The Experts below are selected from a list of 6240 Experts worldwide ranked by ideXlab platform
Trevor A Thorpe - One of the best experts on this subject based on the ideXlab platform.
-
glutathione induced growth of embryogenic tissue of white spruce correlates with changes in Pyrimidine Nucleotide metabolism
Plant Science, 2005Co-Authors: Mark F Belmonte, Claudio Stasolla, Riko Katahira, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Abstract Exogenous applications of reduced glutathione (GSH) and oxidized glutathione (GSSG) promote growth of embryogenic tissue of white spruce during a 7-day subculture period. Compared to control tissue, a statistically significant increase in fresh weight, as well as RNA and DNA content, was observed in the presence of GSH and GSSG during the last days in culture. The effects of these two metabolites on Pyrimidine Nucleotide metabolism was investigated by following the metabolic fate of 14C-orotic acid, a precursor of the de novo synthesis, and 14C-uridine and 14C-uracil, intermediates of the respective salvage and degradation pathways. Compared to control embryos, GSH-treated tissue was able to utilize a larger fraction of supplied orotic acid for UMP production, possibly due to the increased activity of orotate phosphoribosyltransferase (OPRT). The activity of this enzyme increased markedly in tissue cultured with GSH during the last days in culture. Salvage of uridine for Nucleotide and nucleic acid synthesis was observed in all treatments, especially in GSSG-treated tissue at day 7. The increased salvage activity in this tissue correlated with the increase in activities of the two uridine salvage enzymes, uridine kinase (URK) and nucleoside phosphotransferase measured with uridine (NPT(uridine)). Compared to control tissue, tissue treated with either GSH or GSSG was able to utilize a large fraction of uracil for Nucleotide synthesis, denoting a better ability to divert this precursor from degradation. Nucleotide and nucleic acid analyses revealed that in both GSH and GSSG-treated tissue, the endogenous levels of UTP, CTP, as well as those of RNA and DNA, were increased compared to those of control tissue. Overall, the results from this study suggest that GSH and GSSG can induce growth of embryogenic tissue of white spruce through distinct metabolic changes of Pyrimidine Nucleotides.
-
alterations in Pyrimidine Nucleotide metabolism as an early signal during the execution of programmed cell death in tobacco by 2 cells
Journal of Experimental Botany, 2004Co-Authors: Claudio Stasolla, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Changes in Pyrimidine metabolism were investigated during programmed cell death (PCD) of tobacco BY-2 cells, induced by a simultaneous increase in the endogenous levels of nitric oxide (NO) and hydrogen peroxide. The de novo synthesis of Pyrimidine Nucleotides was estimated by following the metabolic fate of the (14)C-labelled orotic acid, whereas the rates of salvage and degradation pathways were studied by measuring the respective incorporation of (14)C-labelled uridine and uracil under different treatments. Nucleic acid metabolism was also examined using labelled thymidine as a marker. The results show that specific alterations in the balance of Pyrimidine Nucleotide synthesis, which include a decreased rate of salvage activity of uracil and uridine and increased salvage activity of thymidine, represent a metabolic switch that establishes proper cellular conditions for the induction of PCD. In particular, a reduction in the utilization of uracil for salvage products occurs very early during PCD, before the appearance of typical cytological features of the death programme, thus representing an early metabolic marker for PCD. These changes are strictly associated with PCD, since they do not occur if NO or hydrogen peroxide are increased individually, or if actinomycin, which inhibits the death programme, is added into the medium in the presence of NO and hydrogen peroxide. The possible roles of these fluctuations in Pyrimidine metabolism on the cellular Nucleotide pool are discussed in relation to the induction of cell death.
-
purine and Pyrimidine Nucleotide metabolism in higher plants
Journal of Plant Physiology, 2003Co-Authors: Claudio Stasolla, Riko Katahira, Trevor A Thorpe, Hiroshi AshiharaAbstract:Purine and Pyrimidine Nucleotides participate in many biochemical processes in plants. They are building blocks for nucleic acid synthesis, an energy source, precursors for the synthesis of primary products, such as sucrose, polysaccharides, phospholipids, as well as secondary products. Therefore, biosynthesis and metabolism of Nucleotides are of fundamental importance in the growth and development of plants. Nucleotides are synthesized both from amino acids and other small molecules via de novo pathways, and from preformed nucleobases and nucleosides by salvage pathways. In this article the biosynthesis, interconversion and degradation of purine and Pyrimidine Nucleotides in higher plants are reviewed. This description is followed by an examination of physiological aspects of Nucleotide metabolism in various areas of growth and organized development in plants, including embryo maturation and germination, in vitro organogenesis, storage organ development and sprouting, leaf senescence, and cultured plant cells. The effects of environmental factors on Nucleotide metabolism are also described. This review ends with a brief discussion of molecular studies on Nucleotide synthesis and metabolism.
-
Pyrimidine Nucleotide and nucleic acid synthesis in embryos and megagametophytes of white spruce picea glauca during germination
Physiologia Plantarum, 2002Co-Authors: Claudio Stasolla, Hiroshi Ashihara, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Pyrimidine Nucleotide synthesis was investigated in isolated germinating zygotic embryos and separated megagametophytes of white spruce by following the metabolic fate of 14C-labelled orotic acid, uridine, and uracil, as well as by measuring the activities of the major enzymes participating in Nucleotide synthesis. The rate of nucleic acid synthesis in these tissues was also examined by tracer experiments and autoradiographic studies conducted with labelled thymidine, and by conventional light microscopy. From our results, it emerges that changes in the contribution of the de novo and salvage pathways of Pyrimidines play an important role during the initial stages of zygotic embryo germination. Preferential utilization of uridine for nucleic acid synthesis, via the salvage pathway, was observed at the onset of germination, before the restoration of a fully functional de novo pathway. Similar metabolic changes, not observed in the gametophytic tissue, were also documented in somatic embryos previously. These alterations of the overall Pyrimidine metabolism may represent a strategy for ensuring the germinating embryos with a large Nucleotide pool. Utilization of 14C-thymidine for nucleic acid synthesis increased in both dissected embryos and megagametophytes during germination. Autoradiographic and light microscopic studies indicated that soon after imbibition, DNA synthesis was preferentially initiated along the embryonic axis, especially in the cortical cells. Apical meristem reactivation was a later event, and the root meristem became activated before the shoot meristem. Taken together, these results indicate that precise changes in Nucleotide and nucleic acid metabolism occur during the early phases of embryo germination.
Claudio Stasolla - One of the best experts on this subject based on the ideXlab platform.
-
glutathione induced growth of embryogenic tissue of white spruce correlates with changes in Pyrimidine Nucleotide metabolism
Plant Science, 2005Co-Authors: Mark F Belmonte, Claudio Stasolla, Riko Katahira, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Abstract Exogenous applications of reduced glutathione (GSH) and oxidized glutathione (GSSG) promote growth of embryogenic tissue of white spruce during a 7-day subculture period. Compared to control tissue, a statistically significant increase in fresh weight, as well as RNA and DNA content, was observed in the presence of GSH and GSSG during the last days in culture. The effects of these two metabolites on Pyrimidine Nucleotide metabolism was investigated by following the metabolic fate of 14C-orotic acid, a precursor of the de novo synthesis, and 14C-uridine and 14C-uracil, intermediates of the respective salvage and degradation pathways. Compared to control embryos, GSH-treated tissue was able to utilize a larger fraction of supplied orotic acid for UMP production, possibly due to the increased activity of orotate phosphoribosyltransferase (OPRT). The activity of this enzyme increased markedly in tissue cultured with GSH during the last days in culture. Salvage of uridine for Nucleotide and nucleic acid synthesis was observed in all treatments, especially in GSSG-treated tissue at day 7. The increased salvage activity in this tissue correlated with the increase in activities of the two uridine salvage enzymes, uridine kinase (URK) and nucleoside phosphotransferase measured with uridine (NPT(uridine)). Compared to control tissue, tissue treated with either GSH or GSSG was able to utilize a large fraction of uracil for Nucleotide synthesis, denoting a better ability to divert this precursor from degradation. Nucleotide and nucleic acid analyses revealed that in both GSH and GSSG-treated tissue, the endogenous levels of UTP, CTP, as well as those of RNA and DNA, were increased compared to those of control tissue. Overall, the results from this study suggest that GSH and GSSG can induce growth of embryogenic tissue of white spruce through distinct metabolic changes of Pyrimidine Nucleotides.
-
alterations in Pyrimidine Nucleotide metabolism as an early signal during the execution of programmed cell death in tobacco by 2 cells
Journal of Experimental Botany, 2004Co-Authors: Claudio Stasolla, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Changes in Pyrimidine metabolism were investigated during programmed cell death (PCD) of tobacco BY-2 cells, induced by a simultaneous increase in the endogenous levels of nitric oxide (NO) and hydrogen peroxide. The de novo synthesis of Pyrimidine Nucleotides was estimated by following the metabolic fate of the (14)C-labelled orotic acid, whereas the rates of salvage and degradation pathways were studied by measuring the respective incorporation of (14)C-labelled uridine and uracil under different treatments. Nucleic acid metabolism was also examined using labelled thymidine as a marker. The results show that specific alterations in the balance of Pyrimidine Nucleotide synthesis, which include a decreased rate of salvage activity of uracil and uridine and increased salvage activity of thymidine, represent a metabolic switch that establishes proper cellular conditions for the induction of PCD. In particular, a reduction in the utilization of uracil for salvage products occurs very early during PCD, before the appearance of typical cytological features of the death programme, thus representing an early metabolic marker for PCD. These changes are strictly associated with PCD, since they do not occur if NO or hydrogen peroxide are increased individually, or if actinomycin, which inhibits the death programme, is added into the medium in the presence of NO and hydrogen peroxide. The possible roles of these fluctuations in Pyrimidine metabolism on the cellular Nucleotide pool are discussed in relation to the induction of cell death.
-
purine and Pyrimidine Nucleotide metabolism in higher plants
Journal of Plant Physiology, 2003Co-Authors: Claudio Stasolla, Riko Katahira, Trevor A Thorpe, Hiroshi AshiharaAbstract:Purine and Pyrimidine Nucleotides participate in many biochemical processes in plants. They are building blocks for nucleic acid synthesis, an energy source, precursors for the synthesis of primary products, such as sucrose, polysaccharides, phospholipids, as well as secondary products. Therefore, biosynthesis and metabolism of Nucleotides are of fundamental importance in the growth and development of plants. Nucleotides are synthesized both from amino acids and other small molecules via de novo pathways, and from preformed nucleobases and nucleosides by salvage pathways. In this article the biosynthesis, interconversion and degradation of purine and Pyrimidine Nucleotides in higher plants are reviewed. This description is followed by an examination of physiological aspects of Nucleotide metabolism in various areas of growth and organized development in plants, including embryo maturation and germination, in vitro organogenesis, storage organ development and sprouting, leaf senescence, and cultured plant cells. The effects of environmental factors on Nucleotide metabolism are also described. This review ends with a brief discussion of molecular studies on Nucleotide synthesis and metabolism.
-
Pyrimidine Nucleotide and nucleic acid synthesis in embryos and megagametophytes of white spruce picea glauca during germination
Physiologia Plantarum, 2002Co-Authors: Claudio Stasolla, Hiroshi Ashihara, Natalia Loukanina, Edward C Yeung, Trevor A ThorpeAbstract:Pyrimidine Nucleotide synthesis was investigated in isolated germinating zygotic embryos and separated megagametophytes of white spruce by following the metabolic fate of 14C-labelled orotic acid, uridine, and uracil, as well as by measuring the activities of the major enzymes participating in Nucleotide synthesis. The rate of nucleic acid synthesis in these tissues was also examined by tracer experiments and autoradiographic studies conducted with labelled thymidine, and by conventional light microscopy. From our results, it emerges that changes in the contribution of the de novo and salvage pathways of Pyrimidines play an important role during the initial stages of zygotic embryo germination. Preferential utilization of uridine for nucleic acid synthesis, via the salvage pathway, was observed at the onset of germination, before the restoration of a fully functional de novo pathway. Similar metabolic changes, not observed in the gametophytic tissue, were also documented in somatic embryos previously. These alterations of the overall Pyrimidine metabolism may represent a strategy for ensuring the germinating embryos with a large Nucleotide pool. Utilization of 14C-thymidine for nucleic acid synthesis increased in both dissected embryos and megagametophytes during germination. Autoradiographic and light microscopic studies indicated that soon after imbibition, DNA synthesis was preferentially initiated along the embryonic axis, especially in the cortical cells. Apical meristem reactivation was a later event, and the root meristem became activated before the shoot meristem. Taken together, these results indicate that precise changes in Nucleotide and nucleic acid metabolism occur during the early phases of embryo germination.
Yuan Wei - One of the best experts on this subject based on the ideXlab platform.
-
total synthesis of 2 deoxycadeguomycin a new pyrrolo 2 3 d Pyrimidine Nucleotide analogue
Tetrahedron Letters, 1994Co-Authors: Eric D. Edstrom, Yuan WeiAbstract:Abstract This paper describes an efficient synthetic route to a novel pyrrolo[2,3- d ]Pyrimidine Nucleotide analogue, 2′-deoxycadeguomycin 4a . The key transformation involves the conversion of the differentially protected pyrrolo[2,3- d ]pyrimidin-2,4-dione base portion in 1a into a protected 2-amino-pyrrolo[2,3- d ]pyrimidin-4-one 3a .
-
Total synthesis of 2′-deoxycadeguomycin, a new pyrrolo[2,3-d]Pyrimidine Nucleotide analogue
Tetrahedron Letters, 1994Co-Authors: Eric D. Edstrom, Yuan WeiAbstract:Abstract This paper describes an efficient synthetic route to a novel pyrrolo[2,3- d ]Pyrimidine Nucleotide analogue, 2′-deoxycadeguomycin 4a . The key transformation involves the conversion of the differentially protected pyrrolo[2,3- d ]pyrimidin-2,4-dione base portion in 1a into a protected 2-amino-pyrrolo[2,3- d ]pyrimidin-4-one 3a .
Eric D. Edstrom - One of the best experts on this subject based on the ideXlab platform.
-
total synthesis of 2 deoxycadeguomycin a new pyrrolo 2 3 d Pyrimidine Nucleotide analogue
Tetrahedron Letters, 1994Co-Authors: Eric D. Edstrom, Yuan WeiAbstract:Abstract This paper describes an efficient synthetic route to a novel pyrrolo[2,3- d ]Pyrimidine Nucleotide analogue, 2′-deoxycadeguomycin 4a . The key transformation involves the conversion of the differentially protected pyrrolo[2,3- d ]pyrimidin-2,4-dione base portion in 1a into a protected 2-amino-pyrrolo[2,3- d ]pyrimidin-4-one 3a .
-
Total synthesis of 2′-deoxycadeguomycin, a new pyrrolo[2,3-d]Pyrimidine Nucleotide analogue
Tetrahedron Letters, 1994Co-Authors: Eric D. Edstrom, Yuan WeiAbstract:Abstract This paper describes an efficient synthetic route to a novel pyrrolo[2,3- d ]Pyrimidine Nucleotide analogue, 2′-deoxycadeguomycin 4a . The key transformation involves the conversion of the differentially protected pyrrolo[2,3- d ]pyrimidin-2,4-dione base portion in 1a into a protected 2-amino-pyrrolo[2,3- d ]pyrimidin-4-one 3a .
Jan Balzarini - One of the best experts on this subject based on the ideXlab platform.
-
introduction of a fluorine atom at c3 of 3 deazauridine shifts its antimetabolic activity from inhibition of ctp synthetase to inhibition of orotidylate decarboxylase an early event in the de novo Pyrimidine Nucleotide biosynthesis pathway
Journal of Biological Chemistry, 2012Co-Authors: Jan Balzarini, Anna Karlsson, Matt A Peterson, Wim Kulik, Federico Gago, Andre B P Van Kuilenburg, Morris J. RobinsAbstract:Abstract The antimetabolite prodrug 3-deazauridine (3DUrd) inhibits cytidine triphosphate (CTP) synthetase upon intracellular conversion to its triphosphate, which selectively depletes the intracellular CTP pools. Introduction of a fluorine atom at C3 of 3DUrd shifts its antimetabolic action to inhibition of the orotidylate (OMP) decarboxylase (ODC) activity of the uridylate (UMP) synthase enzyme complex that catalyzes an early event in Pyrimidine Nucleotide biosynthesis. This results in concomitant depletion of the intracellular UTP and CTP pools. The new prodrug (designated 3F-3DUrd) exerts its inhibitory activity as its monophosphate and is not further converted intracellularly to its triphosphate derivative to a detectable extent. Combinations with hypoxanthine and adenine markedly potentiate the cytostatic activity of 3F-3DUrd. This is likely due to depletion of PRPP (consumed in the HPRT/APRT reaction) and subsequent slowing of the PRPP-dependent OPRT reaction, which depletes OMP, the substrate for ODC. Further efficient anabolism by Nucleotide kinases is compromised apparently due to the decrease in pKa brought about by the fluorine atom which affects the ionization state of the new prodrug. The 3F-3DUrd monophosphate exhibits new inhibitory properties against a different enzyme of the Pyrimidine Nucleotide metabolism, namely the ODC activity of UMP synthase.
-
role of antimetabolites of purine and Pyrimidine Nucleotide metabolism in tumor cell differentiation
Biochemical Pharmacology, 1999Co-Authors: Sigrid Hatse, Erik De Clercq, Jan BalzariniAbstract:Abstract Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of Nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, riboNucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and Pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and Pyrimidine Nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2′-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-β- d -ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the riboNucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
-
role of antimetabolites of purine and Pyrimidine Nucleotide metabolism in tumor cell differentiation
Biochemical Pharmacology, 1999Co-Authors: Sigrid Hatse, Erik De Clercq, Jan BalzariniAbstract:Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of Nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, riboNucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and Pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and Pyrimidine Nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the riboNucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
