58-96-8Relevant articles and documents
Mechanistic studies relevant to bromouridine-enhanced nucleoprotein photocrosslinking: Possible involvement of an excited tyrosine residue of the protein
Norris, Christopher L.,Meisenheimer, Kristen M.,Koch, Tad H.
, p. 201 - 207 (1997)
The results of mechanistic studies on formation of uridine (U) and N-acetyl-m-(5-uridinyl)tyrosine N-ethylamide (2) from irradiation of aqueous, pH 7 solutions of bromouridine (BrU) and N-acetyltyrosine N-ethylamide (1) are reported. Solutions were irradiated with monochromatic laser emission at 266, 308 and 325 nm. Quantum yield measurements as a function of excitation wave-length suggest that both products result from excitation of the tyrosine derivative followed by electron transfer to BrU, possibly with intermediacy of the hydrated electron. The BrU radical anion ejects bromide to form the uridinyl radical, which then abstracts a hydrogen atom from 1 or adds to the aromatic ring of 1. Formation of adduct 2 is a model for photocrosslinking of nucleic acids bearing the bromouracil chromophore to adjacent tyrosine residues of proteins in nucleoprotein complexes. The value of 325 nm excitation in photocrosslinking, where the tyrosine chromophore is more competitive for photons, was demonstrated with an RNA bound to the MS2 bacteriophage coat protein; more than a 60% increase in the yield of photocrosslinking relative to that obtained with 308 nm excitation was achieved.
Hydrolytic Reactions of the Diastereomeric Phosphoromonothioate Analogs of Uridyl(3',5')uridine: Kinetics and Mechanisms for Desulfurization, Phosphoester Hydrolysis, and Transesterification to the 2',5'-Isomers
Oivanen, Mikko,Ora, Mikko,Almer, Helena,Stroemberg, Roger,Loennberg, Harri
, p. 5620 - 5627 (1995)
Hydrolytic reactions of the RP and SP diastereomers of the phosphoromonothioate analog of uridylyl(3',5')uridine (3',5'-UpU), having a nonbridging oxygen replaced with sulfur, have been followed by HPLC over a wide range at 363.2 K.Under neutral and acidic conditions three reactions compete: (i) desulfurization to an equilibrium mixture of 3',5'- and 2',5'-UpU, (ii) hydrolysis to uridine 2'- and 3'-monophosphates with release of uridine (either via a 2',3'-cyclic phosphoromonothioate, or a desulfurized cyclic triester), and (iii) isomerization to the 2',5'-dinucleoside phosphoromonothioate.With both diastereomers, desulfurization predominates over hydrolysis and migration at pH 1-8.Migration proceeds by retention of configuration at phosphorus and is most pronounced in very acidic solutions (H0 > 0.5 mol L-1), representing 20-30percent of the total disappearance of the starting material.At pH 3-6, the proportion of this reaction is less than 10percent.In the latter pH range, all the reactions are pH-independent.At lower pH, first-order dependence on acidity is observed, but at H0 P diastereomer is at pH P isomer.Under alkaline conditions (pH > 9), only base-catalyzed hydrolysis to uridine 2'- and 3'-thiophosphates with release of uridine takes place.At pH 1, the thioate analogs are more than 1 order of magnitude more stable than UpU, while at higher pH the reactivities are comparable.
EM2487, a novel anti-HIV-1 antibiotic, produced by Streptomyces sp. Mer-2487: Taxonomy, fermentation, biological properties, isolation and structure elucidation
Takeuchi, Hitoshi,Asai, Naoki,Tanabe, Kazunori,Kozaki, Teruya,Fujita, Masanori,Sakai, Takashi,Okuda, Akifumi,Naruse, Nobuaki,Yamamoto, Satoshi,Sameshima, Tomohiro,Heida, Naohiko,Dobashi, Kazuyuki,Baba, Masanori
, p. 971 - 982 (1999)
For the purpose of discovering novel agents that inhibit HIV-1 replication at the transcriptional level, we have established cell lines reflecting the HIV-1 long terminal repeat-driven gene expression. Using these cell lines, we have screened approximately 10,000 microorganism products and found that the culture supernatant of Streptomyces sp. Mer-2487 suppresses the HIV-1 Tat-induced gene expression without affecting the basal or tumor necrosis factor-α-induced transcription. The purified active component has a unique structure. This compound has an inhibitory effect on HIV-1 replication in chronically infected cells as well as acutely infected cells, suggesting that the inhibition occurs at a postintegration step of HIV-1 proviral DNA in the HIV-1 replication cycle.
Hydrolysis and desulfurization of the diastereomeric phosphoromonothioate analogs of uridine 2',3'-cyclic monophosphate
Ora,Oivanen,Lonnberg
, p. 3951 - 3955 (1996)
Hydrolyses of the two diastereomeric phosphoromonothioate analogs of uridine 2',3'-cyclic monophosphate [(R(P))- and (S(P))-2',3'-cUMPS] at 363.2 K have been followed by HPLC over pH-range 0-12. In aqueous alkali (pH > 9) only base-catalyzed endocyclic phosphoester hydrolysis to a nearly equimolar mixture of uridine 2'- and 3'-phosphoromonothioates (2'- and 3'-UMPS) takes place, analogously to the hydrolysis of uridine 2',3'-cyclic monophosphate (2',3'-cUMP). The (R(P))- and (S(P))-2',3'-cUMPS are hydrolyzed 50 and 30%, respectively, more slowly than 2',3'-cUMP. Under neutral and acidic conditions, desulfurization of the cyclic thiophosphates to 2',3'-cUMP competes with the phosphoester hydrolysis, both reactions being acid-catalyzed at pH 0.1 mol L-1), where more than 90% of the starting material is degraded via this route. At pH 5 is with the R(P)-isomer 5-fold faster than with the S(P)-isomer. In contrast to 2',3'-cUMP, depyrimidination of the starting material (i.e., release of the uracil base) competes with the hydrolysis of the thiophosphate moiety under neutral conditions (pH 6-8).
Hydrolytic stability of a phosphate-branched oligonucleotide incorporating a ribonucleoside 3′-phosphotriester unit
Loennberg, Tuomas
, p. 315 - 323 (2006)
A phosphate-branched oligonucleotide has been prepared by using an appropriately protected trinucleoside phosphotriester building block in conventional solid-phase synthesis. Hydrolysis of the branched oligonucleotide has been followed over a wide pH range. Comparison of the present results with those previously obtained for simpler analogues indicates that a trinucleoside 3′,3′,5′-monophosphate, when embedded in an oligonucleotide structure, is stabilized toward hydroxide-ion catalyzed cleavage by more than one order of magnitude, lending some support to the feasibility of existence of phosphate-branched RNA X in biological systems. Copyright Taylor & Francis Group, LLC.
Hydrolytic reactions of an RNA dinucleotide containing a 3'-S- phosphorothiolate linkage
Elzagheid, Mohamed,Oivanen, Mikko,Colin,Jones,Cosstick, Richard,Loennberg, Harri
, p. 1265 - 1266 (1999)
The pH-rate profiles (pH 0.2 to 9 at 90°C) for the competing hydrolytic reactions of (3'-deoxy-3'-thioinosylyl)-3',5'-uridine (IspU) have been determined by an HPLC method.
The effective molarity of the substrate phosphoryl group in the transition state for yeast OMP decarboxylase
Sievers, Annette,Wolfenden, Richard
, p. 45 - 52 (2005)
The second order rate constant (kcat/Km) for decarboxylation of orotidine by yeast OMP decarboxylase (ODCase), measured by trapping 14CO2 released during the reaction, is 2 × 10-4 M-1 s-1. This very low activity may be compared with a value of 3 × 107 M-1 s-1 for the action of yeast OMP decarboxylase on the normal substrate OMP. Both activities are strongly inhibited by 6-hydroxy UMP (BMP), and abrogated by mutation of Asp-96 to alanine. These results, in conjunction with the binding affinity of inorganic phosphate as a competitive inhibitor (Ki = 7 × 10-4 M), imply an effective concentration of 1.1 × 109 M for the substrate phosphoryl group in stabilizing the transition state for enzymatic decarboxylation of OMP. The observed difference in rate (1.5 × 1011-fold) is the largest effect of a simple substituent that appears to have been reported for an enzyme reaction.
Cytidine deaminase can deaminate fused pyrimidine ribonucleosides
Li, Yao,Ludford, Paul T.,Tor, Yitzhak,Yang, Shenghua
, p. 6237 - 6243 (2021)
The tolerance of cytidine deaminase (CDA) to expanded heterocycles is exploredviathree fluorescent cytidine analogues, where the pyrimidine core is fused to three distinct five-membered heterocycles at the 5/6 positions. The reaction between CDA and each analogue is followed by absorption and emission spectroscopy, revealing shorter reaction times for all analogues than the native substrate. Pseudo-first order and Michaelis-Menten kinetic analyses provide insight into the enzymatic deamination reactions and assist in drawing comparison to established structure activity relationships. Finally, inhibitor screening modalities are created for each analogue and validated with zebularine and tetrahydrouridine, two known CDA inhibitors.
Kipukasins, nucleoside derivatives from Aspergillus versicolor
Jiao, Ping,Mudur, Sanjay V.,Gloer, James B.,Wicklow, Donald T.
, p. 1308 - 1311 (2007)
Seven new aroyl uridine derivatives (kipukasins A-G; 1-7) were isolated from solid-substrate fermentation cultures of two different Hawaiian isolates of Aspergillus versicolor. The structures of compounds 1-7 were determined by analysis of NMR and MS data. The nucleoside portion of lead compound 1 was assigned as uracil-1-β-D-ribofuranoside by spectral comparison with an authentic standard. The bioactivity of the original A. versicolor extracts was accounted for mainly by the presence of the known metabolite sterigmatocystin, but kipukasins A and B showed modest activity in assays against Gram-positive bacteria.
Mechanistic studies of the 5-iodouracil chromophore relevant to its use in nucleoprotein photo-cross-linking
Norris, Christopher L.,Meisenheimer, Poncho L.,Koch, Tad H.
, p. 5796 - 5803 (1996)
The photoreactivity of the 5-iodouracil chromophore was investigated toward understanding photo-cross-linking of nucleic acids bearing the chromophore to functionality in associated proteins. Irradiation of 5-iodouridine (IU) in the presence of a 10-fold excess of N-acetyltyrosine N-ethylamide (1) at 308 nm with a XeCl excimer laser or at 325 nm with a HeCd laser yields uridine (U) and N-acetyl-m-(5-uridinyl)tyrosine N-ethylamide (2) in a 1:2 mole ratio. In the presence of N-acetylphenylalanine N-ethylamide, uridine and analogous ortho, meta, and para regioisomeric adducts (3o, 3m, and 3p) were formed in a similar U to adduct mole ratio. The primary photochemical process leading to products was established as carbon-iodine bond homolysis in the first excited singlet state from a deuterium labeling experiment, photoacoustic calorimetry, and quantum yield measurements. Photoreduction of IU in 2-propanol-d solvent gave U with no deuterium incorporation. Photoacoustic calorimetric measurements established that triplet benzophenone transferred energy to IU with a rate constant of 2 x 109 M-1 s-1. Further, the reaction of IU with 1 to form 2 was sensitized by benzophenone; however, comparison of quantum yields upon direct and sensitized excitation indicated that, at most, only a small portion of the reactions occurred via the triplet state. With direct excitation of IU, quantum yields as a function of the concentration of 1 showed that U and adduct 2 resulted from a common intermediate proposed to be the 5-uridinyl radical. Uridine formation was enhanced by the presence of hydrogen atom donors at the expense of formation of 2. Quantum yields were independent of excitation wavelength in the region 310-330 nm but not the reaction medium. The quantum yield of uridine formation but not adduct formation was approximately an order of magnitude higher in 90% acetonitrile - 10% water than in pH 7 water. The results are discussed in terms of high-yield cross-linking of nucleic acids bearing the 5-iodouracil chromophore to associated proteins in light of cocrystal X-ray structural data.
