The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
Dane A. Sethre-hofstad - One of the best experts on this subject based on the ideXlab platform.
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Nucleotide P2Y_1 receptor agonists are in vitro and in vivo prodrugs of A_1/A_3 adenosine receptor agonists: implications for roles of P2Y_1 and A_1/A_3 receptors in physiology and pathology
Purinergic Signalling, 2020Co-Authors: Theodore E. Liston, Sonja Hinz, Christa E. Müller, Deborah M. Holstein, Jay Wendling, Roger J. Melton, Mary Campbell, William S. Korinek, R. Rama Suresh, Dane A. Sethre-hofstadAbstract:Rapid phosphoester hydrolysis of endogenous purine and pyrimidine Nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical Nucleotide P2Y_1 receptor (P2Y_1R) agonists and antagonists. These included the riboside Nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained ( N )-methanocarba rings, which were previously reported to form Nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for Nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A_3 and A_1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y_1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to Nucleotide agonists is due to AR activation by active nucleoside metabolites.
Chi-huey Wong - One of the best experts on this subject based on the ideXlab platform.
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Large-Scale Enzymatic Synthesis of Glycans with Cofactor Regeneration
Glycoscience: Biology and Medicine, 2021Co-Authors: Tsung-i Tsai, Chung-yi Wu, Chi-huey WongAbstract:The glycosyltransferases, which catalyze the transfer of a saccharide from a sugar Nucleotide donor to an acceptor, have been used for the synthesis of complex glycoconjugates. Nevertheless, narrow substrate specificity, high cost of both the enzymes and the sugar Nucleotides, and limited enzyme availability limit their application. Moreover, the progression of glycosylation can be plagued by feedback inhibition caused by the generated nucleoside phosphate. Regeneration of the sugar Nucleotide intermediate in situ can reduce the concentration of the nucleoside phosphate by-product by the use of a small amount of the sugar Nucleotide; thus, the expenses of the sugar Nucleotide and product inhibition are reduced simultaneously.
Theodore E. Liston - One of the best experts on this subject based on the ideXlab platform.
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Nucleotide P2Y_1 receptor agonists are in vitro and in vivo prodrugs of A_1/A_3 adenosine receptor agonists: implications for roles of P2Y_1 and A_1/A_3 receptors in physiology and pathology
Purinergic Signalling, 2020Co-Authors: Theodore E. Liston, Sonja Hinz, Christa E. Müller, Deborah M. Holstein, Jay Wendling, Roger J. Melton, Mary Campbell, William S. Korinek, R. Rama Suresh, Dane A. Sethre-hofstadAbstract:Rapid phosphoester hydrolysis of endogenous purine and pyrimidine Nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical Nucleotide P2Y_1 receptor (P2Y_1R) agonists and antagonists. These included the riboside Nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained ( N )-methanocarba rings, which were previously reported to form Nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for Nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A_3 and A_1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y_1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to Nucleotide agonists is due to AR activation by active nucleoside metabolites.
Tsung-i Tsai - One of the best experts on this subject based on the ideXlab platform.
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Large-Scale Enzymatic Synthesis of Glycans with Cofactor Regeneration
Glycoscience: Biology and Medicine, 2021Co-Authors: Tsung-i Tsai, Chung-yi Wu, Chi-huey WongAbstract:The glycosyltransferases, which catalyze the transfer of a saccharide from a sugar Nucleotide donor to an acceptor, have been used for the synthesis of complex glycoconjugates. Nevertheless, narrow substrate specificity, high cost of both the enzymes and the sugar Nucleotides, and limited enzyme availability limit their application. Moreover, the progression of glycosylation can be plagued by feedback inhibition caused by the generated nucleoside phosphate. Regeneration of the sugar Nucleotide intermediate in situ can reduce the concentration of the nucleoside phosphate by-product by the use of a small amount of the sugar Nucleotide; thus, the expenses of the sugar Nucleotide and product inhibition are reduced simultaneously.
Torsten Mohlmann - One of the best experts on this subject based on the ideXlab platform.
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nucleobase and nucleoside transport and integration into plant metabolism
Frontiers in Plant Science, 2014Co-Authors: Christopher Girke, Manuel Daumann, Sandra Niopekwitz, Torsten MohlmannAbstract:Nucleotide metabolism is an essential process in all living organisms. Besides newly synthesized Nucleotides, the recycling (salvage) of partially degraded Nucleotides, i.e., nucleosides and nucleobases serves to keep the homeostasis of the Nucleotide pool. Both types of metabolites are substrates of at least six families of transport proteins in Arabidopsis thaliana (Arabidopsis) with a total of 49 members. In the last years several members of such transport proteins have been analyzed allowing to present a more detailed picture of nucleoside and nucleobase transport and the physiological function of these processes. Besides functioning in Nucleotide metabolism it turned out that individual members of the before named transporters exhibit the capacity to transport a wide range of different substrates including vitamins and phytohormones. The aim of this review is to summarize the current knowledge on nucleobase and nucleoside transport processes in plants and integrate this into Nucleotide metabolism in general. Thereby, we will focus on those proteins which have been characterized at the biochemical level.
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nucleoside transport and associated metabolism
Plant Biology, 2010Co-Authors: Torsten Mohlmann, Sylvia Hach, C Bernard, Ekkehard H NeuhausAbstract:: Nucleosides are intermediates of Nucleotide metabolism. Nucleotide de novo synthesis generates the nucleoside monophosphates AMP and UMP, which are further processed to all purine and pyrimidine Nucleotides involved in multiple cellular reactions, including the synthesis of nucleic acids. Catabolism of these substances results in the formation of nucleosides, which are further degraded by nucleoside hydrolase to nucleobases. Both nucleosides and nucleobases can be exchanged between cells and tissues through multiple isoforms of corresponding transport proteins. After uptake into a cell, nucleosides and nucleobases can undergo salvage reactions or catabolism. Whereas energy is preserved by salvage pathway reactions, catabolism liberates ammonia, which is then incorporated into amino acids. Keeping the balance between nitrogen consumption during Nucleotide de novo synthesis and ammonia liberation by Nucleotide catabolism is essential for correct plant development. Senescence and seed germination represent situations in plant development where marked fluctuations in Nucleotide pools occur. Furthermore, extracellular Nucleotide metabolism has become an immensely interesting research topic. In addition, selected aspects of nucleoside transport in yeast, protists and humans are discussed.
