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

We previously reported that thymidine kinase (TK) activity in a spontaneously TK-deficient (TK-) murine tumor cell line (called L61-M) could be partially restored following brief treatment of the cells in vitro with the potent DNA-hypomethylating agent 5-azacytidine. We now show here that similar results may be obtained by exposing cells in vitro to periodate-oxidized adenosine, a potent inactivator of the S-adenosylhomocysteine hydrolase enzyme. The ability of periodate-oxidized adenosine to induce TK activity within the L61-M cell line was dependent upon the concentration of drug used and the treatment period. Inhibiting DNA synthesis completely prevented the effects of periodate-oxidized adenosine from being observed. Periodate-oxidized adenosine had no obvious mutagenic effect upon the L61-M cell line and had a slight but significant inhibitory effect upon the methylation of the cytosine nucleotides which were incorporated into DNA during the treatment period. These results suggest that during tumor development, alterations in the relative levels of S-adenosylhomocysteine and S-adenosylmethionine may lead to the inhibition of DNA methylation, resulting in the activation of previously quiescent genes, thereby promoting the phenotypic diversification of tumor cell populations as well as their progression from a relatively benign to a highly malignant state.
 ...
PMID:Periodate-oxidized adenosine induction of murine thymidine kinase: role of DNA methylation in the generation of tumor cell heterogeneity. 300 May 79

5-Fluorouracil, 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorocytidine (FCyd), 5-fluoro-2'-deoxycytidine (FdCyd), 5-trifluoro-2'-deoxythymidine (F3dThd), and the 5'-monophosphates and 3',5'-cyclic monophosphates thereof were found to inhibit thymidine kinase-deficient (TK-) mutant strains of herpes simplex virus (HSV) at a much lower concentration than the wild-type (TK+) HSV strains. Other 5-substituted 2'-deoxyuridines that have previously been recognized as potent thymidylate synthase inhibitors behaved in a similar fashion. The activity of FdUrd, FdCyd, F3dThd, and their 3',5'-cyclic monophosphates against TK-HSV was readily reversed by 2'-deoxythymidine (dThd) but not by 2'-deoxyuridine (dUrd). These compounds also inhibited the incorporation of [6-3H]dUrd into DNA at a concentration which was up to 5 orders of magnitude lower than the concentration at which the incorporation of [methyl-3H] dThd was inhibited. Thus, while not being a target for the well established anti-HSV compounds in TK+HSV-infected cells, thymidylate synthase appears to be an important target in TK-HSV-infected cells. In addition to dTMP synthase, TK-HSV-infected cells appear to reveal other therapeutically exploitable targets such as OMP decarboxylase (towards pyrazofurin), CTP synthase (towards carbodine and its cyclopentenyl analogue), dihydrofolate reductase (towards methotrexate), and S-adenosylhomocysteine hydrolase (towards neplanocins).
 ...
PMID:Potent activity of 5-fluoro-2'-deoxyuridine and related compounds against thymidine kinase-deficient (TK-) herpes simplex virus: targeted at thymidylate synthase. 303 43

The recent advances in the chemistry of carbocyclic nucleosides focused on different synthetic approaches that lead to optically pure products as well as a comprehensive overview of their biological properties are discussed. In the latter aspect, molecular recognition of enzymes of pharmacological importance such as: reverse transcriptase, adenosine deaminase, thymidine kinase, DNA cytosine-C5 methyl transferase, S-adenosylhomocysteine hydrolase, etc are considered. The role of conformation and puckering of the glycon moiety in modulating the biological activity and also the use of carbanucleosides as building blocks to prepare oligonucleotides are carefully illustrated.
 ...
PMID:New progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides. 1257 Aug 43