PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “PYRIMIDINES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources
PubMedDate not supplied

Recombination and amplification of pyrimidine-rich sequences may be responsible for initiation and progression of the Xq27 fragile site: an hypothesis.

HYPOTHESIS: A pyrimidine-rich sequence (PRS) of DNA is present as a normal sequence in the q27 band of the human X chromosome. Under conditions of pyrimidine nucleotide triphosphate deprivation during S phase, deoxyuridine monophosphate is misincorporated and has to be excised during G2 by DNA repair mechanisms. When a simple PRS is present on both homologous X chromosomes during oogenesis, PRS may undergo amplification through non-homologous crossing-over to produce the initial lesion of the fragile (X). Carriers of such initial lesions will be unaffected transmitting females or males. When an X chromosome bearing such an initial lesion is itself paired with a homologous X carrying a simple PRS during oogenesis, a much higher rate of non-homologous crossing-over may occur resulting in progression to an even longer stretch of pyrimidine rich DNA in this region; the increased length of PRS through amplification makes the region too long to be repaired during G2 and allows it to be seen as a fragile site in metaphase chromosome preparations. Furthermore, this amplified lesion may interfere with transcription of one or more genes in this region and produce the phenotype of the Martin-Bell syndrome.

Base Sequence↗
PubMed1990

Evaluation of pyrimido[5,4-d]pyrimidine derivatives as peroxyoxalate chemiluminescence reagents using a flow injection system.

Eighteen kinds of pyrimido[5,4-d]pyrimidines together with several commercially available fluorescent compounds such as perylene, Rhodamine B, etc., were evaluated as the reagents for a peroxyoxalate chemiluminescence (CL) detection system by using a flow injection method. The peroxyoxalate CL reaction employed consists of bis(2,4,6-trichlorophenyl)oxalate, hydrogen peroxide, triethylamine, and a fluorophore. Under the conditions used, 2,6-bis[di-(2-hydroxyethyl)amino]-4,8- dipiperidinopyrimido[5,4-d]pyrimidine (Dipyridamole) and 2,4,6,8-tetrathiomorpholinopyrimido[5,4-d]pyrimidine (1i) gave very intense chemiluminescence intensities which were larger than those of any other commercially available fluorescent compounds tested (e.g., 10 times larger than that of perylene).

Chromatography, High Pressure Liquid↗
PubMed2004

Ultrafast proton-coupled electron-transfer dynamics in pyrene-modified pyrimidine nucleosides: model studies towards an understanding of reductive electron transport in DNA.

5-(Pyren-1-yl)-2'-deoxyuridine (PydU) and 5-(Pyren-1-yl)-2'-deoxycytidine (PydC) were used as model nucleosides for DNA-mediated reductive electron transport (ET) in steady-state fluorescence and femtosecond time-resolved transient absorption spectroscopy studies. Excitation of the pyrene moiety in PydU and PydC leads to an intramolecular electron transfer that yields the pyrenyl radical cation and the corresponding pyrimidine radical anion (dU.- and dC.-. By comparing the excited state dynamics of PydC and PydU, we derived information about the energy difference between the two pyrimidine radical anion states. To determine the influence of protonation on the rates of photoinduced intramolecular ET, the spectroscopic investigations were performed in acetonitrile, MeCN, and in water at different pH values. The results show a significant difference in the basicity of the generated pyrimidine radical anions and imply an involvement of proton transfer during electron hopping in DNA. Our studies revealed that the radical anion dC.- is being protonated even in basic aqueous solution on a picosecond time scale (or faster). These results suggest that protonation of dC.- may also occur in DNA. In contrast, efficient ET in PydU could only be observed at low pH values (< 5). In conclusion, we propose--based on the free energy differences and the different basicities--that only dT.- but not dC.- can participate as an intermediate charge carrier for excess electron migration in DNA.

Anions↗
PubMed1991

Alteration in de novo pyrimidine biosynthesis during uridine reversal of pyrazofurin-inhibited DNA synthesis.

Pyrazofurin, a pyrimidine nucleoside analogue with antineoplastic activity, inhibits cell proliferation and DNA synthesis in cells by inhibiting uridine 5'-phosphate (UMP) synthase. It has been previously shown in concanavalin A (con A)-stimulated guinea pig lymphocytes (23) that pyrazofurin-inhibited DNA synthesis could be selectively reversed by exogenous uridine (Urd). In this report, we have examined possible mechanisms for the Urd reversal with experiments that determine the ability of exogenous Urd to (a) interfere with either the intracellular transport of pyrazofurin, or the conversion of pyrazofurin to its intracellularly active form, pyrazofurin-5'-phosphate; (b) reverse the pyrazofurin block of [14C]orotic acid incorporation into DNA; and (c) alter the pattern of exogenous [3H]Urd incorporation into DNA-thymine (DNA-Thy) and DNA-cytosine (DNA-Cyt) during pyrazofurin inhibition of pyrimidine de novo biosynthesis. The results of these experiments showed that Urd reversal does not occur through altered pyrazofurin transport or intracellular conversion to pyrazofurin-5'-phosphate, nor does it alter the distribution of [3H]Urd in DNA-Thy and DNA-Cyt. Instead, these findings indicate that the primary mechanism for exogenous Urd reversal of pyrazofurin inhibition of DNA synthesis involves the reversal of pyrazofurin inhibition of UMP synthase, thus restoring orotic acid incorporation into lymphocyte DNA through the pyrimidine de novo pathway.

Amides↗
PubMed1979

Biochemical genetic analysis of pyrimidine biosynthesis in mammalian cells. II. Isolation and characterization of a mutant of Chinese hamster ovary cells with defective dihydroorotate dehydrogenase (E.C. 1.3.3.1) activity.

A mutant (A204) of Chinese hamster ovary cells (CHO-K1), which is deficient in dihydroorotate (DHO) dehydrogenase (E.C. 1.3,3.1) activity, has been isolated by a replica plating procedure. The mutant does not show a requirement for exogenously added pyrimidines. Examination of intact cells shows that the mutant accumulates a large amount of carbamyl aspartate and is markedly but not totally deficient in biosynthesis of orotate from earlier precursors of pyrimidine biosynthesis, including aspartate and dihydroorotic acid, when compared to wild-type cells. Analysis of cell-free extracts of mutant and wild-type cells shows that the mutant is deficient in DHO dehydrogenase activity, possessing ca. 5% of the wild-type activity. this evidence leads to the conclusion that this mutant, A204, is in fact partially deficient in DHO dehydrogenase, and that in these cells it is this enzyme which carries out the fourth step of de novo pyrimidine biosynthesis.

Animals↗
PubMed1993

Synthesis and study of the anti-inflammatory properties of some pyrazolo[1,5-a]pyrimidine derivatives.

A series of pyrazolo[1,5-a]pyrimidin-7-ones (1c-17c) were synthesized to evaluate in vivo and in vitro effects induced by structural modifications at the 2 position of 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one (FPP028). This substance, which has been previously studied, is a weak inhibitor of prostaglandin biosynthesis and a nonacid analgesic and anti-inflammatory agent devoid of ulcerogenic properties. To gain more insight into the mechanism of action of this class of compounds, several in vivo tests were carried out, such as carrageenan-induced rat paw edema and pleurisy. In vitro tests include some studies of leukocyte functions, such as superoxide production and myeloperoxidase release. In vitro effects on arachidonic acid-, adenosine 5'-diphosphate-, and platelet-activating factor-induced platelet aggregation were also studied. Different anti-inflammatory activities were observed, depending on the nature of substituents at the 2 position; these differences are probably linked to the capacity of these compounds to inhibit leukotrienes and/or prostaglandin biosynthesis with different selectivity. 4,7-Dihydro-4-ethyl-2(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-one (7c) proved to be the most interesting compound of the novel synthesized series, showing powerful pharmacological activity in vivo as well as in vitro, together with very weak acute toxicity.

Animals↗
PubMed2003

Highly potent and selective inhibition of varicella-zoster virus replication by bicyclic furo[2,3-d]pyrimidine nucleoside analogues.

The bicyclic furo[2,3-d]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella-zoster virus (VZV). From extensive structure-activity relationship (SAR) studies, the 6-(p-alkylphenyl)substituted furopyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000-fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV-encoded thymidine kinase. The furo[2,3-d]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydropyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5-fluorouracil. Further development of the furo[2,3-d]pyrimidine nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified.

Animals↗
PubMed2005

Photodimerization in pyrimidine-substituted dipeptides.

Ten N(epsilon)-glycylornithineamide derivatives have been synthesized containing various N(alpha)-linked pyrimidine-1-ylacetyl groups which can undergo (2pi + 2pi) photodimerization on irradiation with UV light at 254 nm. The dimerization efficiency of the free and bound pyrimidine groups was compared in aqueous solution: it was dependent on the substitution of the pyrimidine ring. N(alpha),N(alpha')-bis-(uracil-1-ylacetyl)-(N(epsilon)-glycylornithineamide) and N(alpha),N(alpha')-bis-(5-bromouracil-1-ylacetyl)-(N(epsilon)-glycylornithineamide) were identified as possible candidates for optical data storage.

Acetates↗
PubMed2006

Analysis of urinary nucleosides. V. Identification of urinary pyrimidine nucleosides by liquid chromatography/electrospray mass spectrometry.

Modified urinary nucleosides are potentially invaluable in cancer diagnosis, as they reflect altered RNA turnovers. High-performance liquid chromatography (HPLC) was combined with full-scan mass spectrometry, tandem mass spectrometry, MS(n) analysis and accurate mass measurements in order to identify pyrimidine nucleosides purified from urine. Potential nucleosides were assessed by their evident UV absorbance in the HPLC chromatogram and then further examined by the various mass spectrometric techniques. In this manner numerous pyrimidine nucleosides were identified in the urine samples from cancer patients including pseudouridine, cytidine, two methylcytidines and an acetylcytidine. Furthermore, a number of novel modified pyrimidine nucleosides were tentatively identified via critical interpretation of the combined mass spectrometric data.

Biomarkers, Tumor↗
PubMed1998

High cleavage activity and stability of hammerhead ribozymes with a uniform 2'-amino pyrimidine modification.

The uniform 2'-pyrimidine modifications have been found to inhibit ribozyme cleavage activity. However, in the present study we show that a good cleavage activity can be achieved for the 2'-amino modified ribozymes when their sequences were designed to contain only a few pyrimidines in helix I. In particular, ribozymes with no pyrimidines in helix I cleaved their target RNAs with almost the same efficacy as their unmodified versions. Interestingly, selective 2'-amino modification at positions 2.1 and 2.2 reduced the ribozyme cleavage activity by 8-fold, suggesting that the 2'-amino groups at these two positions may interfere with the formation of the ribozyme active conformation. In addition, uniformly modified ribozymes showed a remarkable stability in serum. Taken together these results should facilitate the design of stable ribozymes with sustained cleavage activity.

Base Sequence↗
PubMed1995

Crystal structure of a pyrimidine dimer-specific excision repair enzyme from bacteriophage T4: refinement at 1.45 A and X-ray analysis of the three active site mutants.

Crystallographic study of bacteriophage T4 endonuclease V, which is involved in the initial step of the pyrimidine dimer-specific excision repair pathway, has been carried out with respect to the wild-type and three different mutant enzymes. This enzyme catalyzes the cleavage of the N-glycosyl bond at the 5'-side of the pyrimidine dimer, and subsequently incises the phosphodiester bond at the apyrimidinic site through a beta-elimination reaction. The structure of the wild-type enzyme refined at 1.45 A resolution reveals the detailed molecular architecture. The enzyme is composed of a single compact domain classified as an all-alpha structure. The molecule is stabilized mainly by three hydrophobic cores, two of which include many aromatic side-chain interactions. The structure has a unique folding motif, where the amino-terminal segment penetrates between two major alpha-helices and prevents their direct contact, and it is incompatible with the close-packing category of helices for protein folding. The concave surface, covered with many positive charges, implies an interface for DNA binding. The glycosylase catalytic center, which comprises Glu23 and the surrounding basic residues Arg3, Arg22 and Arg26, lie in this basic surface. The crystal structures of the three active-site mutants, in which Glu23 was replaced by Gln(E23Q) and Asp (E23D), respectively, and Arg3 by Gln (R3Q), have been determined at atomic resolution. The backbone structures of the E23Q and R3Q mutants were almost identical with that of the wild-type, while the E23D mutation induces a small, but significant, change in the backbone structure, such as an increase of the central kink of the H1 helix at Pro25. In the catalytic center of the glycosylase, however, these three mutations do not generate notable movements of protein atoms, except for significant shifts of some bound water molecules. Thus, the structural differences between the wild-type and each mutant are confined to the remarkably small region around their replaced chemical groups. Combined with the biochemical studies and the difference circular dichroism measurements, these results allow us to conclude that the negatively charged carboxyl group of Glu23 is essential for the cleavage of the N-glycosyl bond, and that the positively charged guanidino group of Arg3 is crucial to bind the substrate, a DNA duplex containing a pyrimidine dimer. The amino terminal alpha-amino group is located at a position approximately 4.4 A away from the carboxyl group of Glu23. These structural features are generally consistent with the reaction scheme proposed by Dodson and co-workers.

Amino Acid Sequence↗
PubMed1998

Synthesis and characterisation of oligodeoxynucleotides containing thio analogues of (6-4) pyrimidine-pyrimidinone photo-dimers.

A method for the preparation of an oligodeoxynucleotide, 20 bases in length, containing centrally located thio analogues of (6-4) pyrimidine-pyrimidinone thymine photo-dimers is reported. The approach is based on the selective irradiation, at 350 nm, of a Tp4ST (4ST = 4-thiothymidine) step within a 20-mer having the sequence: d(ACTCGGACCT(4sT)CGCTGTGAT). Conversion of the S5-(6-4)/S5-thietane pyrimidine-pyrimidinone, initially formed, to its S5-Dewar isomer is by a subsequent irradiation at 300 nm. Both of the photo-dimer-containing oligonucleotides were purified by HPLC (ion exchange and reverse phase) and characterised by base composition analysis. The S5-(6-4)/S5-thietane pyrimidine-pyrimidinone containing 20-mer has a characteristic UV absorbance at 320 nm and exhibits strong fluorescence when excited at this wavelength. As expected, conversion to the S5-Dewar isomer abolished both the 320 nm absorbance and the fluorescence emission. The lengths of the oligonucleotides produced allowed the formation of stable double-stranded DNA, by hybridisation to a complementary sequence. Examination of these duplexes by circular dichroism spectroscopy showed that they formed B-DNA, with little changes to their gross structure as compared to the parent duplex. However, local structural perturbations in the region of the photo-dimer cannot be excluded. The S5-(6-4)/S5-thietane photoproduct lowered the tm by 10.5 deg. C and the Dewar isomer by 12 deg. C. The degree of curvature induced in the DNA sequence by the introduction of the photo-dimers was assessed by analysing the migration of modified and unmodified multimer ladders on polyacrylamide gels. Both photoproducts induced considerable bending into the DNA. A comparison with a six-base-pair T tract, a bending standard that has a known bend angle of 19 degrees, gave values of around 47 degrees for the S5-(6-4)/S5-thietane product and about 28 degrees for the S5-Dewar isomer.

DNA↗
PubMed1980

Photoreactivation of UV induced cell killing, chromosome aberrations, sister chromatid exchanges, mutations and pyrimidine dimers in Xenopus laevis fibroblasts.

Fibroblasts from Xenopus laevis, which possess photoreactivating enzyme were used to study the influence of photoreactivating light on the frequency of pyrimidine dimers in DNA, chromosomal aberrations, sister chromatid exchanges, cell killing and the induction of gene mutations (ouabain-resistance) induced by 254 nm ultraviolet irradiation. The frequency of all biological endpoints studied were reduced following exposure to photoreactivating light parallel to the reduction in the frequencies of pyrimidine dimers (determined as endonuclease sensitive sites). However there was not always an absolute quantitative relationship between the reduction in the frequency of pyrimidine dimers and the reduction in the biological effects. This probably reflects a fast fixation process for the biological effects prior to removal of the dimers by photoreactivation.

Animals↗
PubMed1976

Pyrimidine auxotrophy and the complementation map of the rudimentary locus of Drosophila melanogaster.

The complementation pattern of twelve rudimentary mutations have been analyzed at two different levels. When analyzed on the basis of complementation for a wing abnormality the mutations can be divided into three groups, each of which is believed to affect the activity of one of the first three enzymes of pyrimidine synthesis (Norby, 1973; Jarry and Falk, 1974; Rawls and Fristrom, 1975). However, when the mutants are analyzed for complementation on the basis of a second phenotype, pyrimidine auxotrophy, the distinction between two of these three groups is not evident. The disparity in the two patterns probably reflects a different threshold of gene activity required for the detection of an auxotrophic phenotype as compared to that at which a wing abnormality is detectable. The biochemical basis of these results is interpreted in light of recent data suggesting that at least the first two enzymes of pyrimidine synthesis are contained within a single multifunctional protein complex (Soderholm et al., 1975).

Animals↗
PubMed1981

Are pyrimidine dimers non-instructive lesions?

Published data from yeast and E. coli show that base substitution induced by UV in pyrimidine-pyrimidine sequences is not random, and suggest that fidelity of DNA replication is not entirely lost during transdimer synthesis. These observations question whether cyclobutane pyrimidine dimers are truly non-instructive lesions.

DNA Repair↗
PubMed1976

Hereditary hemolytic anemia with erythrocyte pyrimidine 5'-nucleotidase deficiency in Spain. Clinical, biological and familial studies.

We report a hereditary hemolytic anemia associated with a severe erythrocyte pyrimidine 5'-nucleotidase deficiency in a Spanish family of five members in which the parents are first cousins. Both parents exhibited decreased nucleotidase activity without clinical or hematologic abnormalities. Two children (a male and a female) showed severe pyrimidine 5'-nucleotidase deficiency with hemolytic anemia. The remaining child (a male) showed no signs of the disease. The findings strongly suggest an autosomal recessive mode of inheritance in this enzymopathy. This seems to be the first report of pyrimidine 5'-nucleotidase deficiency in Spain.

Adenosine Triphosphate↗
PubMed1982

Defective excision of pyrimidine dimers and interstrand DNA crosslinks in rad7 and rad23 mutants of Saccharomyces cerevisiae.

Excision of pyrimidine dimers and interstrand DNA crosslinks was examined in the deletion mutants rad7-delta 1, rad23-delta 1, and rad7-delta 1 rad23-delta 1. These mutants remove pyrimidine dimers and crosslinks much less efficiently than the RAD+ strains; only 30-60% of pyrimidine dimers and 25-40% of crosslinks are removed even after prolonged incubation. The rad7 and rad23 mutations may represent defects in protein factors which increase the efficiency of the nicking enzyme complex or make chromatin more accessible to the nicking activity.

Biological Evolution↗