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971.
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974.
Determination of the Phosphorylated Metabolites of Gemcitabine and of Difluorodeoxyuridine by LCMSMS
Richard J. Honeywell Elisa Giovannetti G. J. Peters 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1203-1213
Gemcitabine is an established chemotherapy agent in several solid tumors. Its mechanism of action has been theoretically established and this is supported with strong experimental evidence. However, certain aspects of the resistance mechanism for this agent remain elusive. We present a method of analysis using tandem liquid chromatography and mass spectrometry that provides a broader, yet more focused view of the action of gemcitabine and its primary metabolite, difluorodeoxyuridine in relation to the (deoxy) nucleoside and (deoxy) nucleotide pools in tumor cell lines. Alcoholic cytosole extracts were incubated with alkaline phosphatase reducing the nucleotide pools to their respective nucleosides. Determination of the nucleoside content by a sensitive LCMSMS method before and after incubation enables the calculation of the total amount of phosphorylation of each (deoxy) nucleoside in the cell. Incubation with clinically relevant levels of gemcitabine (dFdC) or difluorodeoxyuridine (dFdU) for 24 hours enabled the determination of the changes in the (deoxy) nucleotide pools in relation to chemotherapeutic and toxicological effects. Confirmation of the presence of dFdC phosphorylation is presented as well as direct evidence of dFdU phosphorylation after both dFdC and dFdU treatment. Differences in the nucleotide pools are presented after dFdC and dFdU incubation, indicating that dFdU might have more chemotherapeutic properties than previously believed. 相似文献
975.
976.
《MABS-AUSTIN》2013,5(8):1381-1390
ABSTRACTHuman IgG antibodies containing terminal alpha 2,6-linked sialic acid on their Fc N-glycans have been shown to reduce antibody-dependent cell-mediated cytotoxicity and possess anti-inflammatory properties. Although terminal sialylation on complex N-glycans can happen via either an alpha 2,3-linkage or an alpha 2,6-linkage, sialic acids on human serum IgG Fc are almost exclusively alpha 2,6-linked. Recombinant IgGs expressed in Chinese hamster ovary (CHO) cells, however, have sialic acids through alpha 2,3-linkages because of the lack of the alpha 2,6-sialyltransferase gene. The impact of different sialylation linkages to the structure of IgG has not been determined. In this work, we investigated the impact of different types of sialylation to the conformational stability of IgG through hydrogen/deuterium exchange (HDX) and limited proteolysis experiments. When human-derived and CHO-expressed IgG1 were analyzed by HDX, sialic acid-containing glycans were found to destabilize the CH2 domain in CHO-expressed IgG, but not human-derived IgG. When structural isomers of sialylated glycans were chromatographically resolved and identified in the limited proteolysis experiment, we found that only alpha 2,3-linked sialic acid on the 6-arm (the major sialylated glycans in CHO-expressed IgG1) destabilizes the CH2 domain, presumably because of the steric effect that decreases the glycan-CH2 domain interaction. The alpha 2,6-linked sialic acid on the 3-arm (the major sialylated glycan in human-derived IgG), and the alpha 2,3-linked sialic acid on the 3-arm, do not have this destabilizing effect. 相似文献
977.
Secondary amide cis peptide bonds are of even lower abundance than the cis tertiary amide bonds of prolines, yet they are of biochemical importance. Using 2D NMR exchange spectroscopy (EXSY) we investigated the formation of cis peptide bonds in several oligopeptides: Ac-G-G-G-NH(2) , Ac-I-G-G-NH(2) , Ac-I-G-G-N-NH(2) and its cyclic form: I-G-G-N in dimethylsulfoxide (DMSO). From the NMR studies, using the amide protons as monitors, an occurrence of 0.13-0.23% of cis bonds was obtained at 296 K. The rate constants for the trans to cis conversion determined from 2D EXSY spectroscopy were 4-9 × 10(-3) s(-1) . Multiple minor conformations were detected for most peptide bonds. From their thermodynamic and kinetic properties the cis isomers are distinguished from minor trans isomers that appear because of an adjacent cis peptide bond. Solvent and sequence effects were investigated utilizing N-methylacetamide (NMA) and various peptides, which revealed a unique enthalpy profile in DMSO. The cyclization of a tetrapeptide resulted in greatly lowered cis populations and slower isomerization rates compared to its linear counterpart, further highlighting the impact of structural constraints. 相似文献
978.
By regulating the pH values, two new zinc(II) coordination polymers, formulated as [Zn4(μ7-CTAI)(μ3-OH)(μ2-OH)3(H2O)2]n·2n(H2O) (1), [Zn2(μ7-CTAII)(H2O)3]n (2) have been prepared by a flexible ligand, cyclohexane-1,2,4,5-tetracarboxylic acid (H4CTA) under hydrothermal conditions. Complex 1 exhibits a two-dimensional binodal (3,6)-connected topological network containing rare octanuclear zinc(II) clusters as the secondary building units (SBU1). Complex 2 displays a three-dimensional binodal (4,8)-connected topological network containing unusual Zn4(COO)6 secondary building units (SBU2). And importantly, the conformation of H4CTA in 1 exhibits (a,e,e,a) fashion and transforms to thermodynamically more stable conformation (e,a,e,e) type in 2 by pH-controlled. In addition, both of the complexes show strong photoluminescence at room temperature, and may be good candidates for potential luminescence materials. 相似文献
979.
Jeffrey S. Church Andrea L. Woodhead Andrew A. Walker Tara D. Sutherland 《Biopolymers》2014,101(6):630-639
Raspy crickets produce silk webs that are used to build shelters. These webs have been found to consist of both fiber and film components. Raman spectra obtained from both components were found to be very similar for a given species. The protein structure of the fibers and films produced by both species was predominately β‐sheet with lesser amounts of β‐turns, unordered and α‐helical protein also detected. The orientation of the β‐sheet backbone in the fiber was determined to be parallel to the fiber axis. Compared to cocoon and dragline silk the orientation distribution exhibits a significant randomly orientated protein component. Amino acid analysis confirmed the presence of glycine, serine, and alanine in both species, which are known to form antiparallel β‐sheet structures. Both species, although at significantly different concentrations, where found to contain proline. This amino acid is uncommon in insect silks, and likely involved in increasing fiber elasticity. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 630–639, 2014. 相似文献
980.
Elucidating protein function from its structure is central to the understanding of cellular mechanisms. This involves deciphering the dependence of local structural motifs on sequence. These structural motifs may be stabilized by direct or water‐mediated hydrogen bonding among the constituent residues. π‐Turns, defined by interactions between (i) and (i + 5) positions, are large enough to contain a central space that can embed a water molecule (or a protein moiety) to form a stable structure. This work is an analysis of such embedded π‐turns using a nonredundant dataset of protein structures. A total of 2965 embedded π‐turns have been identified, as also 281 embedded Schellman motif, a type of π‐turn which occurs at the C‐termini of α‐helices. Embedded π‐turns and Schellman motifs have been classified on the basis of the protein atoms of the terminal turn residues that are linked by the embedded moiety, conformation, residue composition, and compared with the turns that have terminal residues connected by direct hydrogen bonds. Geometrically, the turns have been fitted to a circle and the position of the linker relative to its center analyzed. The hydroxyl group of Ser and Thr, located at (i + 3) position, is the most prominent linker for the side‐chain mediated π‐turns. Consideration of residue conservation among homologous sequences indicates the terminal and the linker positions to be the most conserved. The embedded π‐turn as a binding site (for the linker) is discussed in the context of “nest,” a concave depression that is formed in protein structures with adjacent residues having enantiomeric main‐chain conformations. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 441–453, 2014. 相似文献