Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidine may act as an inducer of thymidine kinase activity in cells of higher plants. The general response is demonstrable in a randomly developing cell population such as is found in germinating wheat embryos. If a synchronously developing cell population is studied, however, potentially inducible cells are found to be susceptible to the inductive effect of thymidine only during about 10 per cent of the G1 period, and close to the interval when thymidine kinase activity normally appears.
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PMID:Inducibility of thymidine kinase by thymidine as a function of interphase stage. 584 Aug 3

A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM. Cytotoxicity was minimal, as determined by trypan blue dye exclusion with norman Vero, WI-38, and NC-37 cell proliferation; the 50% inhibitory dose was 4 to 10 microM in a 4-day assay. When compared with other antiviral drugs, FIAC was active at much lower concentrations than arabinosylcytosine, iododeoxyuridine, and arabinosyladenine. It was slightly more active against herpes simplex virus type 1 than acycloquanosine and slightly more toxic to normal cells. FIAC was about 8,000 times more active against the replication of wild-type herpes simplex virus type 1 than against a mutant strain lacking the expression of virus-specified thymidine kinase. Since FIAC appears to be preferentially phosphorylated by the viral enzyme, this is probably responsible, at least in part, for the selectivity of its antiviral actions. Although FIAC appears to be an arabinosylcytosine analog, its antiviral activity was not reversed by deoxycytidine. The minimal cytotoxicity exhibited by FIAC for normal cells, however, was reversed by equimolar concentrations of deoxycytidine. Thymidine, which reversed the antiviral activity, was effective only when used in great excess.
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PMID:2'-fluoro-5-iodo-aracytosine, a potent and selective anti-herpesvirus agent. 624 96

E-5-Propenyl-2'-deoxyuridine (E-5-propenyl-dUrd) inhibited the growth of herpes simplex virus (HSV) types 1 (HSV-1) and 2 in culture. The concentration of drug required to give a 2-log reduction in virus titer was 5 microM for HSV-1 and 23 microM for HSV-2. The anti-HSV-1 activity of this agent was more potent than 5-propyl-dUrd, equivalent to E-5(3,3,3-trifluoropropenyl)-dUrd, and less potent than E-5-bromovinyl-dUrd. The HSV-1 mutant (B2006) lacking the ability to induce virus-specific thymidine kinase could not be inhibited by E-5-propenyl-dUrd. The binding constants of E-5-propenyl-dUrd to HSV-1, HSV-2, varicella-zoster virus, and human mitochondrial thymidine kinases were established to be 0.2, 6.2, 0.3, and 0.8 microM, respectively. Thymidine phosphorylation catalyzed by human cytosol thymidine kinase could not be inhibited by E-5-propenyl-dUrd at a concentration 10-fold higher than the thymidine in the assay. When thymidine and E-5-propenyl-dUrd were added concomitantly at equal concentrations to virus-infected cells, the antiviral activity was not reversed in HSV-1 and only partially reversed in HSV-2. E-5-Propenyl-dUrd also inhibited the growth of human cells in culture with 50% inhibitory dose of 50 microM. Since this inhibition could be readily reversed by a lower concentration of thymidine, the idea of selective protection is proposed. This approach could avoid the cytotoxic effect of an antiviral agent with properties similar to E-5-propenyl-dUrd without sacrificing antiviral activity.
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PMID:Anti-herpes simplex virus and anti-human cell growth activity of E-5-propenyl-2'-deoxyuridine and the concept of selective protection in antivirus chemotherapy. 626 81

Epstein-Barr virus (EBV) from P3HR-1 cells, but not from B95-8 cells, can induce the synthesis of thymidine kinase (TK) in TK-negative Raji cells. The synthesis of TK was slightly reduced, but not inhibited, when cells were cultivated in the presence of cytosine arabinoside (ara-C). On the other hand, the synthesis of TK in ordinary Raji cells was enhanced in the presence of the drug. Thymidine-beta-D-arabinofuranoside (ara-T) was capable of reducing the conversion rate of thymidine to TdR nucleotides by extracts prepared from superinfected Raji TK-cells, but had no influence on TK activity in cell extracts from ordinary Raji cells and EBV-negative Ramos cells. This suggested a broader substrate specificity of the virally induced enzyme.
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PMID:Synthesis of thymidine kinase (TK) in Epstein-Barr virus-superinfected Raji TK-negative cells. 626 68

A guanosine analog, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG), was found to inhibit herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, cytomegalovirus, and Epstein-Barr virus replication by greater than 50% at concentrations that do not inhibit cell growth in culture. The potency of the drug against all of these viruses is greater than that of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir). DHPG was active against HSV-1 growth during the early phase of virus replication and had no activity when added at a later time after infection. Its antiviral activity was irreversible. Thymidine partially neutralized its action. The anti-HSV-1 activity of DHPG was dependent on the induction and the properties of virus-induced thymidine kinase. Virus variants that induced altered virus thymidine kinase and became resistant to acyclovir were still as sensitive to DHPG as the parental virus. DHPG is active against five different HSV variants with induced altered DNA polymerase and resistance to acyclovir.
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PMID:Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1. 630 4

The role of pseudorabies virus (PRV) thymidine kinase (TK) expression in the pathogenesis of PRV infection of mice was studied with TK-negative (TK-) mutants. Thymidine phosphorylation and arabinosylthymine inhibition of PRV replication and efficiency of plating were used to characterize TK+ and TK- PRV. In addition, a plaque autoradiography procedure was utilized to determine the TK phenotype of individual plaques. TK+ and TK- PRV replicated well in ocular tissues, while TK+ but not TK- did so in ganglion tissue. Mortality was absent after TK- PRV inoculation and widespread after inoculation of similar amounts of TK+ PRV. Latent infection in mice was not detected with either TK+ or TK- PRV. This study indicated the probable importance of PRV TK expression in acute trigeminal ganglion infection.
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PMID:The role of pseudorabies virus thymidine kinase expression in trigeminal ganglion infection. 630 38

Acyclovir inhibits herpes simplex virus (HSV) infections better in human fibroblasts than in green monkey kidney cells. Thymidine and acyclovir compete for the active site of HSV thymidine kinase. Large intracellular pools of thymidine found by high-performance liquid chromatography (HPLC) seemed to be responsible for the reduced activity of acyclovir. Such intracellular thymidine pools could not be measured previously, and the HPLC technique may help in evaluating the expected efficiency of acyclovir in cells and tissues prior to treatment.
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PMID:Intracellular pools of thymidine reduce the antiviral action of acyclovir. 630 20

Little is known concerning the mechanism of myeloid differentiation. A human promyelocytic cell line (HL-60) differentiates to granulocytes or macrophage-like cells when cultured with a variety of agents. How these agents trigger myeloid differentiation is not understood. This study shows that 1.0-10.0 micrograms/ml bromodeoxyuridine (BrdU) induced myeloid differentiation of HL-60 in liquid culture. After 7 days, BrdU (3.0 micrograms/ml) produced only moderate inhibition of HL-60 growth, but induced myeloid maturation with 40% of the cells becoming morphologically more mature; 41% developed the ability to reduce nitroblue tetrazolium (NBT); 19% phagocytized Candida albicans; and 18% developed Fc receptors. The action of BrdU was mimicked by 5-iodo-deoxyuridine. Thymidine (Td) (1- to 10-fold excess) competitively inhibited incorporation of [3H]BrdU into DNA of HL-60 and inhibited the triggering of HL-60 differentiation by BrdU. The BrdU-induced maturation of HL-60 correlated with the incorporation of BrdU into DNA of HL-60. DNA buoyant density studies showed that about 46% of the Td was replaced by BrdU in each DNA strand of HL-60 as the cells differentiated in culture containing 3 micrograms/ml BrdU for 7 days. We established 20 thymidine kinase (TK)-deficient HL-60 clones. The HL-60 TK-deficient cells were unable to phosphorylate Td, to incorporate either [3H]Td or [3H]BrdU or differentiate in the presence of BrdU (1-1000 micrograms/ml). The HL-60 TK-deficient cells retained the ability to differentiate in the presence of other HL-60 inducers. Taken together, the studies suggest myeloid differentiation of HL-60 is triggered because of incorporation of BrdU into DNA of the cells.
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PMID:The study of human myeloid differentiation using bromodeoxyuridine (BrdU). 657 32

Mercuric chloride at a narrow range of concentration (2 to 2.5 X 10(-5)M) facilitated [3H]thymidine incorporation into acid-insoluble material (DNA fraction) of cultured human T lymphoid cells, Molt-4F, after 72-hr culture with the metal. This effect by mercury was observed in spite of the decrease in growth rate and DNA contents of the cells. Thymidine kinase activity in Molt-4F cells treated with 2 X 10(-5)M mercury decreased to 50 to 60% of the control activity. The stimulation of [3H]thymidine incorporation into the cells by mercury, therefore, might be independent of the increase in thymidine kinase activity. 3H-Thymidine incorporation by the control cells decreased as culture time passed. In contrast to the control, [3H]thymidine incorporation by mercury-treated cells increased until 72-hr culture. [3H]Thymidine uptake by the control cells after 24, 48, or 72-hr culture increased until 20 min of incubation period, but thereafter no increase in the uptake was observed until 60 min. On the other hand, [3H]thymidine uptake by the cells treated with mercury for 24 to 72 hr increased linearly until 60 min of incubation period. These results seemed to indicate that the mercury stimulation of [3H]thymidine incorporation might be attributable not to the actual increase of DNA synthesis but to the suppression of the culture time-dependent decrease in the incorporation by the control cells.
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PMID:A mechanism for the stimulation by inorganic mercury of [3H] thymidine incorporation into DNA in cultured Molt-4F cells. 660 74

Thymidine kinase [ATP: thymidine 5'-phosphotransferase, EC 2.7.1.21] has been purified more than 3,500 fold from microplasmodia of Physarum polycephalum. Properties of the enzyme were determined on preparations purified 1,400 fold. Thymidine was transformed to dTMP while a stoichiometric quantity of ATP was transformed to ADP. 5-Iododeoxyuridine, 5-bromodeoxyuridine, and 5-fluorodeoxyuridine acted as competitive inhibitors for the thymidine substrate while 5-bromodeoxyuridine could be used as a substrate. In contrast uridine did not inhibit the enzymatic activity while deoxyuridine was a very poor competitive inhibitor in agreement with the observation that deoxyuridine could not be used as a substrate. Two apparent Michaelis constants were found for thymidine. Only the highest Michaelis constant could be decreased in the presence of increasing concentrations of ATP. Among the various nucleoside mono, di, or triphosphates studied only ATP and to a less extent dATP could be used as phosphate donors. A non competitive inhibition for thymidine was observed with dTTP. dTMP, dTDP, and dTTP acted as competitive inhibitors for ATP. None of the nucleoside mono, di, or triphosphates studied showed an activatory effect at low concentrations of ATP, even in the presence of dTTP. However, dUTP and dGDP acted as competitive inhibitors for ATP.
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PMID:Characterization of the thymidine kinase of Physarum polycephalum. 684 40


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