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Handbook of Experimental Pharmacology 2017After decades of intensive research on adenosine-3',5'-cyclic monophosphate (cAMP)- and guanosine-3',5'-cyclic monophosphate (cGMP)-related second messenger systems,... (Review)
Review
After decades of intensive research on adenosine-3',5'-cyclic monophosphate (cAMP)- and guanosine-3',5'-cyclic monophosphate (cGMP)-related second messenger systems, also the noncanonical congeners cyclic cytidine-3',5'-monophosphate (cCMP) and cyclic uridine-3',5'-monophosphate (cUMP) gained more and more interest. Until the late 1980s, only a small number of cCMP and cUMP analogs with sometimes undefined purities had been described. Moreover, most of these compounds had been rather synthesized as precursors of antitumor and antiviral nucleoside-5'-monophosphates and hence had not been tested for any second messenger activity. Along with the recurring interest in cCMP- and cUMP-related signaling in the early 2000s, it became evident that well-characterized small molecule analogs with reliable purities would serve as highly valuable tools for the evaluation of a putative second messenger role of cyclic pyrimidine nucleotides. Meanwhile, for this purpose new cCMP and cUMP derivatives have been developed, and already known analogs have been resynthesized and highly purified. This chapter summarizes early medicinal chemistry work on cCMP and cUMP and analogs thereof, followed by a description of recent synthetic developments and an outlook on potential future directions.
Topics: Animals; Crystallization; Cyclic CMP; Humans; Molecular Structure; Nucleotides, Cyclic; Permeability; Prodrugs; Uridine Monophosphate
PubMed: 27896476
DOI: 10.1007/164_2015_41 -
Advances in Space Research : the... 1997The abiogenic synthesis of pyrimidine nucleotides in solid state has been investigated. Our experiment indicates that natural nucleotides are produced in thin films...
The abiogenic synthesis of pyrimidine nucleotides in solid state has been investigated. Our experiment indicates that natural nucleotides are produced in thin films prepared from nucleoside and inorganic phosphate by irradiating with vacuum ultraviolet light (VUV, lambda=100-200 nm). We have investigated the influence of the type of nucleic acids base (thymidine, cytosine, uracil) and the structure of sugar moiety (ribose or deoxyribose) on the course and yield of reaction. We compared the action of vacuum ultraviolet light with action of gamma-radiation, heat and biology significant UV (254 nm) which have been investigated earlier. The occurrence of these reaction in open space is discussed.
Topics: Cytidine; Dinucleoside Phosphates; Evolution, Chemical; Extraterrestrial Environment; Nucleosides; Phosphorylation; Photochemistry; Pyrimidine Nucleotides; Thymidine; Ultraviolet Rays; Vacuum
PubMed: 11541333
DOI: 10.1016/s0273-1177(97)00353-0 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2024Besides being a key player in numerous fundamental biological processes, RNA also represents a versatile platform for the creation of therapeutic agents and efficient...
Besides being a key player in numerous fundamental biological processes, RNA also represents a versatile platform for the creation of therapeutic agents and efficient vaccines. The production of RNA oligonucleotides, especially those decorated with chemical modifications, cannot meet the exponential demand. Due to the inherent limits of solid-phase synthesis and in vitro transcription, alternative, biocatalytic approaches are in dire need to facilitate the production of RNA oligonucleotides. Here, we present a first step towards the controlled enzymatic synthesis of RNA oligonucleotides. We have explored the possibility of a simple protection step of the vicinal cis-diol moiety to temporarily block ribonucleotides. We demonstrate that pyrimidine nucleotides protected with acetals, particularly 2',3'-O-isopropylidene, are well-tolerated by the template-independent RNA polymerase PUP (polyU polymerase) and highly efficient coupling reactions can be achieved within minutes - an important feature for the development of enzymatic de novo synthesis protocols. Even though purines are not equally well-tolerated, these findings clearly demonstrate the possibility of using cis-diol-protected ribonucleotides combined with template-independent polymerases for the stepwise construction of RNA oligonucleotides.
Topics: RNA; DNA-Directed RNA Polymerases; Oligonucleotides; Ribonucleotides; Nucleotides; Pyrimidine Nucleotides
PubMed: 38403849
DOI: 10.1002/chem.202400137 -
Trends in Molecular Medicine Oct 2018Innovations in epitranscriptomics have resulted in the identification of more than 160 RNA modifications to date. These developments, together with the recent discovery... (Review)
Review
Innovations in epitranscriptomics have resulted in the identification of more than 160 RNA modifications to date. These developments, together with the recent discovery of writers, readers, and erasers of modifications occurring across a wide range of RNAs and tissue types, have led to a surge in integrative approaches for transcriptome-wide mapping of modifications and protein-RNA interaction profiles of epitranscriptome players. RNA modification maps and crosstalk between them have begun to elucidate the role of modifications as signaling switches, entertaining the notion of an epitranscriptomic code as a driver of the post-transcriptional fate of RNA. Emerging single-molecule sequencing technologies and development of antibodies specific to various RNA modifications could enable charting of transcript-specific epitranscriptomic marks across cell types and their alterations in disease.
Topics: Cardiovascular Diseases; Congenital Abnormalities; Epigenesis, Genetic; High-Throughput Nucleotide Sequencing; Humans; Metabolic Diseases; Methylation; Mitochondrial Diseases; Neoplasms; Nervous System Diseases; Purine Nucleotides; Pyrimidine Nucleotides; RNA; RNA Processing, Post-Transcriptional; Transcriptome
PubMed: 30120023
DOI: 10.1016/j.molmed.2018.07.010 -
Canadian Journal of Microbiology Jun 2018Regulation of pyrimidine biosynthesis by pyrimidines in the emerging, opportunistic human pathogen Pseudomonas monteilii ATCC 700476 was evident. When wild-type cells...
Regulation of pyrimidine biosynthesis by pyrimidines in the emerging, opportunistic human pathogen Pseudomonas monteilii ATCC 700476 was evident. When wild-type cells were grown on succinate in the presence of uracil or orotic acid, the activities of all 5 pyrimidine biosynthetic enzymes were depressed while the activities of 3 of the enzymes decreased in glucose-grown cells supplemented with uracil or orotic acid compared with unsupplemented cells. Pyrimidine limitation of succinate- or glucose-grown pyrimidine auxotrophic cells lacking orotate phosphoribosyltransferase activity resulted in more than a doubling of the pyrimidine biosynthetic enzyme activities relative to their activities in uracil-grown cells. Independent of carbon source, pyrimidine-limited cells of the pyrimidine auxotrophic cells deficient for dihydroorotase activity generally resulted in a slight elevation or depression of the pyrimidine biosynthetic enzyme activities compared with their activities in cells grown under saturating uracil conditions. Aspartate transcarbamoylase activity in P. monteilii was regulated at the enzyme activity level, since the enzyme was strongly inhibited by CTP, UMP, GMP, GDP, ADP, and UTP. In summary, the regulation of pyrimidine biosynthesis in P. monteilii could be used to control its growth or to differentiate it biochemically from other related species of Pseudomonas.
Topics: Aspartate Carbamoyltransferase; Glucose; Orotate Phosphoribosyltransferase; Pseudomonas; Pyrimidine Nucleotides; Succinic Acid; Uracil
PubMed: 29486129
DOI: 10.1139/cjm-2018-0015 -
Journal of Agricultural and Food... Sep 2001Profiles of nucleotide levels in two varieties of Japanese green teas (cv. Yabukita and Saemidori), a Chinese green tea (Longjing), and two Japanese black teas (cv.... (Comparative Study)
Comparative Study
Profiles of nucleotide levels in two varieties of Japanese green teas (cv. Yabukita and Saemidori), a Chinese green tea (Longjing), and two Japanese black teas (cv. Benifuuki and Benihikari) were determined and compared with that of fresh tea leaves. The concentration of 5'-nucleotides in green tea was much higher than in black tea. Nucleoside diphosphates were present in larger amounts than nucleoside triphosphates in manufactured green and black teas, whereas the triphosphates predominated in fresh tea leaves. Low levels of 3'-nucleotides were found in green and black teas. Inosine 5'-monophosphate, which is utilized as a seasoning component, was found in all manufactured teas in concentrations ranging from 50 to 200 nmol/g of dry weight. The levels of both inosine 5'-monophosphate and guanosine 5'-monophosphate were high in Chinese Longjing green tea. The unique profiles of nucleotides in manufactured teas may be a consequence of the action of degradation enzymes, such as ribonuclease, apyrase, phosphatase, nucleotidase, and adenosine 5'-monophsphate deaminase during the commercial processing of the young leaves.
Topics: Chromatography, High Pressure Liquid; Food Handling; Plant Leaves; Purines; Pyrimidine Nucleotides; Tea; Time Factors
PubMed: 11559141
DOI: 10.1021/jf0104679 -
Archives of Microbiology Aug 2020The control of pyrimidine nucleotide formation in the bacterium Pseudomonas aurantiaca ATCC 33663 by pyrimidines was studied. The activities of the pyrimidine...
The control of pyrimidine nucleotide formation in the bacterium Pseudomonas aurantiaca ATCC 33663 by pyrimidines was studied. The activities of the pyrimidine biosynthetic pathway enzymes were investigated in P. aurantiaca ATCC 33663 cells and from cells of an auxotroph lacking orotate phosphoribosyltransferase activity under selected culture conditions. All activities of the pyrimidine biosynthetic pathway enzymes in ATCC 33663 cells were depressed by uracil addition to the minimal medium when succinate served as the carbon source. In contrast, all pyrimidine biosynthetic pathway enzyme activities in ATCC 33663 cells were depressed by orotic acid supplementation to the minimal medium when glucose served as the carbon source. The orotidine 5'-monophosphate decarboxylase activity in the phosphoribosyltransferase mutant strain increased by more than sixfold in succinate-grown cells and by more than 16-fold in glucose-grown cells after pyrimidine limitation showing possible repression of the decarboxylase by a pyrimidine-related compound. Inhibition by ATP, GTP, UTP and pyrophosphate of the in vitro activity of aspartate transcarbamoylase in ATCC 33663 was observed. The findings demonstrated control at the level of pyrimidine biosynthetic enzyme synthesis and activity for the P. aurantiaca transcarbamoylase. The control of pyrimidine synthesis in P. aurantiaca seemed to differ from what has been observed previously for the regulation of pyrimidine biosynthesis in related Pseudomonas species. This investigation could prove helpful to future work studying pseudomonad taxonomic analysis as well as to those exploring antifungal and antimicrobial agents produced by P. aurantiaca.
Topics: Aspartate Carbamoyltransferase; Biosynthetic Pathways; Diphosphates; Gene Expression Regulation, Bacterial; Orotate Phosphoribosyltransferase; Orotidine-5'-Phosphate Decarboxylase; Pseudomonas; Pyrimidine Nucleotides; Pyrimidines; Succinic Acid; Uracil
PubMed: 32125450
DOI: 10.1007/s00203-020-01842-x -
The Journal of Biological Chemistry Jul 2001The binding change model for the F(1)-ATPase predicts that its rotation is intimately correlated with the changes in the affinities of the three catalytic sites for...
The binding change model for the F(1)-ATPase predicts that its rotation is intimately correlated with the changes in the affinities of the three catalytic sites for nucleotides. If so, subtle differences in the nucleotide structure may have pronounced effects on rotation. Here we show by single-molecule imaging that purine nucleotides ATP, GTP, and ITP support rotation but pyrimidine nucleotides UTP and CTP do not, suggesting that the extra ring in purine is indispensable for proper operation of this molecular motor. Although the three purine nucleotides were bound to the enzyme at different rates, all showed similar rotational characteristics: counterclockwise rotation, 120 degrees steps each driven by hydrolysis of one nucleotide molecule, occasional back steps, rotary torque of approximately 40 piconewtons (pN).nm, and mechanical work done in a step of approximately 80 pN.nm. These latter characteristics are likely to be determined by the rotational mechanism built in the protein structure, which purine nucleotides can energize. With ATP and GTP, rotation was observed even when the free energy of hydrolysis was -80 pN.nm/molecule, indicating approximately 100% efficiency. Reconstituted F(o)F(1)-ATPase actively translocated protons by hydrolyzing ATP, GTP, and ITP, but CTP and UTP were not even hydrolyzed. Isolated F(1) very slowly hydrolyzed UTP (but not CTP), suggesting possible uncoupling from rotation.
Topics: Adenosine Triphosphate; Catalytic Domain; Guanosine Triphosphate; Hydrolysis; Inosine Triphosphate; Kinetics; Models, Chemical; Protein Conformation; Proton-Translocating ATPases; Purine Nucleotides; Pyrimidine Nucleotides; Uridine Triphosphate
PubMed: 11279248
DOI: 10.1074/jbc.M102200200 -
Pyrimidine nucleotide synthesis in Pseudomonas nitroreducens and the regulatory role of pyrimidines.Microbiological Research Dec 2014Control of pyrimidine biosynthesis in the commercially important, hydrocarbon-utilizing bacterium Pseudomonas nitroreducens ATCC 33634 was investigated. When...
Control of pyrimidine biosynthesis in the commercially important, hydrocarbon-utilizing bacterium Pseudomonas nitroreducens ATCC 33634 was investigated. When glucose-grown wild-type cells were supplemented with uracil or orotic acid, the pyrimidine biosynthetic activities were depressed. Pyrimidine limitation of glucose-grown cells of an orotate phosphoribosyltransferase mutant caused aspartate transcarbamoylase and dihydroorotase activities to increase by about 4-fold while the other enzyme activities about doubled. In succinate-grown phosphoribosyltransferase mutant cells subjected to pyrimidine limitation, transcarbamoylase and dehydrogenase activities rose by about 5-fold while dihydroorotase activity more than tripled. In an OMP decarboxylase mutant, pyrimidine limitation of glucose-grown cells increased transcarbamoylase, dihydroorotase, dehydrogenase and phosphoribosyltransferase activities by 4-, 10-, 6- and 3.8-fold, respectively. Pyrimidine limitation of the succinate-grown decarboxylase mutant cells increased aspartate transcarbamoylase or dihydroorotase by more than 4-fold and the other activities by about 2-fold. Pyrimidine biosynthetic enzyme synthesis appeared to be regulated by pyrimidines with the regulation being influenced by the carbon source present. Aspartate transcarbamoylase activity in Ps. nitroreducens was regulated at the level of enzyme activity since the enzyme was strongly inhibited by UDP, pyrophosphate, ATP and ADP. Overall, the regulation of pyrimidine biosynthesis in Ps. nitroreducens can be used to differentiate it from other taxonomically related species of Pseudomonas.
Topics: Aspartate Carbamoyltransferase; Pseudomonas; Pyrimidine Nucleotides; Pyrimidines
PubMed: 24867376
DOI: 10.1016/j.micres.2014.04.003 -
Biochimica Et Biophysica Acta Jan 1989The activity of phosphoribosylpyrophosphate (PRPP) synthetase (ATP: D-ribose-5-phosphate pyrophosphotransferase, EC 2.7.6.1) is decreased in the erythrocyte in...
Pyrimidine nucleotides impair phosphoribosylpyrophosphate (PRPP) synthetase subunit aggregation by sequestering magnesium. A mechanism for the decreased PRPP synthetase activity in hereditary erythrocyte pyrimidine 5'-nucleotidase deficiency.
The activity of phosphoribosylpyrophosphate (PRPP) synthetase (ATP: D-ribose-5-phosphate pyrophosphotransferase, EC 2.7.6.1) is decreased in the erythrocyte in hereditary pyrimidine 5'-nucleotidase (P5N) deficiency. Given the increased pyrimidine nucleotide content of the P5N-deficient erythrocyte, we evaluated the effects of prototypic pyrimidine nucleotides on the activity of PRPP synthetase. In normal hemolysate a 1.0 mM combination of cytidine tri-, di- and monophosphate (CTP/CDP/CMP) inhibited PRPP synthetase activity and changed the ribose 5-phosphate (R5P) saturation curve from a hyperbola to a biphasic shape. Untreated crude hemolysate from P5N-deficient erythrocytes showed a biphasic R5P kinetic curve. Since the activity of PRPP synthetase is dependent on its state of subunit aggregation, we examined PRPP synthetase subunit aggregation using gel permeation chromatography. P5N-deficient erythrocytes had a decreased absolute amount of aggregated PRPP synthetase and almost a total loss of disaggregated PRPP synthetase. Using normal hemolysate, 1 mM CTP/CDP/CMP interfered with the ability of 1.0 mM ATP and 2.0 mM MgCl2 to promote PRPP synthetase subunit aggregation. Increasing the MgCl2 to 6.0 mM overcame the inhibitory effect of CTP/CDP/CMP. Thus, the decreased PRPP synthetase activity of the P5N-deficient erythrocyte is due, at least in part, to the ability of the accumulated pyrimidine nucleotides to sequester magnesium and to interfere with the subunit aggregation of PRPP synthetase.
Topics: 5'-Nucleotidase; Adenosine Monophosphate; Adenosine Triphosphate; Anemia, Hemolytic, Autoimmune; Cytidine Diphosphate; Cytidine Monophosphate; Cytidine Triphosphate; Erythrocytes; Humans; Kinetics; Macromolecular Substances; Magnesium; Magnesium Chloride; Nucleotidases; Phosphotransferases; Pyrimidine Nucleotides; Ribose-Phosphate Pyrophosphokinase; Ribosemonophosphates
PubMed: 2535789
DOI: 10.1016/0167-4838(89)90065-4