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Although deoxythymidylate cannot be provided directly by ribonucleotide reductase, the gene encoding thymidylate synthase ThyA is absent from the genomes of a large number of nonsymbiotic microbes. We show that ThyX (Thy1) proteins of previously unknown function form a large and distinct class of thymidylate synthases. ThyX has a wide but sporadic(More)
Glial activation contiguous to deposits of amyloid peptide (Abeta) is a characteristic feature in Alzheimer's disease. We performed complementary in vitro and in vivo experiments to study the extent, kinetics, and mechanisms of microglial generation of nitric oxide (NO) induced by challenge with Abeta. We showed that Abeta fibrils dose-dependently induced a(More)
Femtosecond spectroscopy was performed on CO-liganded (fully reduced and mixed-valence states) and O(2)-liganded quinol oxidase bd from Escherichia coli. Substantial polarization effects, unprecedented for optical studies of heme proteins, were observed in the CO photodissociation spectra, implying interactions between heme d (the chlorin ligand binding(More)
Biological reactions in protein complexes involve structural dynamics spanning many orders of magnitude in time. In standard descriptions of catalysis by enzymes, the transition state between reactant and product is reached by thermal, stochastic motion. In the ultrashort time domain, however, the protein moiety and cofactor motions leading to altered(More)
Chronic glial activation possibly plays a role in chronic neurodegeneration in Alzheimer's disease (AD). It has been shown that amyloid peptide is capable of activating microglial cells in vitro. The aim of this study was to further characterize the structural preconditions for amyloid peptide in order to activate glial cells and to investigate whether this(More)
BACKGROUND 5-fluorouracil, a commonly used chemotherapeutic agent, up-regulates expression of human thymidylate synthase (hTS). Several different regulatory mechanisms have been proposed to mediate this up-regulation in distinct cell lines, but their specific contributions in a single cell line have not been investigated to date. We have established the(More)
Hef is an archaeal member of the DNA repair endonuclease XPF (XPF)/Crossover junction endonuclease MUS81 (MUS81)/Fanconi anemia, complementation group M (FANCM) protein family that in eukaryotes participates in the restart of stalled DNA replication forks. To investigate the physiological roles of Hef in maintaining genome stability in living archaeal(More)
Electron transfer (ET) within proteins occurs by means of chains of redox intermediates that favor directional and efficient electron delivery to an acceptor. Individual ET steps are energetically characterized by the electronic coupling V, driving force DeltaG, and reorganization energy lambda. lambda reflects the nuclear rearrangement of the redox(More)
Nature has established two mechanistically and structurally unrelated families of thymidylate synthases that produce de novo thymidylate or dTMP, an essential DNA precursor. Representatives of the alternative flavin-dependent thymidylate synthase family, ThyX, are found in a large number of microbial genomes, but are absent in humans. We have exploited the(More)
ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the functionally analogous human enzyme, thus providing means for selective inhibition of bacterial growth. To identify novel compounds with anti-bacterial activity against the human pathogenic bacterium Helicobacter pylori, based on our earlier biochemical and(More)
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