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Takuma Sasaki - One of the best experts on this subject based on the ideXlab platform.
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antitumor activity of sugar modified cytosine Nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:β β β-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous Nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of Nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both Nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine Nucleosides, such as (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-β-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-β β β β-D-ribo-pentofuranosyl)cytosine (ECyd), developed by our groups, are discussed here. (Cancer Science 2004; 95: 105–111)
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antitumor activity of sugar modified cytosine Nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:Nucleoside analogues which show antimetabolic activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as 1-beta-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous Nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of Nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both Nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine Nucleosides, such as (2'S)-2'-deoxy-2'-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-beta-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-beta-D-ribo-pentofura-nosyl)cytosine (ECyd), developed by our groups, are discussed here.
Piero Luigi Ipata - One of the best experts on this subject based on the ideXlab platform.
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Nucleoside recycling in the brain and the nucleosidome: a complex metabolic and molecular cross-talk between the extracellular nucleotide cascade system and the intracellular nucleoside salvage
Metabolomics, 2015Co-Authors: Piero Luigi Ipata, Rossana PesiAbstract:The transports of Nucleosides from blood into neurons and astrocytes are essential prerequisites to enter their metabolic utilization in brain. Adult brain does not possess the de novo nucleotide synthesis, and maintains its nucleotide pools by salvaging preformed Nucleosides imported from liver. Once Nucleosides enter the brain through the blood brain barrier and the nucleoside transporters, they become obligatory precursors for the synthesis of RNA and DNA and a plethora of other important functions. However, an aliquot of nucleotides are transferred into vesicular nucleotide transporters, and then in the extracellular space by exocytosis of the vesicles, where ATP and UTP interact with a vast heterogeneity of purine and pyrimidine receptors. Their signal actions are terminated by the ectonucleotidase cascade system, which degrades ATP and UTP into adenosine and uridine, respectively. The low specificity of the vesicular nucleotide transporters may explain the presence in the extracellular space of GTP and CTP, which are equally degraded to their respective Nucleosides by the ectonucleotidases. The main four Nucleosides are re-imported either into the same cell, or in adjacent cells, e.g. between two astrocytes, or between a neuron and an astrocyte, to regenerate nucleoside triphosphates. The molecular network of this metabolic cross-talk, involving the ectonucleotidases, the nucleoside transporters, the nucleotide salvage system, the nucleotide transport into the vesicular nucleotide transporters, and the exocytotic release of nucleotides, called by us the “nucleosidome”, serves the nucleoside recycling in the brain, with a considerable spatial–temporal advantage.
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The functional logic of cytosolic 5'-nucleotidases.
Current medicinal chemistry, 2013Co-Authors: Piero Luigi Ipata, Balestri FAbstract:Adenosine- and uridine-cytidine kinases, purine-nucleoside phosphorylase, hypoxanthine-guanine phosphoribosyl transferase, and several related enzymes, are components of the salvage pathways which reduce the loss of intracellular purine and pyrimidine rings. Although this could explain the role of these enzymes, it poses a problem of the role of the cytosolic 5'-nucleotidase. Why are Nucleosides produced from nucleoside-monophosphates, only to be converted back to the same compounds? To date, it is well established that a cross talk exists between the extracellular and intracellular nucleoside metabolism. In districts, such as brain, which are dependent on salvage nucleotide synthesis, Nucleosides are produced through the action of the ecto-5'-nucleotidase, the last component of a series of plasma-membrane bound enzyme proteins, catalyzing the successive dephosphorylation of released nucleoside-triphosphates. Both nucleosidetriphosphates (mainly ATP and UTP) and Nucleosides (mainly adenosine), act as extracellular signals. Once transported into cell cytosol, all Nucleosides are salvaged back to nucleoside-triphosphates, with the exception of inosine, whose salvage is limited to IMP. Intracellular balance of Nucleosides is maintained by the action of several enzymes, such as adenosine deaminase, uridine phosphorylase and cytidine deaminase, and by at least three 5'-nucleotidases, the ADP activated AMP preferring cN-IA, the ATP-ADP activated IMP-GMP preferring cN-II, and the UMP-CMP preferring cN-III. Here we are reviewing the mechanisms whereby cytosolic 5'-nucleotidases control changes in nucleoside and nucleotide concentration, with the aim to provide a common basis for the study of the relationship between biochemistry and other related disciplines, such as physiology and pharmacology.
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key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain
Neurochemistry International, 2007Co-Authors: Francesco Balestri, Catia Barsotti, Ludovico Lutzemberger, Marcella Camici, Piero Luigi IpataAbstract:Abstract Uridine, the major circulating pyrimidine nucleoside, participating in the regulation of a number of physiological processes, is readily uptaken into mammalian cells. The balance between anabolism and catabolism of intracellular uridine is maintained by uridine kinase, catalyzing the first step of UTP and CTP salvage synthesis, and uridine phosphorylase, catalyzing the first step of uridine degradation to β-alanine in liver. In the present study we report that the two enzymes have an additional role in the homeostatic regulation of purine and pyrimidine metabolism in brain, which relies on the salvage synthesis of nucleotides from preformed Nucleosides and nucleobases, rather than on the de novo synthesis from simple precursors. The experiments were performed in rat brain extracts and cultured human astrocytoma cells. The rationale of the reciprocal regulation of purine and pyrimidine salvage synthesis in brain stands (i) on the inhibition exerted by UTP and CTP, the final products of the pyrimidine salvage pathway, on uridine kinase and (ii) on the widely accepted idea that pyrimidine salvage occurs at the nucleoside level (mostly uridine), while purine salvage is a 5-phosphoribosyl-1-pyrophosphate (PRPP)-mediated process, occurring at the nucleobase level. Thus, at relatively low UTP and CTP level, uptaken uridine is mainly anabolized to uridine nucleotides. On the contrary, at relatively high UTP and CTP levels the inhibition of uridine kinase channels uridine towards phosphorolysis. The ribose-1-phosphate is then transformed into PRPP, which is used for purine salvage synthesis.
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key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain
Neurochemistry International, 2007Co-Authors: Francesco Balestri, Catia Barsotti, Ludovico Lutzemberger, Marcella Camici, Piero Luigi IpataAbstract:Uridine, the major circulating pyrimidine nucleoside, participating in the regulation of a number of physiological processes, is readily uptaken into mammalian cells. The balance between anabolism and catabolism of intracellular uridine is maintained by uridine kinase, catalyzing the first step of UTP and CTP salvage synthesis, and uridine phosphorylase, catalyzing the first step of uridine degradation to beta-alanine in liver. In the present study we report that the two enzymes have an additional role in the homeostatic regulation of purine and pyrimidine metabolism in brain, which relies on the salvage synthesis of nucleotides from preformed Nucleosides and nucleobases, rather than on the de novo synthesis from simple precursors. The experiments were performed in rat brain extracts and cultured human astrocytoma cells. The rationale of the reciprocal regulation of purine and pyrimidine salvage synthesis in brain stands (i) on the inhibition exerted by UTP and CTP, the final products of the pyrimidine salvage pathway, on uridine kinase and (ii) on the widely accepted idea that pyrimidine salvage occurs at the nucleoside level (mostly uridine), while purine salvage is a 5-phosphoribosyl-1-pyrophosphate (PRPP)-mediated process, occurring at the nucleobase level. Thus, at relatively low UTP and CTP level, uptaken uridine is mainly anabolized to uridine nucleotides. On the contrary, at relatively high UTP and CTP levels the inhibition of uridine kinase channels uridine towards phosphorolysis. The ribose-1-phosphate is then transformed into PRPP, which is used for purine salvage synthesis.
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recycling of α d ribose 1 phosphate for nucleoside interconversion
Biochimica et Biophysica Acta, 1997Co-Authors: Francesco Giorgelli, Cinzia Bottai, Cosima Scolozzi, Marcella Camici, Laura Mascia, Piero Luigi IpataAbstract:Abstract Mobilization of the ribose moiety and of the amino group of guanosine may be realized in rat liver extract by the concerted action of purine nucleoside phosphorylase and guanase. Ribose 1-phosphate formed from guanosine through the action of purine nucleoside phosphorylase acts as ribose donor in the synthesis of xanthosine catalyzed by the same enzyme. The presence of guanase, which irreversibly converts guanine to xanthine, affects the overall process of guanosine transformation. As a result of this purine pathway, guanosine is converted into xanthosine, thus overcoming the lack of guanosine deaminase in mammals. Furthermore, in rat liver extract the activated ribose moiety stemming from the catabolism of purine Nucleosides can be transferred to uracil and, in the presence of ATP, used for the synthesis of pyrimidine nucleotides; therefore, purine Nucleosides can act as ribose donors for the salvage of pyrimidine bases.
Kathleen M. Giacomini - One of the best experts on this subject based on the ideXlab platform.
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Functional Characterization of a Human Purine-Selective, Na ϩ -Dependent Nucleoside Transporter (hSPNT1) in a Mammalian Expression System 1
2020Co-Authors: Marci E Schaner, Juan Wang, Lei Zhang, Karin M Gerstin, Kathleen M. GiacominiAbstract:ABSTRACT Nucleosides and nucleoside analogs are actively transported in the human kidney. With the recent cloning of a purine-selective, Na ϩ -dependent, nucleoside transporter (hSPNT1, also termed hCNT2) from human kidney, it is now possible to study the interaction of Nucleosides and nucleoside analogs with this transport protein and gain a more detailed knowledge of the underlying mechanisms of nucleoside transport in the human kidney. In this study we examined the substrate selectivity of hSPNT1 for Nucleosides and nucleoside analogs. We determined that the naturally occurring Nucleosides adenosine, inosine, and uridine are substrates for this carrier, whereas thymidine is not. The nucleoside analogs (0.5 mM) 2Ј,3Ј-dideoxyadenosine; 2Ј,3Ј-dideoxyinosine; and 2-chloro-2Јdeoxyadenosine (2CdA), significantly inhibited the uptake of [
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interaction of nucleoside analogues with the sodium nucleoside transport system in brush border membrane vesicles from human kidney
Pharmaceutical Research, 1993Co-Authors: Claire M Brett, Carla B Washington, Marcelo M Gutierrez, Kathleen M. GiacominiAbstract:The therapeutic efficacy of Nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant Nucleosides or analogues interact with the recently characterized Na+-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na+-driven 3H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring Nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na+–uridine transport was determined. At a concentration of 100 µM the naturally occurring Nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a Ki of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring Nucleosides are substrates of the Na+–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The Ki of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.
Zachary Lee Johnson - One of the best experts on this subject based on the ideXlab platform.
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structural basis of concentrative nucleoside transport
Biophysical Journal, 2017Co-Authors: Marscha Hirschi, Zachary Lee JohnsonAbstract:Nucleosides are essential molecules for the living cell. As precursors to nucleotides they serve to fuel the salvage pathway of DNA and RNA synthesis. Certain tissues, such as the brain and bone marrow, lack the capacity for de novo synthesis and therefore rely completely on the influx of Nucleosides. Concentrative nucleoside transporters (CNTs) utilize sodium or proton gradients to transport Nucleosides across the cell membrane. These secondary active transporters also play an essential role in the termination of adenosine signaling, which controls important cellular processes such as neuromodulation and cardiovascular function. In addition to natural substrates CNTs are also the conduit for many anti-cancer and anti-viral drugs, making them of special interest from a pharmacological point of view. Notably, CNTs are the main transport route for a popular pancreatic cancer drug, gemcitabine. We previously reported on the structure of CNT from Vibrio cholerae in complex with various substrates and nucleoside-like drugs. Each of these structures captured the transporter in the inward-facing occluded conformation. In order to describe the transport mechanism in further detail we performed crystallization studies with CNT from Neisseria wadsworthii (CNTNW). CNTNW is highly homologous to human CNT3, sharing 38% sequence identity and nearly identical substrate binding sites. Here we present crystal structures of CNTNW captured in alternative conformations. We confirmed the physiological relevance of the conformations by crosslinking experiments. Our structural analyses and functional studies provide new insights into the mechanism of CNTs and cellular nucleoside uptake in molecular detail.
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Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4
2016Co-Authors: Zachary Lee Johnson, Cheom-gil Cheong, Seok-yong LeeAbstract:Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine plays a role in a variety of signaling processes 1,2. Transporting Nucleosides across cell membranes provides the major source of Nucleosides in many cell types and is also responsible for the termination of adenosine signaling. Due to their hydrophilic nature, Nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to Nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes 3–5. A wide range of nucleoside-derived drugs has been shown to depend, at least in part, on NTs for transport across cell membranes including anticancer drugs (e.g., Ara-C and gemcitabine) and antiviral drugs (e.g., AZT and ribavirin) 4,6–13. Concentrative nucleoside transporters (CNTs), members of the solute carrier transporter superfamily SLC28, use an ion gradient to actively transport Nucleosides as well as nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by CNTs is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 Å. Our functional data show that the transporter utilizes a sodium gradient for nucleoside transport like its huma
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crystal structure of a concentrative nucleoside transporter from vibrio cholerae at 2 4 a
Nature, 2012Co-Authors: Zachary Lee Johnson, Cheom-gil Cheong, Seok-yong LeeAbstract:Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of Nucleosides across cell membranes provides the major source of Nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, Nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to Nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both Nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 A. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.
Akira Matsuda - One of the best experts on this subject based on the ideXlab platform.
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antitumor activity of sugar modified cytosine Nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:β β β-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous Nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of Nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both Nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine Nucleosides, such as (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-β-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-β β β β-D-ribo-pentofuranosyl)cytosine (ECyd), developed by our groups, are discussed here. (Cancer Science 2004; 95: 105–111)
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antitumor activity of sugar modified cytosine Nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:Nucleoside analogues which show antimetabolic activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as 1-beta-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous Nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of Nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both Nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows antitumor activity against solid tumors. This suggests that differences in the pharmacological activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of sugar-modified cytosine Nucleosides, such as (2'S)-2'-deoxy-2'-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-beta-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-beta-D-ribo-pentofura-nosyl)cytosine (ECyd), developed by our groups, are discussed here.
