Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphorylation of arabinofuranosylthymine (araThd) has been studied both in non-infected cells and in those infected with herpes simplex virus (HSV-1, Lennette; HSV-1, IES and HSV-2, D-316). In these experiments, HSV strains were used which either contain (Lennette, TK+ and D-316 TK+) or lack (IES, TK-) the capacity to induce pyrimidine deoxyribonucleoside kinase. It was found that extracellularly administered araThd is phosphorylated to ara TTP via araTMP and araTDP in both non-infected and in HSV-infected cells. The phosphorylating capacity is more than tenfold lower in non-infected cells than in infected cells. Interestingly, cells infected with the TK- strain have a tenfold higher phosphorylating capacity than normal, uninfected cells, a fact which might indicate that host cell deoxythymidine kinase is induced during HSV infection. AraTMP is incorporated into cellular DNA but not into HSV DNA. This finding is in contrast to observations with arabinofuranosyladenine, which is incorporated into both cellular and HSV DNA. In vitro experiments with HSV-induced DNA polymerase show that araTTP strongly inhibits the enzyme activity. Therefore we conclude that the inhibition of HSV DNA polymerase by araTTP (formed intracellularly from araThd) is the explanation for the observed antiviral activity of araThd.
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PMID:Phosphorylation of arabinofuranosylthymine in non-infected and herpesvirus (TK+ and TK-)-infected cells. 22 22

Human cytomegalovirus (HCMV, a betaherpes virus) is the cause of serious disease in immunologically compromised individuals, including those with acquired immunodeficiency syndrome. One of the compounds used in the chemotherapy of HCMV infections is the nucleoside analogue 9-(1,3-dihydroxy-2-propoxymethyl)-guanine (ganciclovir). The mechanism of action of this drug is dependent on the formation of the nucleoside triphosphate, which is a strong inhibitor of the viral DNA polymerase. Thymidine kinase, which is encoded by many of the herpesviruses, catalyses the initial phosphorylation of ganciclovir. But there is no evidence for the coding of this enzyme by HCMV, and DNA sequence analysis of the HCMV genome has shown that there is no open reading frame characteristic of a herpesvirus thymidine kinase. Here we present biochemical and immunological evidence that the HCMV UL97 open reading frame codes for a protein capable of phosphorylating ganciclovir. This protein seems to be responsible for the selectivity of ganciclovir and will be useful tool in the understanding and refinement of the antiviral activity of new selective anti-HCMV compounds.
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PMID:Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. 131 59

A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A. Harrington, R. W. Morrison, Jr., C. U. Lambe, D. J. Nelson, D. R. Averett, K. Biron, and P. A. Furman, Proc. Natl. Acad. Sci. USA 86:1051-1055, 1989) that was subsequently found to cause hematological toxicity at high oral doses in rats. Eleven structurally related inactivators of herpes simplex virus (HSV) ribonucleotide reductase were therefore tested in vivo for hematological toxicity and for potentiation of ACV. None of the novel ribonucleotide reductase inactivators was hematologically toxic to rats following oral dosing at 60 mg/kg/day for 30 days. Four of these inactivators statistically improved the antiviral topical potency of ACV on HSV type 1-infected nude mice. A promising compound, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-infected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus strains tested, i.e., wild-type (ACV-sensitive) HSV type 1 and HSV type 2 strains and three mutant (ACV-resistant) HSV type 1 strains. The latter included a virus expressing a DNA polymerase resistant to inhibition by ACV triphosphate, a virus deficient in thymidine kinase (the enzyme responsible for phosphorylating ACV), and a virus expressing an altered thymidine kinase, which catalyzes the normal phosphorylation of thymidine but not of ACV. BW 348U87 and ACV are currently being developed as a combination topical therapy for cutaneous herpes infections.
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PMID:Inactivators of herpes simplex virus ribonucleotide reductase: hematological profiles and in vivo potentiation of the antiviral activity of acyclovir. 132 41

Cytomegalovirus (CMV) infection is extremely common in patients with advanced human immunodeficiency virus infection, in whom it can produce a variety of clinical syndromes. Ganciclovir is a guanosine analogue that selectively inhibits CMV DNA polymerase when intracellularly phosphorylated to its active form. In patients with CMV retinitis, induction therapy with ganciclovir results in high rates of clinical and virologic response; maintenance therapy is required to forestall progression of disease. Clinically relevant resistance of CMV to ganciclovir has recently been reported. Decreased phosphorylation of ganciclovir to its active form has been observed in cells infected with resistant strains, suggesting that CMV may encode a ganciclovir-phosphorylating enzyme whose function is deleted by mutation, conferring resistance. Further study is needed to establish the mechanism of resistance and to define the prevalence of resistance in the clinical setting.
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PMID:Clinical use of ganciclovir for cytomegalovirus infection and the development of drug resistance. 184 21

The regulation of the base excision repair enzymes uracil DNA glycosylase and hypoxanthine DNA glycosylase was examined in 2 different progeroid cell strains. The immunoreactivity of the uracil DNA glycosylase in progeroid cells was examined by enzyme linked immunosorbent assay (ELISA) and by immunoblot analysis. The enzyme was recognized in a quantitative manner by 2 different anti-human uracil DNA glycosylase monoclonal antibodies in the ELISA. Western blot analysis identified a glycosylase protein of Mr = 37,000. In randomly proliferating progeroid cells, the uracil DNA glycosylase was enhanced 3-fold during cell growth. In synchronous cells, uracil DNA glycosylase and hypoxanthine DNA glycosylase were induced with an extent of induction (5-6-fold) comparable to that observed for normal human cells. Further, the activity of each base excision repair enzyme was enhanced with a comparable temporal sequence prior to the induction of DNA synthesis and DNA polymerase activity. These results indicate a normal cell cycle regulation of base excision repair in progeroid cells.
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PMID:Proliferation-dependent regulation of DNA glycosylases in progeroid cells. 207 60

Phosphorylation is a major post-translational regulatory mechanism and plays a key role in transduction of mitogenic signals in cell proliferation. The role of phosphorylation and dephosphorylation in regulating the activities of a multiprotein DNA polymerase alpha complex was examined. Treatment of the HeLa cell multiprotein DNA polymerase alpha with calf intestinal alkaline phosphatase resulted in the inactivation of DNA polymerase alpha and DNA primase but had no effect on deoxyribonuclease- and primer-recognition proteins. A protein kinase co-purified with the multiprotein DNA polymerase alpha and was partially purified from HeLa cells. The partially purified kinase was active in phosphorylating dephosphorylated polymerase alpha and used casein and histones as exogenous substrates. This study demonstrates that phosphorylation-dephosphorylation may have modulated the activities of DNA replicative enzymes and suggests a role for specific phosphatases and kinases in this process.
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PMID:Phosphorylation of HeLa cell multiprotein DNA polymerase alpha complex: impact on activity and partial purification of the associated kinase. 256 5

The physical association of mammalian excision repair enzymes with DNA was examined as a function of cell proliferation. The molecular weight distribution of two nuclear base excision repair enzymes, the uracil DNA glycosylase and the hypoxanthine DNA glycosylase, were examined by sucrose step gradient analysis. The sedimentation of DNA polymerase activity as well as the distribution of parental and replicating DNA were determined simultaneously. In confluent BHK-21 fibroblasts, basal levels of both DNA glycosylases, DNA polymerase beta, and parental DNA sedimented to the 20%/40% sucrose border. In proliferating BHK-21 cells, induced levels of both DNA glycosylases, DNA polymerase alpha, and replicating DNA sedimented to the 40%/50% sucrose border. The physical association of the repair enzymes with DNA was demonstrated by detergent treatment and by DNase digestion. As defined by [35S] methionine pulse labeling analysis, newly synthesized DNA repair enzymes were localized with either parental or replicating DNA. These results suggested that the physical association of mammalian DNA repair enzymes with nuclear DNA was dependent on the proliferative state of the cell.
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PMID:Physical association of base excision repair enzymes with parental and replicating DNA in BHK-21 cells. 272 Jun 64

9-([2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U) is more potent and has a more prolonged inhibitory effect against Epstein-Barr virus (EBV) in vitro than does acyclovir (ACV). To assess the mechanism of this difference, we first compared the extent of phosphorylation of the two drugs in superinfected Raji cells. BW B759U is phosphorylated to levels 100-fold higher than is ACV. In addition, lower levels of phosphorylation of BW B759U and ACV were observed in uninfected Raji cells. Studies on the kinetics of formation of BW B759U triphosphate in superinfected Raji cells indicated that drug-phosphorylating activity was detected as early as 3 h after superinfection; this activity was steadily maintained for the first 7 h, followed by a burst of activity between 7 and 10 h and a doubling of phosphorylation between 10 and 25 h. During the superinfection cycle, the pool sizes of deoxyribonucleoside and ribonucleoside triphosphates were increased and reached their maxima at 10 h after infection. The maximal amount of triphosphorylated drug in a virus producer cell, P3HR-1 (LS), was obtained at 21 h after drug treatment. During long-term drug treatment, approximately 44 and 77% reduction in EBV genome copies per cell was observed on days 3 and 7, respectively. In a separate experiment, after treatment of P3HR-1 (LS) cells with BW B759U for 36 h, 4.2 pmol of BW B759U triphosphate per 10(6) cells was achieved. After the cells were released into drug-free medium, drug triphosphate was rapidly decreased to 11% of the original level in 1 day. Thereafter, the decrease was slow but steady, down to 0.22 pmol/10(6) P3HR-1 cells by 5 days. We calculated that 0.22 pmol of BW B759U triphosphate per 10(6) cells represents a cellular concentration of 0.22 microM, which is theoretically enough to inhibit EBV replication. This is based upon a comparison with the 50% effective dose of BW B759U (0.05 microM) for inhibition of genome replication and a Ki of 0.08 microM for BW B759U triphosphate inhibition of EBV DNA polymerase.
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PMID:Metabolic activation of 9([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human lymphoblastoid cell lines infected with Epstein-Barr virus. 302 90

The acyclovir resistant mutant of varicella-zoster virus ACV-R (A 8) induced the same level of thymidine kinase activity in infected cells as the parent Kawaguchi strain. However, it induced less deoxycytidine kinase activity and did not induce phosphorylating activity for the nucleotide analogue, 9-(2 hydroxy-ethoxymethyl)-guanine-(acyclovir). Another acyclovir resistant mutant, ACV-R (A 4), which is cross-resistant to phosphonoacetate and is thought to be a viral DNA polymerase mutant, induced the same level of phosphorylating activities for thymidine, deoxycytidine and acyclovir as the parent strain. The altered substrate specificity of thymidine kinase induced by ACV-R (A 8) is concluded to confer resistance to acyclovir on ACV-R (A 8).
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PMID:Thymidine kinase with altered substrate specificity of acyclovir resistant varicella-zoster virus. 302 11

Human SY5Y neuroblastoma cells which were differentiated in culture by treatment with 7S murine nerve growth factor for 5 weeks and selection with aphidicolin (L. Jensen, Dev. Biol. 120:56-64, 1987) demonstrated a considerably slower rate of removal of DNA adducts of benzo[a]pyrene, benzo[a]pyrenediolepoxide, and N7-methylguanine than did undifferentiated mitotic cells. A dramatic decline in unscheduled DNA synthesis induced by UV radiation was similarly observed. DNA polymerase beta and uracil DNA glycosylase were unchanged after differentiation, DNA polymerase alpha and DNA methylase decreased roughly threefold, and total apurinic-apyrimidinic endonuclease activity increased roughly threefold after treatment.
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PMID:A reduced rate of bulky DNA adduct removal is coincident with differentiation of human neuroblastoma cells induced by nerve growth factor. 314 94


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