The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Staffan Eriksson - One of the best experts on this subject based on the ideXlab platform.
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novel antiviral c5 substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates
Journal of Medicinal Chemistry, 2011Co-Authors: Dimitrios Topalis, Ugo Pradere, Vincent Roy, Christophe Caillat, Ahmed Azzouzi, Julie Broggi, Robert Snoeck, Graciela Andrei, Jay Lin, Staffan ErikssonAbstract:Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine Monophosphate (TMP) kinase, but not for Uridine Monophosphate−cytosine Monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC50 = 3 μM) and against varicella zoster virus in vitro (IC50 = ...
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structural and functional investigations of ureaplasma parvum ump kinase a potential antibacterial drug target
FEBS Journal, 2007Co-Authors: Louise Egebladwelin, Martin Welin, Liya Wang, Staffan ErikssonAbstract:The crystal structure of Uridine Monophosphate kinase (UMP kinase, UMPK) from the opportunistic pathogen Ureaplasma parvum was determined and showed similar three-dimensional fold as other bacterial and archaeal UMPKs that all belong to the amino acid kinase family. Recombinant UpUMPK exhibited Michaelis–Menten kinetics with UMP, with Km and Vmax values of 214 ± 4 µm and 262 ± 24 µmol·min−1·mg−1, respectively, but with ATP as variable substrate the kinetic analysis showed positive cooperativity, with an n value of 1.5 ± 0.1. The end-product UTP was a competitive inhibitor against UMP and a noncompetitive inhibitor towards ATP. Unlike UMPKs from other bacteria, which are activated by GTP, GTP had no detectable effect on UpUMPK activity. An attempt to create a GTP-activated enzyme was made using site-directed mutagenesis. The mutant enzyme F133N (F133 corresponds to the residue in Escherichia coli that is involved in GTP activation), with F133A as a control, were expressed, purified and characterized. Both enzymes exhibited negative cooperativity with UMP, and GTP had no effect on enzyme activity, demonstrating that F133 is involved in subunit interactions but apparently not in GTP activation. The physiological role of UpUMPK in bacterial nucleic acid synthesis and its potential as target for development of antimicrobial agents are discussed.
Qinhua Wang - One of the best experts on this subject based on the ideXlab platform.
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dietary supplement with nucleotides in the form of Uridine Monophosphate or Uridine stimulate intestinal development and promote nucleotide transport in weaned piglets
Journal of the Science of Food and Agriculture, 2019Co-Authors: Chunyan Xie, Qinhua Wang, Zhiyong Fan, Hong WangAbstract:BACKGROUND Nucleotides are key constituents of milk, where they are utilized in cell replication, although there are limited studies for weaned piglets. This study evaluated the effects of Uridine Monophosphate (UMP) with Uridine (UR) feed supplementation on the intestinal development and nucleotide transport in weaned piglets. RESULTS Supplementation with UMP significantly increased (P 0.05) in growth performance was observed among three groups. Piglets fed supplementary UR exhibited greater (P < 0.05) crypt depth in the duodenum and ileum when compared with those in the supplementary UMP and control groups. Real-time quantitative polymerase chain reaction (RT-qPCR) results revealed that UR supplementation increased (P < 0.05) the relative mRNA levels of genes encoding the transmembrane proteins ZO-1 and occludin in the duodenum mucosa, and ZO-1 in the jejunum mucosa (P < 0.05). Similarly, UR supplementation increased (P < 0.05) expression of solute carriers SLC28A1 and SLC29A1 in the duodenum mucosa. Conversely, claudin-1 expression in the duodenum mucosa was inhibited (P < 0.05) by dietary supplementation with UMP or UR. CONCLUSION Collectively, our data indicated that dietary supplementation with UMP or UR was conducive to stimulating intestinal development and promoting nucleotide transport in weaned piglets. © 2019 Society of Chemical Industry.
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Uridine ump metabolism and their function on the gut in segregated early weaned piglets
Food & Function, 2019Co-Authors: Chunyan Xie, Qinhua Wang, Dan Wan, Yan Zhang, Yulong YinAbstract:Uridine Monophosphate (UMP) is a major nucleotide analogue in mammalian milk and Uridine (UR) is its gastro-intestinal metabolite in vivo. This study aims to investigate the functional effects of UMP and UR on the gut in vitro and in vivo. Twenty-one piglets were randomly allotted into three groups, the control group, UMP group and UR group, and orally administered UMP or UR for 10 days. Results showed that UMP and UR supplements improved the ADG of piglets, and decreased the diarrhea rate. UR increased the jejunum villus length/crypt depth ratio, Claudin-3 and E-cadherin expression, and the pyrimidine nucleotide metabolic enzymes including CMPK1, RRM2, UPRT, CTPS1 and CTPS2 in the duodenal mucosa. Both the UMP and UR decreased the expression of CAD and RRM2 at the jejunal mucosa. Moreover, UMP and UR increased the apoptosis ratio of intestinal epithelial cells in in vivo and in vitro experiments. Taken together, oral administration of UR and UMP could improve the small intestinal morphology, promote epithelial cell apoptosis and renewal of intestinal villus tips, and benefit intestinal development and health thus improving the growth performance and reducing the risk of diarrhea in early-weaned piglets.
Yulong Yin - One of the best experts on this subject based on the ideXlab platform.
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Uridine ump metabolism and their function on the gut in segregated early weaned piglets
Food & Function, 2019Co-Authors: Chunyan Xie, Qinhua Wang, Dan Wan, Yan Zhang, Yulong YinAbstract:Uridine Monophosphate (UMP) is a major nucleotide analogue in mammalian milk and Uridine (UR) is its gastro-intestinal metabolite in vivo. This study aims to investigate the functional effects of UMP and UR on the gut in vitro and in vivo. Twenty-one piglets were randomly allotted into three groups, the control group, UMP group and UR group, and orally administered UMP or UR for 10 days. Results showed that UMP and UR supplements improved the ADG of piglets, and decreased the diarrhea rate. UR increased the jejunum villus length/crypt depth ratio, Claudin-3 and E-cadherin expression, and the pyrimidine nucleotide metabolic enzymes including CMPK1, RRM2, UPRT, CTPS1 and CTPS2 in the duodenal mucosa. Both the UMP and UR decreased the expression of CAD and RRM2 at the jejunal mucosa. Moreover, UMP and UR increased the apoptosis ratio of intestinal epithelial cells in in vivo and in vitro experiments. Taken together, oral administration of UR and UMP could improve the small intestinal morphology, promote epithelial cell apoptosis and renewal of intestinal villus tips, and benefit intestinal development and health thus improving the growth performance and reducing the risk of diarrhea in early-weaned piglets.
Ru Bo Zhang - One of the best experts on this subject based on the ideXlab platform.
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the fate of h atom adducts to 3 Uridine Monophosphate
Journal of Physical Chemistry B, 2010Co-Authors: Ran Wang, Ru Bo Zhang, Leif A ErikssonAbstract:The stabilities of the adducts deriving from H free radical addition to the O2, O4, and C5 positions of 3'-Uridine Monophosphate (3'UMP) are studied by the hybrid density functional B3LYP approach. Upon H atom addition at the O2 position, a concerted low-barrier proton-transfer process will initially occur, followed by the potential ruptures of the N-glycosidic or beta-phosphate bonds. The rupture barriers are strongly influenced by the rotational configuration of the phosphate group at the 3' terminal, and are influenced by bulk solvation effects. The O4-H adduct has the highest thermal stability, as the localization of the unpaired electron does not enable cleavage of either the C1'-N1 or the C3'-O(P) bonds. For the most stable adduct, with H atom added to the C5 position, the rate-controlled step is the H2'a abstraction by the C6 radical site, after which the subsequent strand rupture reactions proceed with low barriers. The main unpaired electron densities are presented for the transient species. Combined with previous results, it is concluded that the H atom adducts are more facile to drive the strand scission rather than N-glycosidic bond ruptures within the nucleic acid bases.
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distinct hydroxy radical induced damage of 3 Uridine Monophosphate in rna a theoretical study
Chemistry: A European Journal, 2009Co-Authors: Ru Bo Zhang, Leif A ErikssonAbstract:RNA strand scission and base release in 3'-Uridine Monophosphate (UMP), induced by OH radical addition to uracil, is studied at the DFT B3LYP/6-31+G(d,p) level in the gas phase and in solution. In particular, the mechanism of hydrogen-atom transfer subsequent to radical formation, from C2' on the sugar to the C6 site on the base, is explored. The barriers of (C2'-)H2'(a) abstraction by the C6 radical site range from 11.2 to 20.0 kcal mol(-1) in the gas phase and 14.1 to 21.0 kcal mol(-1) in aqueous solution, indicating that the local surrounding governs the hydrogen-abstraction reaction in a stereoselective way. The calculated N1-C1' (N1-glycosidic bond) and beta-phosphate bond strengths show that homolytic and heterolytic bond-breaking processes are largely favored in each case, respectively. The barrier for beta-phosphate bond rupture is approximately 3.2-4.0 kcal mol(-1) and is preferred by 8-12 kcal mol(-1) over N1-glycosidic bond cleavage in both the gas phase and solution. The beta-phosphate bond-rupture reactions are exothermal in the gas phase and solution, whereas N1-C1' bond-rupture reactions require both solvation and thermal corrections at 298 K to be energetically favored. The presence of the ribose 2'-OH group and its formation of low-barrier hydrogen bonds with oxygen atoms of the 3'-phosphate linkage are highly important for hydrogen transfer and the subsequent bond-breakage reactions.
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theoretical studies of damage to 3 Uridine Monophosphate induced by electron attachment
Chemistry: A European Journal, 2008Co-Authors: Ru Bo Zhang, Ke Zhang, Leif A ErikssonAbstract:Low-energy electrons (LEE) are well known to induce nucleic acid damage. However, the damage mechanisms related to charge state and structural features remain to be explored in detail. In the present work, we have investigated the N1-glycosidic and C3'-O(P) bond ruptures of 3'-UMP (UMP=Uridine Monophosphate) and the protonated form 3'-UMPH with -1 and zero charge, respectively, based on hybrid density functional theory (DFT) B3 LYP together with the 6-31+G(d,p) basis set. The glycosidic bond breakage reactions of the 3'UMP and 3'UMPH electron adducts are exothermic in both cases, with barrier heights of 19-20 kcal mol(-1) upon inclusion of bulk solvation. The effects of the charge state on the phosphate group are marginal, but the C2'-OH group destabilizes the transition structure of glycosidic bond rupture of 3'-UMPH in the gas phase by approximately 5.0 kcal mol(-1). This is in contrast with the C3'-O(P) bond ruptures induced by LEE in which the charge state on the phosphate influences the barrier heights and reaction energies considerably. The barrier towards C3'-O(P) bond dissociation in the 3'UMP electron adduct is higher in the gas phase than the one corresponding to glycosidic bond rupture and is dramatically influenced by the C2'-OH group and bulk salvation, which decreases the barrier to 14.7 kcal mol(-1). For the C3'-O(P) bond rupture of the 3'UMPH electron adduct, the reaction is exothermic and the barrier is even lower, 8.2 kcal mol(-1), which is in agreement with recent results for 3'-dTMPH and 5'-dTMPH (dTMPH=deoxythymidine Monophosphate). Both the Mulliken atomic charges and unpaired-spin distribution play significant roles in the reactions
Leif A Eriksson - One of the best experts on this subject based on the ideXlab platform.
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the fate of h atom adducts to 3 Uridine Monophosphate
Journal of Physical Chemistry B, 2010Co-Authors: Ran Wang, Ru Bo Zhang, Leif A ErikssonAbstract:The stabilities of the adducts deriving from H free radical addition to the O2, O4, and C5 positions of 3'-Uridine Monophosphate (3'UMP) are studied by the hybrid density functional B3LYP approach. Upon H atom addition at the O2 position, a concerted low-barrier proton-transfer process will initially occur, followed by the potential ruptures of the N-glycosidic or beta-phosphate bonds. The rupture barriers are strongly influenced by the rotational configuration of the phosphate group at the 3' terminal, and are influenced by bulk solvation effects. The O4-H adduct has the highest thermal stability, as the localization of the unpaired electron does not enable cleavage of either the C1'-N1 or the C3'-O(P) bonds. For the most stable adduct, with H atom added to the C5 position, the rate-controlled step is the H2'a abstraction by the C6 radical site, after which the subsequent strand rupture reactions proceed with low barriers. The main unpaired electron densities are presented for the transient species. Combined with previous results, it is concluded that the H atom adducts are more facile to drive the strand scission rather than N-glycosidic bond ruptures within the nucleic acid bases.
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distinct hydroxy radical induced damage of 3 Uridine Monophosphate in rna a theoretical study
Chemistry: A European Journal, 2009Co-Authors: Ru Bo Zhang, Leif A ErikssonAbstract:RNA strand scission and base release in 3'-Uridine Monophosphate (UMP), induced by OH radical addition to uracil, is studied at the DFT B3LYP/6-31+G(d,p) level in the gas phase and in solution. In particular, the mechanism of hydrogen-atom transfer subsequent to radical formation, from C2' on the sugar to the C6 site on the base, is explored. The barriers of (C2'-)H2'(a) abstraction by the C6 radical site range from 11.2 to 20.0 kcal mol(-1) in the gas phase and 14.1 to 21.0 kcal mol(-1) in aqueous solution, indicating that the local surrounding governs the hydrogen-abstraction reaction in a stereoselective way. The calculated N1-C1' (N1-glycosidic bond) and beta-phosphate bond strengths show that homolytic and heterolytic bond-breaking processes are largely favored in each case, respectively. The barrier for beta-phosphate bond rupture is approximately 3.2-4.0 kcal mol(-1) and is preferred by 8-12 kcal mol(-1) over N1-glycosidic bond cleavage in both the gas phase and solution. The beta-phosphate bond-rupture reactions are exothermal in the gas phase and solution, whereas N1-C1' bond-rupture reactions require both solvation and thermal corrections at 298 K to be energetically favored. The presence of the ribose 2'-OH group and its formation of low-barrier hydrogen bonds with oxygen atoms of the 3'-phosphate linkage are highly important for hydrogen transfer and the subsequent bond-breakage reactions.
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theoretical studies of damage to 3 Uridine Monophosphate induced by electron attachment
Chemistry: A European Journal, 2008Co-Authors: Ru Bo Zhang, Ke Zhang, Leif A ErikssonAbstract:Low-energy electrons (LEE) are well known to induce nucleic acid damage. However, the damage mechanisms related to charge state and structural features remain to be explored in detail. In the present work, we have investigated the N1-glycosidic and C3'-O(P) bond ruptures of 3'-UMP (UMP=Uridine Monophosphate) and the protonated form 3'-UMPH with -1 and zero charge, respectively, based on hybrid density functional theory (DFT) B3 LYP together with the 6-31+G(d,p) basis set. The glycosidic bond breakage reactions of the 3'UMP and 3'UMPH electron adducts are exothermic in both cases, with barrier heights of 19-20 kcal mol(-1) upon inclusion of bulk solvation. The effects of the charge state on the phosphate group are marginal, but the C2'-OH group destabilizes the transition structure of glycosidic bond rupture of 3'-UMPH in the gas phase by approximately 5.0 kcal mol(-1). This is in contrast with the C3'-O(P) bond ruptures induced by LEE in which the charge state on the phosphate influences the barrier heights and reaction energies considerably. The barrier towards C3'-O(P) bond dissociation in the 3'UMP electron adduct is higher in the gas phase than the one corresponding to glycosidic bond rupture and is dramatically influenced by the C2'-OH group and bulk salvation, which decreases the barrier to 14.7 kcal mol(-1). For the C3'-O(P) bond rupture of the 3'UMPH electron adduct, the reaction is exothermic and the barrier is even lower, 8.2 kcal mol(-1), which is in agreement with recent results for 3'-dTMPH and 5'-dTMPH (dTMPH=deoxythymidine Monophosphate). Both the Mulliken atomic charges and unpaired-spin distribution play significant roles in the reactions
