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)

Enhanced mitotic activity and stimulated DNA synthesis associated with unchanged activity of thymidine and thymidylate kinases were observed in mouse kidneys induced to proliferate by intracardiac injection of lead acetate, and in rat livers following repeated administration of 5-azacytidine. On the other hand, the enhanced thymidine kinase activity evoked by L-tryptophan given by intubation at later stages of liver regeneration was paralleled by the enhanced incorporation of thymidine into DNA only to a very small degree.
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PMID:Stimulated DNA synthesis in livers and kidneys induced to proliferate associated with unchanged thymidine and thymidylate kinase activities. 5 7

The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells. The IDO activity is induced strongly in many cell types by IFN-gamma but rather poorly by IFN-alpha or -beta. A genomic DNA clone containing part of the transcribed region of the IDO gene and approximately 13 kilobases (kb) of the 5'-upstream DNA sequence was isolated and analyzed. An approximately 1.4-kb fragment of this clone, containing 329 nucleotides of the transcribed sequence and approximately 1.1 kb of the 5'-upstream sequence, when ligated to chloramphenicol acetyltransferase (CAT) structural gene made its expression inducible by IFN-gamma, but this construct responded poorly, if at all, to IFN-alpha 2. Deletion constructs derived from this plasmid narrowed down the IFN-gamma-responsive region to a 151-nucleotide segment (-495/-344) which also contained a 14-nucleotide sequence (GGTTTCAGTTTTCC) highly homologous to the IFN(alpha)-stimulated response element (ISRE) that has been found so far in all cellular genes inducible with IFN-alpha or -beta. Expression of CAT activity was stimulated by IFN-gamma more effectively than by IFN-alpha 2 when a 155-nucleotide fragment (-495/-340) containing the 151-nucleotide segment required for IFN-gamma response was inserted before herpes simplex virus thymidine kinase promoter linked to CAT structural gene. The results indicate that despite the presence of an ISRE, the control region of the IDO gene can distinguish between IFN-gamma and IFN-alpha. This may account for the differential activation of IDO gene expression by IFN-gamma as against IFN-alpha or -beta in intact cells, and suggests that the response of ISRE to IFN-alpha or -beta may be governed by other features in the upstream control region of this gene.
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PMID:Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alpha. 217 56

The effect of a single intravenous or oral administration of mitomycin C (MMC), 5-fluorouracil (5-FU) or cyclophosphamide (CP) on drug absorption was studied in rats in relation to changes in membrane characteristics. At 48 h after pretreatment, a differential effect on the absorption of sulfanilamide and L-tryptophan was observed in in situ recirculation experiments. Intravenous MMC administration suppressed the absorption of both sulfanilamide and L-tryptophan to a similar extent as a higher oral dose of this agent. Dosing with 5-FU via both routes caused the largest but almost equal suppression of L-tryptophan absorption. However, CP had no effect on the absorption of the two drugs. Differences in these effects were considered to reflect their pharmacological and pharmacokinetic properties. Absorption of drugs from the small intestine had a positive correlation with small intestinal wet weight regardless of the antitumor drug used, pretreatment doses and routes of administration and the results indicated that the change in absorptive surface area played a major role in this phenomenon. Toxicity to intestinal mucosa was shown to derive from an effect on dividing cells in the crypts because MMC and 5-FU preferentially decreased thymidine kinase activity. However, at the membrane level, increased mucosal membrane permeability was also confirmed by measuring the release rates of D-glucose from liposomes consisting of mucosal total lipids obtained from the antitumor drug-treated rats. Pretreatment with lipophilic and polymeric prodrugs of MMC did not exhibit any effect on drug absorption and thus, the possibility of alleviation of toxicity and adverse reactions via the prodrug approach was suggested.
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PMID:Effects of mitomycin C, 5-fluorouracil and cyclophosphamide on drug absorption, enzyme activities and mucosal lipid composition of intestine. 312 38

The effect of 5-azacytidine on tryptophan-mediated induction of various enzymes in rat livers was analyzed. Pretreatment of animals with 5-azacytidine results in a different response of tryptophan oxygenase to tryptophan and cortisone administration. While the hormonal induction of this enzyme was not affected by the drug, the tryptophan-mediated induction was stimulated. Pretreatment of rats with 5-azacytidine resulted also in the enhancement of liver tyrosine aminotransferase activity. There was no difference between the effect of tryptophan and cortisone. Tryptophan affects also the level of thymidine kinase at various stages of liver regeneration. 5-azacytidine given 16-40 hours prior to partial hepatectomy resulted in the enhancement of thymidine kinase activity at 24 hours of regeneration.
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PMID:Tryptophan-mediated induction of hepatic enzymes stimulated by 5-azacytidine pretreatment. 616 9

The thymidine kinase (TK) of herpes simplex virus type 1 (HSV-1) contains three regions of homology to other ATP utilizing enzymes. We have altered one region of the protein, which seems to play an important role in phosphorylation substrates by site-directed mutagenesis. When the aspartate 162 was changed to asparagine, the enzyme lost its activity. To identify the inactive protein, expressed by a vaccinia vector in eukaryotic cells, a monospecific antiserum against a bacterial tryptophan E-HSV-1 TK fusion protein was made. These results support the suggestion that aspartate 162 is essential for the enzymatic activity.
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PMID:Site-directed mutagenesis in the active site of the herpes simplex virus type 1 thymidine kinase gene. 839 86

Collagenase, a prototypic matrix metalloproteinase, plays a major role in the degradation of the extracellular matrix. The essential amino acid L-tryptophan was recently shown to stimulate the expression of collagenase gene in human dermal fibroblast cultures. In this study, we focused our attention on the mechanisms responsible for activation of collagenase transcription by L-tryptophan. Incubation of fibroblasts with L-tryptophan resulted in a dose- and time-dependent elevation of collagenase and tissue inhibitor of metalloproteinase mRNA levels. The maximum enhancement in collagenae mRNA was approximately 50-fold. This effect was not abolished by cycloheximide, suggesting independence from ongoing protein synthesis. Transient cell transfections with a promoter/reporter gene construct containing 3.8 kb of 5' flanking DNA of the human collagenase gene linked to the chloramphenicol acetyl transferase (CAT) gene or a construct containing three phorbol ester-responsive AP-1 binding sequences (12-O-tetradecanoyl-phorbol-13-acetate-responsive element) in front of the thymidine kinase promoter linked to the CAT gene indicated enhancement of promoter activity by L-tryptophan. Furthermore, electrophoretic DNA mobility shift assays demonstrated enhanced DNA-protein complex formation specific for an AP-1 binding site probe with nuclear extracts prepared from cells incubated with L-tryptophan. These results collectively suggest that activation of collagenase gene expression in dermal fibroblasts by L-tryptophan is mediated through AP-1 binding elements in the collagenase gene promoter that are sufficient for gene response.
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PMID:L-tryptophan induces expression of collagenase gene in human fibroblasts: demonstration of enhanced AP-1 binding and AP-1 binding site-driven promoter activity. 886 82

Three non-sense mutants of varicella-zoster virus (VZV) thymidine kinase (TK) gene, VZTK325, VZTK278 and VZTK224, were isolated. The mutants had a single nucleotide substitution at codons 326, 279 and 225, which changed the codon of TGG (tryptophan) to the stop codon TGA. The wild type (WT) and mutant TKs were expressed in E. coli cells and their characteristics were evaluated. VZTK224 lost TK activity, but VZTK325 and VZTK278 maintained 74.8% and 21.2% of the WT TK activity. On the other hand, all mutants lost the thymidylate kinase activity. Moreover, VZTK325 and VZTK278 polypeptides were heat-labile. These data suggest that the carboxy-terminal portion of herpesvirus TK plays an important role in the stable folding of TK and thymidylate kinase activity.
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PMID:Analysis of the non-sense mutants of varicella-zoster virus thymidine kinase. 941 14

A heterogeneous herpes simplex virus type 2 (HSV-2) population was characterised from an AIDS patient with relapsing genital ulcer. The isolate had an unusual antiviral spectrum, showing resistance to penciclovir and susceptibility to acyclovir. Two viral populations were plaque purified, one resistant and the other susceptible to both antiviral drugs. The resistant clone was deficient in thymidine kinase (TK) activity and a nucleotide substitution, thymine for cytosine, at position 153 was identified in its TK gene. This mutation resulted in an amino acid change, arginine to tryptophan, in the ATP binding site. In the deficient mutant, a loss of virulence was observed in mice.
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PMID:Characterisation of penciclovir resistant acyclovir sensitive herpes simplex virus type 2 isolated from an AIDS patient. 1504 49

The gene coding for arylformamidase (Afmid, also known as kynurenine formamidase) was inactivated in mice through the removal of a shared bidirectional promoter region regulating expression of the Afmid and thymidine kinase (Tk) genes. Afmid/Tk -deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system. Afmid-catalyzed hydrolysis of N-formyl-kynurenine is a key step in tryptophan metabolism and biosynthesis of kynurenine-derived products including kynurenic acid, quinolinic acid, nicotinamide, NAD, and NADP. A disruption of these pathways is implicated in neurotoxicity and immunotoxicity. In wild-type (WT) mice, Afmid-specific activity (as measured by formyl-kynurenine hydrolysis) was 2-fold higher in the liver than in the kidney. Formyl-kynurenine hydrolysis was reduced by approximately 50% in mice heterozygous (HZ) for Afmid/Tk and almost completely eliminated in Afmid/Tk knockout (KO) mice. However, there was 13% residual formyl-kynurenine hydrolysis in the kidney of KO mice, suggesting the existence of a formamidase other than Afmid. Liver and kidney levels of nicotinamide plus NAD/NADP remained the same in WT, HZ and KO mice. Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine. Gradual kidney deterioration and subsequent failure in KO mice is consistent with high levels of tissue-specific Afmid expression in the kidney of WT but not KO mice. On this basis, the most significant function of the kynurenine pathway and Afmid in mice may be in eliminating toxic metabolites and to a lesser extent in providing intermediates for other processes.
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PMID:Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype. 1586 19

We describe the clinical, morphological and genetic findings in two siblings with the myopathic form of mitochondrial DNA depletion syndrome (MIM 251880). Sequencing of the thymidine kinase-2 gene revealed two heterozygous missense mutations, a C-->T mutation at nucleotide 191 resulting in a change of threonine to methionine at residue 64 in exon 3, and a C-->T mutation at nucleotide 547 resulting in an arginine to tryptophan amino acid change at residue 183 in exon 8. Both mutations changed highly conserved residues in the gene and neither one has been described previously. This report extends the phenotypic expression of mutations in the thymidine kinase-2 gene.
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PMID:Novel mutations in the thymidine kinase 2 gene (TK2) associated with fatal mitochondrial myopathy and mitochondrial DNA depletion. 1590 88


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