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:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of metabolic enzymes, adenosine and thymidine, has been studied in the blood serum and lymphocytes of healthy people and oncological patients aged 23-80. An increase in the activity of thymidine kinase (EC 2.7.1.2), an enzyme of thymidine biosynthesis, was observed in the blood serum of oncological patients against a background of a sharp decrease in the activity of thymidine phosphorylase (EC 2.4.2.4), a catabolic enzyme. The revealed enzymic shifts have been observed in breast cancer patients after 36, in patients with the stomach cancer--after 46. It is found that an increase in the activity of adenosine deaminase (EC 3.5.4.4) and 5-nucleotidase of AMP (EC 3.1.3.5) in the blood serum of oncological patients is accompanied by a sharp decrease in the activity of these enzymes in lymphocytes.
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PMID:[Activity of adenosine and thymidine metabolism enzymes in the blood of cancer patients of various ages]. 233 24

The study was concerned with comparison of the activity of thymidine kinase, thymidine phosphorylase, adenosine desaminase and AMP 5'-nucleotidase in serum of cancer patients and healthy subjects. A significant change in 5'-nucleotidase level was registered in patients over 60 years of age and in those of adenosine desaminase and thymidine phosphorylase in patients older than 70 years. A comparative evaluation of the activity of those enzymes showed an increase in thymidine kinase activity matched by a sharp drop in that of thymidine phosphorylase in patients over 45 years. A sharp increase in the activity of adenosine metabolizing enzymes in cancer serum was accompanied by its decrease in lymphocytes. Among surgical patients, significant changes in the activity were observed in radically operated cases only.
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PMID:[The enzymatic activity of DNA metabolism of the blood in patients operated on in stomach cancer]. 254 45

Exposure of U-937 cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in specific alterations in thymidine metabolism. Within 24 h after treatment with 1.62 x 10(-9) M TPA, the reciprocal alteration in the activities of opposing enzymes of thymidine metabolism observed during normal cell culture growth was reversed. In TPA-treated cells, the activities of anabolic enzymes thymidine kinase (EC 2.7.1.75)and thymidylate synthase (EC 2.1.1.45) declined with time linearly to 20 and 16% of those of untreated cells by 72 h. Incorporation of [3H]thymidine and [3H]deoxyuridine into acid-insoluble fractions also decreased in parallel with the decline in enzyme activities. In contrast, the activities of catabolic enzymes thymidine phosphorylase (EC 2.4.2.4) and dihydrothymine dehydrogenase (EC 1.3.1.2) increased. The rise in thymidine phosphorylase activity peaked at 48 h with 406% elevation over the control. The activity of dihydrothymine dehydrogenase was not altered for the first 24 h, but it increased up to 338% by 96 h. Immunotitration of dihydrothymine dehydrogenase with monoclonal antibody against this enzyme showed that the rise in activity in the differentiated cells was due to the increase in the amount of enzyme protein. No significant difference was observed in the Km values for the substrate of each enzyme between untreated and TPA-treated cells. These metabolic alterations during induced differentiation were in line with the changes in cell morphology and accompanied by an accumulation of the cells in G1 at the expense of S phase. These observations indicate that induced differentiation of U-937 cells results in a reversal of the enzymic phenotype of thymidine metabolism and suggest that emergence of thymidine metabolic imbalance may serve as an early marker of differentiation of these cells.
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PMID:Reversal of enzymic phenotype of thymidine metabolism in induced differentiation of U-937 cells. 268 98

Benzylacyclouridines were developed as specific and potent competitive inhibitors of uridine phosphorylase with Ki values in the nanomolar range. These compounds have no activity against thymidine phosphorylase, uridine kinase, thymidine kinase and orotate phosphoribosyltransferase. Benzylacyclouridines potentiate the chemotherapeutic effect of FdUrd. Coadministration of uridine phosphorylase inhibitor with FdUrd caused selective toxicity against tumors with low or no thymidine phosphorylase, but not against the host tissues which have thymidine phosphorylase, and thus retain the capacity to cleave FdUrd, and hence overcome its toxicity. There are distinct differences between uridine phosphorylase and thymidine phosphorylase. Benzylacyclouridines competitively inhibit the nucleoside transport of mammalian cells. The structure-activity relationship of inhibitors of uridine phosphorylase showed that a large hydrophobic pocket exists where C-5 of uracil binds, and that it is necessary to have the 3'-hydroxyl group and syn-configuration around the N-glycosidic bond for the nucleosides or their analogs to bind. Dihydrouracil dehydrogenase was found to be widely distributed among mammalian cells, where it was previously believed to be present only in the liver and the kidney. The structure-activity relationship of its inhibitors revealed benzyloxybenzyluracil and 2,6-pyridinediol as most potent. Also identified for orotate phosphoribosyltransferase was 2,4-pyridinediol.
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PMID:Development of inhibitors of pyrimidine metabolism. 269 11

The C-1300 neuroblastoma tumor which arises spontaneously in the A/J mouse has been maintained in this mouse strain. Two different cell populations have been recognized in cultured C-1300 mouse neuroblastoma (MNB): (1) round, "neuroblast-like" cells, growing in suspension (poorly attached), that have a highly malignant behavior when injected into the A/J mouse (T1 cells); and (2) flat, "epithelioid" cells that attach well to surfaces and show low malignancy towards the inoculated animals (T2 cells). The specific activities of the pyrimidine metabolizing enzymes thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and thymidine kinase (TK) were examined in both MNB cell lines by a new radiochromatographic method. Enzymatic activities of TP and DPD in the cytosols of T2 (weakly malignant) cells were up to 15 times higher than those of T1 (strongly malignant) cells, whereas the mean TP/DPD activity ratio was 16 in either cell line. TP and DPD activity levels increased with time of growth in culture in T2 cells while no such increase was seen in the T1 cells. Maximal TK activity was similar in both cell lines but dropped more rapidly in the T2 cells as cell densities increased. The enzymatic activity levels of TP and DPD but not of TK correlated inversely with neoplastic expression of MNB cells. The observed patterns of pyrimidine metabolizing enzymes in MNB cells could result in an increased thymidine pool in T1 cells whenever TK activity is suppressed, whereas such conditions would favor the generation of thymine in the T2 cells.
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PMID:Correlations of dihydropyrimidine dehydrogenase, thymidine phosphorylase and thymidine kinase activities in strongly and weakly malignant cultured murine neuroblastoma cells. 271 95

1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and the 5-iodo (FIRU), 5-bromo (FBrRU), 5-chloro (FClRU) and 5-fluoro (FFRU) analogues of 1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)uracil were examined in four in vitro tests designed to evaluate their potential as radiopharmaceuticals in a non-invasive diagnostic test for herpes simplex encephalitis (HSE). The tests involved, (a) cellular uptake studies--which showed that all five nucleosides are selectively trapped in rabbit kidney cells infected with herpes simplex virus, type I, which codes for its own thymidine kinase; (b) incubation studies--which showed that, in human platelets, FIAU, FIRU and FFRU are not degraded by thymidine phosphorylase (an enzyme which catalyzes the glycosidic bond cleavage of physiological nucleosides); (c) a transport study, using mouse erythrocytes--which indicated that all five nucleosides have good affinity for a NBMPR-sensitive nucleoside transporter, with inhibition constants (Ki values in the range of 0.177-0.41; and (d) determination of octanol/water partition coefficients--which (log P = -0.14 to -1.67) indicated that FIAU is the most lipophilic of the five compounds studied, and may therefore cross the blood-brain barrier most readily. We conclude from the results that FIAU is the most promising compound for further evaluation in HSE animal models. The combination of tests described in this study provide a useful screening protocol for evaluation of other nucleoside analogues of potential use in a diagnostic test for HSE.
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PMID:The in vitro evaluation of nucleoside analogues as probes for use in the noninvasive diagnosis of herpes simplex encephalitis. 285 77

The behavior of the activities of thymidine metabolizing enzymes, dihydrothymine dehydrogenase (EC 1.3.1.2) and thymidine phosphorylase (EC 2.4.2.4) for thymidine degradation, thymidine kinase (EC 2.7.1.75) and thymidylate synthase (EC 2.1.1.45) for DNA synthesis, was elucidated in cytosolic extracts from normal human lymphocytes and 13 human leukemia-lymphoma cell lines. In the normal human lymphocytes, the activities of dihydrothymine dehydrogenase, thymidine phosphorylase, thymidine kinase, and thymidylate synthase were 6.88, 796, 0.30, and 0.29 nmol/h/mg protein, respectively. In leukemia-lymphoma cell lines, the activities of synthetic enzymes, thymidine kinase, and thymidylate synthase, increased two- to 79-fold and 22- to 407-fold of the normal lymphocyte values. In contrast, the activities of the catabolic enzymes, dihydrothymine dehydrogenase and thymidine phosphorylase, decreased to 5-42% and 3-38% of the values of normal lymphocytes. As a result, the ratio of activities of thymidine kinase/dihydrothymine dehydrogenase was elevated by 7- to 1170-fold, respectively. Thus, reciprocal behavior in the activities of the opposing enzymes in thymidine metabolism was observed in human leukemia-lymphoma cells. Polyclonal and monoclonal antibodies against dihydrothymine dehydrogenase were prepared and studies on immunotitration of this enzyme with these antibodies showed that the enzyme protein amount in Jurkat leukemic cells was 36% of that of normal lymphocytes. This was in good agreement with the decrease in the activity of the enzyme to 32%, indicating that the decrease in activity in the leukemic cells was due to the decline in the amount of enzyme protein. The metabolic imbalances in thymidine utilization appear to be characteristic of human leukemia-lymphoma cells. These observations should confer selective advantages to the lymphoproliferating cells and mark out the catabolic, as well as the synthetic, enzymes as important targets in the design of chemotherapy.
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PMID:Behavior of activities of thymidine metabolizing enzymes in human leukemia-lymphoma cells. 291 46

Dictyostelium discoideum strain HPS 401 contains a spontaneous mutation that lowers the amount of thymidine required for cell growth relative to that of the auxotrophic parental strain HPS 400. Growth studies in defined medium show that as little as 8 micrograms thymidine/ml supports maximal growth of HPS 401, whereas 50 micrograms/ml is required by HPS 400. In contrast, both strains require over 40 micrograms thymidylate/ml to achieve maximal growth. HPS 401 exhibits thymidineless death when grown without thymidine; relative viability decreases to less than 0.01% after 190 h incubation. Assays for enzymes related to thymidine metabolism reveal that none of the strains tested (HPS 401, HPS 400, and prototrophic HPS 83 cells) contain detectable thymidine phosphorylase activity and that the specific activity of thymidine kinase is the same in these three strains. Thin-layer chromatography of extracts from cells grown on radiolabeled thymidine shows that there is no detectable conversion of thymidine to thymine in any of these strains. These analyses show that HPS 401 has rapid intracellular accumulation of thymidine, while only slight uptake is observed with HPS 400 or wild-type strains. HPS 401 also shows greater uptake of uridine in comparison to HPS 400 and wild-type cells. Thymidylate uptake was the same for all three strains. Thus, the mutation giving rise to the HPS 401 phenotype selectively increases the uptake of thymidine into the cell, where it can be efficiently utilized for DNA synthesis by the "salvage" pathways of nucleotide metabolism.
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PMID:Enhanced thymidine uptake causes the lowered thymidine requirement of D. discoideum auxotroph HPS 401. 316 46

Biosynthesis of pyrimidine nucleotides was intensified in proliferating tissues. Age-dependent alterations in activities of thymidine kinase and thymidine phosphorylase were found in healthy persons of 17-70 years old. Distinct increase in activity of thymidine kinase was observed in patients with gastric ulcer but the activity was decreased with ageing. Alterations in the ratio between anabolic and catabolic reactions involving thymidine were studied also in patients with gastric tumor depending on age.
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PMID:[Age-related characteristics of thymidine metabolism in healthy subjects and in patients with stomach ulcer and cancer]. 381 Dec 86

Unlike enteric bacteria, Pseudomonas spp. generally lack thymidine phosphorylase and thymidine kinase activities, thus preventing their utilization of exogenous thymine or thymidine and precluding specific radioactive labeling of their DNA in vivo. To overcome this limitation, a DNA fragment encoding thymidine kinase (EC 2.7.1.21) from Escherichia coli was cloned into pKT230, a small, broad-host-range plasmid derived from plasmid RSF1010. From transformed E. coli colonies, the recombinant plasmid bearing the thymidine kinase gene was conjugally transferred to Pseudomonas stutzeri, Pseudomonas aeruginosa, Pseudomonas mendocina, Pseudomonas alcaligenes, and Pseudomonas pseudoalcaligenes. Thymidine kinase activity was expressed in all of these species, and all gained the ability to incorporate exogenous [2-14C]thymidine into their DNA. Thymidine incorporation into P. stutzeri was enhanced 12-fold more in mutants lacking thymidylate synthetase activity. These mutants produced higher levels of thymidine kinase and were thymidine auxotrophs; thymineless death resulted from removal of thymidine from a growing culture.
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PMID:Thymidine salvage in Pseudomonas stutzeri and Pseudomonas aeruginosa provided by heterologous expression of Escherichia coli thymidine kinase gene. 392 94


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