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At least 19 recordsLinked to original sources
PubMed1976

Active site of ribonucleoside diphosphate reductase from Escherichia coli. Inactivation of the enzyme by 2'-substituted ribonucleoside diphosphates.

Ribonucleoside diphosphate reductase is an allosteric enzyme consisting of two nonidentical subunits, proteins B1 and B2. B1 contains dithiols which participate in the oxidation-reduction reactions of electron transport, while B2 contains a free radical essential for activity. Ribonucleoside diphosphates are bound to B1 but not to B2. Addition of 2'-deoxy-2'-chloro ribonucleoside diphosphates to ribonucleotide reductase irreversibly inactivates B1 without affecting B2. The reaction is specific since (a) it requires the presence of active B2, (b) it is controlled by allosteric effectors, (c) B1 is protected against inactivation by the normal substrates, and (d) the chloro-substituted nucleoside monophosphates have no effect. The inactivation of B1 is caused by a modification of the oxidation-reduction dithiols. The chloro derivatives decompose into free base, chloride ion, and 2-deoxyribose 5-diphosphate as a consequence of reaction with the enzyme. 2'-Deoxy-2"-azido ribonucleoside diphosphates cause an irreversible inactivation of B2 without affecting B1. The reaction is specific by the above criteria, indicating that the azido derivatives also bind to the active site of the enzyme. On reduction by ribonucleotide reductase, the azido derivatives function as radical scavengers and selectively destroy the free radical of B2, indicating that this radical participates in ribonucleotide reduction directly. On the basis of these results, a model of the active site of ribonucleotide reductase is proposed in which the site is formed from both B1 and B2. In the site the electron-donating oxidation-reduction active dithiols of B1 are in close contact with the free radical of B2. The azido derivative also inactivates the adenosylcobalamin-dependent ribonucleoside triphosphate reductase from Lactobacillus leichmannii and a ribonucleotide reductase preparation from calf thymus, indicating a general involvement of free radical intermediates in enzyme-catalyzed ribonucleotide reduction.

Escherichia coli↗
PubMed1985

Anti-leishmanial effect of allopurinol ribonucleoside and the related compounds, allopurinol, thiopurinol, thiopurinol ribonucleoside, and of formycin B, sinefungin and the lepidine WR6026.

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Adenosine↗
PubMed1989

Transition-state stabilization by adenosine deaminase: 1,6-addition of water to purine ribonucleoside, the enzyme's affinity for 6-hydroxy-1,6-dihydropurine ribonucleoside, and the effective concentration of substrate water at the active site.

Positions of equilibria of highly unfavorable addition reactions, whose products are present at concentrations below the limits of detection, can be determined from equilibria of combination of anionic nucleophiles with quaternized enamines. Applied to the newly prepared 1-methylpurinium ribonucleoside cation, this method yields approximate equilibrium constants of 2 X 10(-9) M-1 for addition of water and 4 X 10(-5) M-1 for addition of N-acetylcysteine to neutral purine ribonucleoside, in dilute aqueous solution. Positions of 13C magnetic resonances and UV absorption maxima of the above complexes and comparison with those of adenosine deaminase complexes strongly suggest that purine ribonucleoside is bound by adenosine deaminase as the 1,6 covalent hydrate, not as a covalently bonded complex formed by addition of a thiol group at the active site. The favorable position of equilibrium of the hydration reaction on the enzyme, together with its extremely unfavorable position in free solution, indicates that the effective activity of substrate water at the active site is in the neighborhood of 10(10) M. The Ki value of the active diastereomer of 6-hydroxy-1,6-dihydropurine ribonucleoside is estimated as 1.6 X 10(-13) M, more than 8 orders of magnitude lower than the apparent dissociation constants of enzyme complexes with the substrate adenosine or the product inosine. The enzyme's remarkable affinity for this hydrated species, which is vanishingly rare in free solution, seems understandable in terms of the hydrate's close resemblance to a hydrated intermediate approaching the transition state in direct water attack on adenosine.

Adenosine Deaminase↗
PubMed1984

Development of a chromatographic method for the quantitative determination of minor ribonucleosides in physiological fluids. Characterization and quantitative determination of minor ribonucleosides in physiological fluids, Part I.

We describe an on-line multi-column high performance liquid chromatographic method for the selective clean-up and analysis of major and minor ribonucleosides in physiological fluids. Quantitative data obtained for the determination of some methylated ribonucleosides in human urines are compared with those obtained with the traditional off-line method. The on-line technique developed in our laboratory is distinguished from the off-line method by the following features: Sample clean-up and analysis of the target-compounds can easily be automatized, Total time of analysis, for example of urinary ribonucleosides, is decreased to 35 minutes, Laborious and error-prone evaporation and redissolution steps are avoided, Reliability of the overall analytical system can be controlled with ease, Small sample-volumes can be applied directly, Sensitive samples can be processed very rapidly under mild conditions, Results obtained with the on-line and off-line-techniques compare well.

Boronic Acids↗
PubMed1995

Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine.

6-Methylmercaptopurine ribonucleoside-5'-phosphate (MeSPuRMP), the sole metabolite of 6-methylmercaptopurine ribonucleoside (MeSPuRib), is a strong inhibitor of purine de novo synthesis, inducing depletion of intracellular purine nucleotides and subsequent cell death in several tumor cell lines. In this study prevention of MeSPuRib cytotoxicity by compounds of the purine salvage pathway was studied in Molt F4 human malignant T-lymphoblasts. Adenosine, adenine and inosine were able to prevent depletion of the adenine nucleotide pool when used in combination with 0.5 microM MeSPuRib, but had virtually no effect on depletion of guanine nucleotides. Nevertheless, these three purine compounds were able to reduce the cytotoxic effects induced by MeSPuRib. Addition of guanosine to cells treated with 0.5 microM MeSPuRib normalized the guanine nucleotide pool, but adenine nucleotides remained depleted. Under these conditions, inhibition of cell growth was significantly decreased. With the combination of guanosine and 10 microM MeSPuRib, cytotoxicity was increased compared to 10 microM MeSPuRib alone, associated with a depletion of adenine nucleotides to 9% of untreated cells. Since cell growth and cell viability of Molt F4 cells are less inhibited by MeSPuRib under conditions where adenine nucleotide depletion is prevented by purine compounds (and where the other nucleotides are depleted) we conclude that depletion of adenine nucleotides is an important factor in MeSPuRib cytotoxicity.

Adenine↗
PubMed1980

Ribonucleoside metabolism by mouse oocytes: metabolic cooperativity between the fully grown oocyte and cumulus cells.

Ribonucleoside uptake and metabolism were studied in mouse oocytes arrested at dictyate and metaphase II, with or without attached cumulus cells. Uptake of uridine and guanosine decreased after meiotic maturation, whereas that of adenosine and cytidine remained unaltered. Dictyate oocytes free of cumulus cells (denuded) phosphorylated all of the radiolabeled ribonucleosides. Little radiolabeled ribonucleoside-5'-triphosphate was found. This is in contrast to the early mouse embryo, which rapidly converts ribonucleosides to the 5'-triphosphate (Daentl and Epstein, "71; Clegg and Piko, "77). Following meiotic maturation, the major metabolite present when metaphase II oocytes were cultured with cytidine or uridine was the ribonucleoside, whereas the 5'-monophosphate was still the major species for oocyte cultured with guanosine or adenosine. Ribonucleoside uptake was increased and the distribution of phosphorylated metabolites was different for cumulus-enclosed dictyate oocytes compared to their denuded counterparts. This increase in uptake and alteration in metabolite distribution was not observed for cumulus-enclosed metaphase II oocytes. These results are discussed in terms of gap junction-mediated metabolic cooperatively between the cumulus cells and the fully grown oocyte and the possible role this type of cell-to-cell interaction may serve during oocyte growth.

Adenosine↗
PubMed1978

Synthesis and biological activity of N6-(n-alkylureido)purine ribonucleosides and their 5'-phosphates.

Syntheses and biological activities of 12 N6-(n-alkylureido)purine ribonucleosides (alkyl chain length of 1--10, 16, and 18 carbons) and three N6-(n-alkylureido)purine ribonucleoside 5'-phosphates (chain length of 4, 9, and 10 carbons) are described. The N6-(n-alkylureido)purine ribonucleosides were prepared by a reaction of (2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine-6-carbamate and n-alkylamine in refluxing pyridine. The 5'-nucleotides were prepared by direct phosphorylation of the corresponding ribonucleoside with phosphorus oxychloride and triethyl phosphate. Some N6-(n-alkylureido)purine ribonucleosides (n-octyl, n-nonyl, and n-decyl) and their nucleotides showed a marked antiproliferative activity against L-1210 cells in culture.

Animals↗
PubMed1982

Antileishmanial action of 4-thiopyrazolo (3.4-d) pyrimidine and its ribonucleoside. Biological effects and metabolism.

Thiopurinol [4-thiopyrazolo(3.4-dyprimidine, TPP] and its ribonucleoside (TPPR) were effective in vitro against the intracellular and extracellular forms of L. braziliensis and L. mexicana. They also inhibited the transformation of the amastigote of L. donovani to the promastigote. These thio-analogues had about the same activity as allopurinol [4-hydroxypyrazolo(3.4-d)pyrimidine, HPP] and its ribonucleoside (HPPR). the thiopyrazolopyrimidines were converted primarily to the ribonucleoside-5' -phosphate (TPPR-MP) and to an unidentified metabolite, but not to any of the adenine ribonucleoside analogues previously shown to be formed from allopurinol and its ribonucleoside. There was an antagonism between the growth-inhibitory effects of allopurinol and thiopurinol. This is consistent with the findings that the intracellular concentrations of TPP and TPPR-MP are sufficient to inhibit the conversion of allopurinol to allopurinol ribonucleotide (HPPR-MP) by the hypoxanthine-guanine phosphoribosyltransferase by 30 per cent and the amination of HPPR-MP by adenylosuccinate synthetase by 50 per cent respectively. Consequently, the incorporation of the aminated product (aminopyrazolopyrimidine) into RNA was substantially decreased. The difference in metabolism between the thio- and hydroxypyrazolopyrimidines suggests a difference in their mechanisms of action against the pathogenic leishmania.

Allopurinol↗
PubMed1989

Binding of pyrimidin-2-one ribonucleoside by cytidine deaminase as the transition-state analogue 3,4-dihydrouridine and the contribution of the 4-hydroxyl group to its binding affinity.

Cytidine deaminase, purified to homogeneity from constitutive mutants of Escherichia coli, was found to bind the competitive inhibitors pyrimidin-2-one ribonucleoside (apparent Ki = 3.6 x 10(-7) M) and 5-fluoropyrimidin-2-one ribonucleoside (apparent Ki = 3.5 x 10(-8) M). Enzyme binding resulted in a change of the lambda max of pyrimidin-2-one ribonucleoside from 303 nm for the free species to 239 nm for the bound species. The value for the bound species was identical with that of an oxygen adduct formed by combination of hydroxide ion with 1,3-dimethyl-2-oxopyrimidinium (239 nm), but lower than that of a sulfur adduct formed by combination of the thiolate anion of N-acetylcysteamine with 1,3-dimethyl-2-oxopyrimidinium (259 nm). The results suggest that pyrimidin-2-one ribonucleoside is bound by cytidine deaminase as an oxygen adduct, probably the covalent hydrate 3,4-dihydrouridine, rather than intact or as an adduct involving a thiol group of the enzyme. In dilute solution at 25 degrees C, the equilibrium constant for formation of a single diastereomer of 3,4-dihydrouridine from pyrimidin-2-one ribonucleoside was estimated as approximately 4.7 x 10(-6), from equilibria of dissociation of water, protonation of 1-methylpyrimidin-2-one, and combination of the 1,3-dimethylpyrimidinium cation with the hydroxide ion.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytidine↗
PubMed1978

Metabolic signals produced by purine ribonucleosides stimulate proinsulin biosynthesis and insulin secretion.

Inosine, guanosine and adenosine strongly stimulated proinsulin biosynthesis and insulin secretion in isolated mouse pancreatic islets. None of the purine ribonucleosides stimulated insulin secretion in rat islets, although as reported [jain & Logothetopoulos (1977) Endocrinilogy 100, 923-927] inosine and guanosine, but no adenosine, were potent stimulants of proinsulin biosynthesis in this species. The purine bases had no effect in either species. D-Ribose, which enhanced proinsulin biosynthesis at 0.3 and 0.6 mM but not at 5mM in rat pancreatic islets [jain & Logothetopoulos (1977) Endocrinology 100, 923-927], produced no secretory signals in rat islets and was without any effect on proinsulin biosynthesis and insulin secretion in mouse islets. The rates of oxidation of 14C-labelled purine ribonucleosides and D-ribose in islets of the two species correlated well with their effectiveness as inducers of insulin secretion and proinsulin biosynthesis. Specific inhibitors of purine ribonucleoside phosphorylase, adenosine deaminiase and of purine ribonucleoside transport suppressed the stimulatory effects of nucleosides in pancreatic islets without altering the effect of D-glucose. The same inhibitors also markedly diminished the oxidation rats of the labelled purine ribonucleosides. The experiments clearly indicate that porinsulin biosynthesis and insulin secretion are modulated through metabolic signals and not through interactions of intact substrate molecules with cell receptors.

Animals↗
PubMed1986

Direct clean-up and analysis of ribonucleosides in physiological fluids.

We describe the group-selective separation and quantification of unmodified, modified and hypermodified ribonucleosides in physiological fluids (urine, serum) by on-line multidimensional high-performance affinity chromatography (HPAC)-reversed-phase liquid chromatography (RPLC). The excretion levels and patterns of ribonucleosides such as N1-methyladenosine, N1-methylinosine, N2-methylguanosine, N2-dimethylguanosine, N6-carbamoylthreonyladenosine and 2-pyridone-5-carboxamido-N-ribofuranoside were determined in urines from a control group and from patients with different diseases. The HPAC-RPLC method applied represents a powerful tool, e.g. as a non-invasive screening test, a method to investigate disorders in ribonucleoside and/or RNA metabolism, a method for drug monitoring during nucleoside chemotherapy, and a method to study renal ribonucleoside reutilization.

Adolescent↗
PubMed1984

Synthesis and in vitro biological evaluation of N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine (L-alanosine AICO ribonucleoside).

L-Alanosine [3-(hydroxynitrosoamino)-L-alanine] is an antitumor antibiotic that at the present is undergoing phase II clinical trials. Its mode of action as well as its metabolism has been extensively studied, and the metabolite N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosoamino)-L-alanine ribonucleotide (L-alanosine AICOR) proved to be an extremely potent inhibitor of de novo purine biosynthesis and is thus primarily responsible for the antitumor activity of the drug. The synthesis of the corresponding ribonucleoside, i.e., N-[(5-amino-1-beta-D-ribofuranosyl-1H-imidazol-4-yl)carbonyl]-3- (hydroxynitrosamino)-L-alanine ribonucleoside (L-alanosine AICO ribonucleoside), was accomplished by condensation of a suitably protected derivative of L-alanosine with N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1H-im idazole-4-carboxylate followed by the removal of the protective groups. The biological activity of L-alanosine AICO ribonucleoside was tested in vitro on whole tumor cells and on the isolated enzyme adenylosuccinate synthetase and in vivo on murine experimental leukemia. The compound was found to be inactive in these tests.

Antibiotics, Antineoplastic↗