TY - JOUR. T1 - Isolation and characterization of phosphonoacetic acid-resistant mutants of human cytomegalovirus. AU - DAquila, R. T.. AU - Summers, W. C.. PY - 1987. Y1 - 1987. N2 - Mutants of the human cytomegalovirus (HCMV) that were 6- to 13-fold more resistant to phosphonoacetic acid than the wild-type HCMV (Towne) were isolated. Extracts from mycoplasma-free, mutant-infected cells had phosphonoacetate-resistant DNA polymerase activity in vitro. This strongly suggests that the selected mutations are in the HCMV DNA polymerase genes of these viruses.. AB - Mutants of the human cytomegalovirus (HCMV) that were 6- to 13-fold more resistant to phosphonoacetic acid than the wild-type HCMV (Towne) were isolated. Extracts from mycoplasma-free, mutant-infected cells had phosphonoacetate-resistant DNA polymerase activity in vitro. This strongly suggests that the selected mutations are in the HCMV DNA polymerase genes of these viruses.. UR - ...
Summary Aphidicolin, a tetracyclic diterpenoid which inhibits the DNA polymerase-α activities of many eukaryotic cells, inhibited herpes simplex virus growth and DNA synthesis in infected cultures and the activity of the virus DNA polymerase in vitro. A wide range of stable aphidicolin sensitivities was represented amongst a collection of virus strains with no prior exposure to this drug, but viruses with polymerase mutations selected for resistance to phosphonoacetic acid (PAA) or to acycloguanosine typically showed increased sensitivity to aphidicolin. Of 16 unrelated PAA-resistant variants, 7 were hypersensitive to aphidicolin. A number of mutants with temperature-sensitive (ts) lesions in the polymerase gene also showed increased aphidicolin sensitivity (e.g. HSV-1[mP17]tsH) or aphidicolin hypersensitivity (e.g. HSV-1[KOS]tsD9, tsC4). Resistance or hypersensitivity of virus growth and DNA synthesis in vivo were correlated with resistance or hypersensitivity of virus DNA polymerase reactions in
The tumor suppressor p53 is stabilized following the induction of deficiencies in nucleotide pool levels by antimetabolites. N-(phosphonacetyl)-L-aspartate (PALA) reversibly inhibits aspartate transcarbamylase, causing interruption of de novo pyrimidine synthesis; hydroxyurea (HU) reversibly inhibits ribonucleotide reductase, inhibiting the conversion of ribonucleotide triphosphates to deoxynucleotide triphosphates. When HCT116, a human colon carcinoma cell line, is treated with either HU or PALA, p53 accumulates and cells arrest in S-phase. Beyond these similarities, the cellular responses to PALA and HU are strikingly different. Chk1 is phosphorylated to a far greater extent in HU-treated HCT116 cells than following PALA treatment. The lack of Chk1 phosphorylation observed during PALA treatment was found to be due to the p53-dependent transcriptional activation of the Wip1 phosphatase, rather than the inactivity of ATR. Chromatin immunoprecipitation studies performed on PALA-treated cells ...
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TIGR02335 (PSSM ID: 131388): Conserved Protein Domain Family hydr_PhnA, This family consists of examples of phosphonoacetate hydrolase, an enzyme specific for the cleavage of the C-P bond in phosphonoacetate
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The three-dimensional structure of Bacillus subtilis aspartate transcarbamoylase (ATCase; aspartate carbamoyltransferase; carbamoyl-phosphate:L-aspartate carbamoyltransferase, EC 2.1.3.2) has been solved by the molecular replacement method at 3.0 A resolution and refined to a crystallographic R factor of 0.19. The enzyme crystallizes in the space group C2 with unit cell dimensions a = 258.5, b = 153.2, and c = 51.9 A and beta = 97.7 degrees. The asymmetric unit is composed of three monomers related by noncrystallographic threefold symmetry. A total of 295 of 304 amino acid residues have been built into the monomer. The last 9 residues in the C terminus were not included in the final model. Each monomer consists of 34% alpha-helix and 18% beta-strand. Three solvent-exposed loop regions (residues 69-84, 178-191, and 212-229) are not well defined in terms of electron density. The catalytic trimer of ATCase from B. subtilis shows great similarity to the catalytic trimer in Escherichia coli ATCase, ...
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en] Acyclovir/therapeutic use ; Amantadine/therapeutic use ; Animals ; Antibodies, Viral/immunology ; Antiviral Agents/pharmacology/therapeutic use ; Chemical Phenomena ; Chemistry ; Foscarnet ; Idoxuridine/therapeutic use ; Immunity, Cellular ; Immunity, Innate ; Immunotherapy/veterinary ; Interferons/immunology/therapeutic use ; Phosphonoacetic Acid/analogs & derivatives/therapeutic use ; Vidarabine/therapeutic use ; Virus Diseases/drug therapy/immunology/therapy/veterinary ; Virus Replication/drug ...
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A Phase I clinical trial of N-(phosphonacetyl)-l-aspartate, an antimetabolite which inhibits a key enzyme in the de novo pathway of pyrimidine biosynthesis, was conducted. N-(Phosphonacetyl)-l-aspartate was given as an i.v. 15-min infusion once daily for five days; cycles of treatment were repeated every three weeks. Thirty-four patients received treatment. Dose-limiting toxicity was observed at 1500 to 2000 mg/sq m/day and was manifested by skin rash, diarrhea, and stomatitis. Rash and diarrhea usually began during the first week of treatment and persisted up to Day 17 of a cycle of therapy. No consistent hematopoietic, hepatic, or renal toxicity was observed. One partial response in a patient with colon carcinoma was seen and continues at more than eight months. Stable disease was observed in three patients with colon carcinoma, two patients with hypernephroma, one patient with pancreatic carcinoma, and one patient with melanoma. The predictability and reversibility of toxicity and the ...
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
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Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits replication of herpes viruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to foscarnet. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to foscarnet and may not respond to therapy with foscarnet. The combination of foscarnet and ganciclovir has been shown to have enhanced activity in vitro ...
Herpes simplex virus (HSV) entry into cells is triggered by the binding of envelope glycoprotein D (gD) to a specific receptor, such as nectin-1 or herpesvirus entry mediator (HVEM), resulting in activation of the fusion effectors gB and gH and virus penetration. Rates of spontaneous mutation have been estimated under optimal growth conditions for a variety of DNA-based microbes, including viruses, bacteria, and eukaryotes. Rates of spontaneous mutation determine the ability of viruses to evolve, infect new hosts, evade immunity and undergo drug resistance. Tumor suppressor gene inactivation is a crucial event in oncogenesis. We have measured the spontaneous production of mutants in derivatives of herpes simplex virus type 1 resistant to phosphonoacetic acid. In fact, wild type HSV-1 and the antimutator HSV-1 PAAr5 exhibited a 2-4 fold higher frequency than HSV-2 in the non-HSV DNA mutatagenesis assay. Msh2, Msh3, and Msh6 are mammalian homologues of the bacterial DNA mismatch repair (DMR) mutS ...
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Tips for EEG recording using Enobio or StarStim = In this page we provide some tips and tricks to work with our systems. Here are some useful resources you should also check this Jove video on the combination of EEG and tDCS: - [http://www.jove.com/video/50426/simultaneous-eeg-monitoring-during-transcranial-direct-current StarStim tCS EEG recording (Jove)] as well as these tutorial videos: {{#ev:youtube, JdcG1Qdq4h8,500,center,An introduction to NIC}} {{#ev:youtube,I5uU20ut8Fk,500,center,Configuration of NIC for stimulation: from simple to advanced}} == Plan your session well before starting == You should have a clear plan covering all the details in your recording session. Prepare to be patient. Setting up always takes a bit longer than expected, and when carrying out experiments ... the third times the charm! Keep your device charged! It is best to ensure you have more than 50% charge before you start. Where do you want to place the electrodes? For how long do you want to record? Do you ...