogenates. Between 3 h and 5 h after fertilization the phosphorylation of transported guanosine begins to increase as it enters the embryo. By 7 h after fertilization, more than 95% of the guanosine entering the embryo is phosphorylated to the mono-, di- and triphosphates. More than 80% is phosphorylated to guanosine triphosphate. The timing of increased guanosine phosphorylation correlates with a decrease in the acid-soluble GTP pools in the embryo, suggesting that increased guanosine kinase activity is a response to increased GTP demand. These results, in view of the importance of GTP in many cellular processes, imply a crucial role for guanosine kinase activation in GTP pool maintenance and cellular metabolism during early sea-urchin development.

Animals↗
PubMed1992

Studies on ribonucleoside-diphosphate reductase from Escherichia coli. The product dCDP is a competitive inhibitor and functions as a spectroscopic probe for the substrate binding site; demonstration by enzyme kinetics and 1H NMR.

Ribonucleoside-diphosphate reductase (EC 1.17.4.1) from Escherichia coli consists of two protein subunits, R1 of 171.5 kDa and R2 of 86.8 kDa, and catalyzes the reduction of all four common ribonucleoside diphosphates. In a search for ligands that bind weakly to the enzyme active site and may be in fast exchange suitable for NMR studies, we have found that the product dCDP is a competitive inhibitor. Kinetics with CDP as substrate shows Km = 4.8 x 10(-5) M and dCDP inhibits with Ki = 1.6 x 10(-4) M. With an assumed diffusion limited binding rate approximately less than 10(9) M-1s-1, the dissociation rate of dCDP would be approximately less than 10(5) s-1. In 1H-NMR experiments studying linewidths, i.e. spin-spin relaxation, dCDP is indeed demonstrated to be in fast exchange. Enzyme subunit R1 causes a line broadening of dCDP resonances. Unexpectedly less broadening was observed when subunit R2 combined with R1. No paramagnetic interaction from the tyrosyl radical of R2 could be detected. It is concluded that dCDP is a promising NMR probe for studies of active-site properties of the enzyme.

Binding Sites↗
PubMed1992

Tandem cloning of bacteriophage T4 nrdA and nrdB genes and overproduction of ribonucleoside diphosphate reductase (alpha 2 beta 2) and a mutationally altered form (alpha 2 beta 2(93)).

To investigate the role of ribonucleoside diphosphate reductase in the deoxyribonucleoside triphosphate synthetase multienzyme complex induced by bacteriophage T4 infection and to study the expression of the T4 nrdA and nrdB genes, we have constructed separate plasmid expression strains overproducing their respective alpha 2 and beta 2 protein products. Because complementation of the two proteins to form an active alpha 2 beta 2 enzyme presented complications, nrdA and nrdB, each with its own tac promoter, were also cloned in tandem into a single expression vector. The resulting plasmid (pnrdAB) overproduces ribonucleoside diphosphate reductase. Phage T4 nrdB93, described by Wirak et al. (D. O. Wirak, K. S. Cook, and G. R. Greenberg, J. Biol. Chem. 263:6193-6201, 1988) contains a lesion in exon II of the gene. The mutation causes not only a temperature-sensitive inactivation of the catalytic structure of the beta 2(93) protein and of its ability to interact with alpha 2 protein to form the alpha 2 beta 2(93) enzyme but also a profound non-temperature-sensitive decrease in the formation of the beta 2(93) protein. An expression vector overproducing active alpha 2 beta 2(93) was constructed by site-directed mutagenesis of the nrdB gene.

Base Sequence↗
PubMed2000

Differences in DNA packaging genes and sensitivity to benzimidazole ribonucleosides between human cytomegalovirus strains AD169 and Towne.

The AD169 strain of human cytomegalovirus was approximately twofold more sensitive to polyhalogenated benzimidazole ribonucleosides than Towne strain. Sequence differences between the two strains have been identified in genes UL51, UL52, UL56, UL77, UL89 and UL104. Because these genes are involved in cleavage and packaging of viral DNA and the benzimidazole ribonucleosides inhibit this process, these sequence differences may be involved in the difference in drug sensitivity.

Benzimidazoles↗
PubMed1986

The age dependency of the creatinine-related concentration of ribonucleosides in human urine.

We investigated the urinary excretion of ribonucleosides and an unidentified substance in 345 healthy probands from the age of a few weeks to 40 years. The concentration of ribonucleosides, related to the corresponding concentration of creatinine, decreases until nearly 20 years and remains constant between 20 and 40 years. The polynomial functions describing this dependency are presented. The biological significance of our findings is briefly discussed.

Adolescent↗
PubMed1999

The ribonucleoside diphosphate reductase inhibitor (E)-2'-deoxy-(fluoromethylene)cytidine as a cytotoxic radiosensitizer in vitro.

(E)-2'-Deoxy-(fluoromethylene)cytidine (FMdC) is known as an inhibitor of ribonucleoside diphosphate reductase, a key enzyme in the de novo pathway of DNA synthesis. FMdC was tested as a modifier of radiation response in vitro on a human colon carcinoma cell line (WiDr), and the observed radiosensitization was confirmed on two human cervix cancer cell lines (C33-A and SiHa). Using the clonogenic assay, the effect ratio (ER) at a clinically relevant dose level of 2 Gy was 2.10 (50 nM FMdC), 1.70 (30 nM FMdC), and 1.71 (40 nM FMdC) for the three cell lines WiDr, C33-A, and SiHa, respectively. A more detailed analysis of the importance of timing and concentration of FMdC was done on the WiDr cell line alone, yielding an increased ER(2Gy) with increasing concentration and duration of exposure to the drug, ranging from 1.0 (6 h) to 1.8 (72 h) at 30 nM FMdC and from 1.2 (6 h) to 3.5 (24 h) at 300 nM. We investigated the effect of FMdC on the cellular deoxynucleotide triphosphate pool in WiDr cells and demonstrated a marked depletion of dATP and a significant rise of TTP levels. Cell cycle analysis showed early S-phase accumulation induced by FMdC alone, G2-M block induced by irradiation alone, and an increased accumulation of cells in G2-M if both modalities are used. Our data suggest that FMdC is a radiation response modifier in vitro on different cancer cell lines. The observed radiosensitization may in part be explained by alteration of the deoxynucleotide triphosphate pool, which is consistent with the effect of FMdC on ribonucleoside diphosphate reductase.

Antineoplastic Agents↗
PubMed1975

Potentiation of cytostatic effect of sulfur- or chlorine-containing purines and related ribonucleosides by amphotericin-B on cultured mouse leukemia cells.

Synergistic effects of sulfur-containing purines and related ribonucleosides (6-thioinosine, 6-thioguanine, 6-thiocyanatopurine, 6-methylthioinosine, 6-thiocyanatoguanine, 6-thiocyanatoguanosine, 6-phenacylthioinosine, 6-nitrobenzlythioinosine, 6-(p-chlorobenzyl)thioinosine, 6-(p-nitrobenzyl)thioguanosine, 6-benzylthioinosine, 6-ethylthioinosine, 6-benzylthioguanine, 6-benzylthiopurine, 6-methylthiopurine, and 6-thiocyanatoinosine) and chlorine-containing purine and its ribonucleoside, (6-chloropuine and 6-chloropurine riboside), in combination with the polyene antibiotic, Amphotericin-B, on cell survival and synthesis of DNA were examined in mouse leukemia L5178Y cells. 6-Methylthioinosine, 6-thiocyanatopurine, 6-thiocyanatoinsoine, 6-methylthiopurine, and 6-thiocyanatoguanine (or -guanosine) among sulfur-containing compounds were strongly potentiated by Amphotericin-B, and 6-chloropurine riboside, which is electronically analogous to methylthioinosine, was also enhanced by the polyene. Thiocyanoto or methylthio group at position 6 of the purine ring seems to be important for the polyene-mediated potentiation. 6-Methylthioinosine alone had much greater effect on DNA synthesis of HeLa cells than on L5178Y cells, and Amphotericin-B failed to potentiate the action of 6-methylthioinosine in HeLa cells.

Amphotericin B↗
PubMed1985

Simple synthetic procedure for 2'- and 3'-tetrahydropyranyl ribonucleoside derivatives involving regioselective acylation with acyl chlorides, and synthesis of ribonucleotide oligomers.

Acylation of ribonucleosides through acyl chlorides in pyridine was induced with high regioselectivity under a controlled condition to give the corresponding 2',5'-diacylates in excellent yields and 2'-acylates, depending on the amount of the acyl chlorides used. On the other hand, a treatment of these resulting acylates on a silica gel (Wakogel C-300, Wako Pure Chemical Co. Ltd.) conducted their transformation into the corresponding 3',5'-diacylates or 3'-acylates effectively. These resulting 2',5'- and 3',5'-diacylates were further derived, by the known method, into the 3'- and 2'-O-tetrahydropyran-2-yl ribonucleoside derivatives, respectively, with which some ribonucleotide oligomer syntheses have been performed.

Acylation↗
PubMed1979

Schedule-dependency assessments of ribonucleoside diphosphate reductase inhibitors when used in combination with platinum compounds plus cyclophosphamide in the treatment of advanced L1210 leukemia.

Each of three ribonucleoside diphosphate reductase inhibitors was used as a third drug in combination with selected antitumor platinum (Pt) agents and cyclophosphamide (CY) in the treatment of advanced L1210 leukemia in C57BL/6 x DBA/2 mice. Each was synergistic with the various Pt plus CY combinations but the effect was highly schedule dependent. The collective cure rate was 68% when hydroxyurea (HU) was given as a single injection with Pt plus CY; the cure rate was 15% when HU was administered on a divided-dose schedule with Pt plus CY. The collective cure rate was 53% when guanazole was given as a single injection with Pt plus CY, but was only 8% when it was given on a divided-dose schedule with Pt plus CY. The effect of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, when used as a third drug with the various Pt plus CY regimens, was not schedule dependent as assessed by the collective cure rate. A therapeutic synergy between CY and each of the three ribonucleoside diphosphate reductase inhibitors was also observed.

Animals↗
PubMed1983

Synthesis of phosphono-pyrimidine and -purine ribonucleosides.

The reaction of the lithiated species of 2', 3', 5'-tri-O-protected uridines and 6-chloropurine ribonucleoside with diethyl chlorophosphate provided the corresponding diethyl phosphonate derivatives (III, IV and VIII). The Arbuzov-reaction of 2', 3', 5'-tri-O-protected 4-chloro-2(1H)-pyrimidinone ribonucleoside with triethyl phosphite afforded the diethyl phosphonate derivative (VI).

Chemical Phenomena↗
PubMed1982

Synthesis of 6- and 8-alkynylated purines and their ribonucleosides by the coupling of halopurines with alkynes.

Coupling reaction of 6-iodo- or 6-chloropurine with alkynes in the presence of (PPh3) 2PdCl2-CuI catalyst in triethylamine to give 6-alkynylated purines was achieved by the use of dipolar aprotic solvent as co-solvent. Under the reaction conditions, ribonucleoside as well as its tri-O-acetate of 6-chloropurine also gave the corresponding alkynylated products in high yields. Though similar reaction for 8-bromo-derivatives of adenine and guanine gave poor yields, the 8-alkynylated free bases could be obtained by acid hydrolysis of the alkynylated ribonucleosides. 6-Alkynylated purines exhibited moderate to weak cytokinin activity in Amaranthus test.

Alkynes↗
PubMed1980

Ribonucleoside and ribonucleotide derivatives in polynucleotide synthesis.

Suitably protected ribonucleotide and ribonucleoside derivatives have been employed as versatile intermediates in both oligoribo- and oligodeoxyribonucleotide synthesis by the phosphotriester method. Thus, the barium salt of 5'-O-dimethoxytrityl-2'-O-(o-nitrobenzyl) uridine-3' p-chlorophenyl-phosphate was used to prepare U-U-U as one example of a procedure that has general applicability in the construction of oligoribonucleotides. In addition, ribonucleosides like N4,O2',O3'-tribenzoylcytidine, and ribonucleotides such as the 2',3'-O-bis(dimethoxytrityl) and 2',3'-O-methoxymethylidene derivatives of uridine-5' p-chlorophenyl phosphate, provide a convenient means of introducing 3'- and/or 5'-terminal phosphate residues into oligonucleotides at the phosphotriester level.

Indicators and Reagents↗
PubMedDate not supplied

[Ribonucleoside and 2'-deoxyribonucleoside 5'-phosphonates: synthesis and antiviral activity].

Groups of 5'-phosphonates of natural 2'-deoxynucleosides and ribonucleosides were synthesized by condensation of 3'-acetylated 2'-deoxynucleosides or 2',3'-substituted (2',3'-O-isopropylidene, 2',3'-O-methoxymethylene, or 2',3'-O-ethoxymethylene) ribonucleosides. As condensing agents, either N,N'-dicyclohexylcarbodiimide or 2,4,6-triisopropylbenzenesulphonyl chloride were used. Nucleoside 5'-ethoxycarbonyl-phosphonates were converted into corresponding nucleoside 5'-aminocarbonylphosphonates by the action of ammonia in methanol. All compounds were tested for inhibition of several viruses, including human herpes simplex virus type 2 and cytomegalovirus, but showed no activity. A few compounds insignificantly inhibited human immunodeficiency virus type 1 reproduction. Thymidine 5'-hydrogenphosphonate neutralized the anti HIV action of 3'-azido-3'-deoxythymidine, thus indirectly showing that it could be partly hydrolyzed in cell culture to corresponding thymidine.

Antiviral Agents↗
PubMed2003

Hydrolytic cleavage of purine ribonucleosides in Aspergillus phoenicis.

Cell-free extracts of nitrate-grown Aspergillus phoenicis could catalyze the hydrolytic cleavage of the N-glycosidic bond of inosine, guanosine and adenosine to the corresponding base and ribose by the nucleoside hydrolase. No evidence was obtained concerning the hydrolytic degradation of N-glycosidic bond of pyrimidine ribonucleosides namely cytidine and uridine by the same extracts. Optimum pH and temperature for adenosine, guanosine and inosine hydrolysis were the same at pH 3.5 and 55 degrees C, respectively. Citrate buffer showed the highest hydrolase activity when compared to the analogous activity obtained with the other buffers used. The rate of hydrolysis of the three nucleosides was in the order inosine > guanosine > adenosine. Incubation of extracts at 55 degrees C for 15 minutes caused about 85%, 75% and 62% loss of activity with adenosine, guanosine and inosine respectively. Dialyzing the extract caused a decrease in enzyme activity. Addition of inorganic arsenate to the reaction mixture (containing adenosine, guanosine or inosine) did not affect the amount of ribose liberated. Addition of EDTA at a concentration of 5 x 10(-3) M caused an inhibition of about 50%, however a complete inhibition for enzyme activity was obtained at 10(-2) M EDTA. MgSO4, CoSO4 and ZnSO4 at a final concentration of 5 x 10(-3) M showed activation of ribonucleoside hydrolase.

Aspergillus↗
PubMed1996

Purification and properties of a human nicotinamide ribonucleoside kinase.

Nicotinamide ribonucleoside kinase (NRK) phosphorylates at least two nucleoside analogs of potential clinical interest, tiazofurin and 3-deazaguanosine. In this study NRK has been purified to near homogeneity from human placenta. The purification procedure consists of several chromatographic steps including salt precipitation, DE-52 chromatography, sucrose density gradient fractionation, hydroxylapatite chromatography, and anion exchange FPLC. The final enzyme preparation is homogeneous as judged by a single silver-stainable band on both nondenaturing and denaturing polyacrylamide gels. The molecular weight of the enzyme, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration on Superdex 75 HR 10/30, is approximately 29 and 32 kDa, respectively. The isoelectric pH for NRK is 5.6. The reaction requires ATP. The pH optimum is in the region 6.5-9.0. NRK in the purified preparations, with added bovine serum albumin, was stable for days at 4 degrees C and for months at -70 degrees C. The enzyme is very unstable at low protein concentration. NRK phosphorylated several substrates including nicotinamide ribonucleoside, guanosine, tiazofurin, and 3-deazaguanosine with apparent Km values of 9.6, 115, 90, and 16.5 microM, respectively.

Chromatography, DEAE-Cellulose↗
PubMed1985

A comparison of the dose response effects of pyrimidine ribonucleosides and adenosine on sleep in rats.

The dose-response effects of intracerebroventricular (ICV) infusion of the pyrimidine ribonucleosides cytidine and uridine and the purine ribonucleoside adenosine on sleep and wakefulness (W) in rats were examined and compared. All three drugs were administered at doses of 1,10, and 100 nmol in volumes of 5 microliter, with control animals receiving equivolumetric infusions of 0.9% saline. Treatment with 1 nmol cytidine significantly increased W and decreased both deep slow wave sleep (S2) and total sleep (TS) during both the 3-6 and 0-6 h recording periods. In addition, this dose of cytidine significantly increased light slow wave sleep (S1) during the first 3 h of recording. The 10 nmol dose of cytidine increased W and decreased TS during the 0-6 h recording. ICV administration of uridine produced no significant changes in sleep and W at any dose during any of the recording periods examined. In contrast, adenosine exhibited significant hypnotic effects at all doses examined. All three doses of adenosine significantly reduced W and increased TS during both the 0-3 and 0-6 h recording periods. The 1 and 100 nmol doses of adenosine also significantly increased S2 during both the 0-3 and 0-6 h periods. In addition, the 100 nmol dose of adenosine significantly decreased W and increased both S2 and TS during the second 3 h of recording. Both the 1 and 100 nmol doses of adenosine also significantly reduced the latencies to the onset of rapid eye movement (REM) sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1987

Determination of ribonucleoside triphosphates and deoxyribonucleoside triphosphates in Novikoff hepatoma cells by high-performance liquid chromatography.

A rapid, specific, and sensitive method has been developed for the determination of ribonucleoside and deoxyribonucleoside triphosphates in Novikoff hepatoma cells. A simple three-step procedure was used. Extraction of the biological material with 5% cold trichloroacetic acid (TCA); elimination of TCA by ethilic ether wash and concentration of the sample by lyophilization; and separation of CTP, dCTP, ATP, dATP, UTP, dTTP, GTP, dGTP and their quantitation by anionic-exchange high-performance liquid chromatography under isocratic conditions. All the compounds were identified by comparing their retention times with those of pure compounds, by cochromatography with single pure ribonucleoside triphosphates (NTPs) or deoxyribonucleoside triphosphates (dNTPs), and by comparing the 280 nm:254 nm spectral ratios of the peaks with those of known NTP and dNTP standards. The specific activity of all the above mentioned nucleotides also was determined in Novikoff hepatoma cells labeled with [32P]orthophosphate.

Animals↗
PubMed1975

Fluctuations in deoxyribo- and ribonucleoside triphosphate pools during the mitotic cycle of Physarum polycephalum.

Fluctuations in the pools of deoxyribo- and ribonucleoside triphosphates have been measured during the synchronous mitotic cycle of the slime mould Physarum polycephalum. The most pronounced fluctuation of the deoxyribonucleoside triphosphates was seen shortly before and after initiation of DNA synthesis. The pools of dTTP, dATP, dCTP and dGTP expanded before initiation of DNA synthesis and decreased again in early S phase. The pools of ribonucleoside triphosphates increased during mitosis and again 1 h after mitosis and 5 h after mitosis.

DNA Replication↗