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 bICP0 protein encoded by bovine herpesvirus 1 (BHV-1) is believed to activate transcription and consequently productive infection. Expression of full-length bICP0 protein is toxic in transiently transfected mouse neuroblastoma cells (neuro-2A) in the absence of other viral genes. However, bICP0 does not appear to directly induce apoptosis. Although bICP0 is believed to be functionally similar to the herpes simplex virus type 1-encoded ICP0, the only protein domain that is well conserved is a C3HC4 zinc ring finger located near the N terminus of both proteins. Site-specific mutagenesis of the zinc ring finger of bICP0 demonstrated that it was important for inducing aggregated chromatin structures in transfected cells and toxicity. The zinc ring finger was also required for stimulating productive infection in bovine cells and for trans-activating the thymidine kinase (TK) promoter of herpes simplex virus type 1. Deletion of amino acids spanning 356-677 of bICP0 altered subcellular localization of bICP0 and prevented trans-activation of the TK promoter. However, this deletion did not prevent trans-activation of the viral genome. Taken together, these studies indicated that bICP0 has several functional domains, including the zinc ring finger, which stimulate productive infection and influence cell survival.
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PMID:The zinc ring finger in the bICP0 protein encoded by bovine herpesvirus-1 mediates toxicity and activates productive infection. 1117 88

Sodium 2-mercaptoethanesulfonate reacts with the metal ions Pd(II), Pt(II), Ag(I), Cd(II) and Zn(II) to yield complexes containing multiple anionic sulfonate sites. On the basis of spectroscopic and other analytical data the complexes were assigned the tentative molecular formulas: Pd6(SCH2CH2SO3Na)12, Ptn(SCH2CH2SO3Na)2n+2, Agn(SCH2CH2SO3Na)n, Na2Zn4(SCH2CH2SO3Na)10, and Na2Cd4(SCH2CH2SO3Na)10. The complexes displayed a variety of differences in activity towards DNA and RNA viruses. The platinum complex showed no measurable cytotoxicity and exhibited a spectrum of antiviral activity resembling that of dextran sulfate. It was active against HIV-1 and HIV-2, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase-deficient HSV-1, human cytomegalovirus, vesicular stomatitis virus (VSV), influenza A virus, respiratory syncytial virus (RSV), Sindbis virus, Junin virus and Tacaribe virus. The palladium complex also showed no measurable cytotoxicity, but was completely inactive against most viruses, with one notable exception: both HIV-1 and HIV-2 were substantially inhibited by the palladium complex. The silver complex showed significantly less antiviral activity and greater cytotoxicity than the platinum complex but did show some selectivity against RSV. The zinc complex showed only modest activity against VSV, RSV, Junin virus, and Tacaribe virus, and like the silver compound was more cytotoxic than either the platinum or palladium complex. The cadmium complex was toxic to all of the cell lines used for in vitro evaluation of antiviral activity. Based on these results, the platinum and palladium compounds appear to be promising candidates for further studies, that is, as vaginal microbicides in the prevention of genital HIV and/or HSV transmission.
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PMID:Polysulfonates derived from metal thiolate complexes as inhibitors of HIV-1 and various other enveloped viruses in vitro. 1244 91

The docking methodology was applied to three different therapeutically interesting enzymes: human dihydroorotate dehydrogenase (DHODH), Herpes simplex virus type I thymidine kinase (HSV1 TK) and human phosphodiesterase 4 (PDE4). Programs FlexX, AutoDock and DOCK where used. The three targets represent three distinct cases. For DHODH and HSV1 TK, the binding modes of substrate and inhibitors within the active site are known, while the binding orientation of cAMP within PDE4 has been solely hypothesized. Active site of DHODH is mainly hydrophobic and the binding mode of the inhibitor brequinar was used as a template for evaluating the docking strategies. The presence of cofactors revealed to be crucial for the definition of the docking site. The HSV1 TK active site is small and polar and contains crystal water molecules and ATP. Docking of thymidine and aciclovir (ACV) within the active site was analyzed by keeping or removing water molecules. It showed the crucial role of water in predicting the binding of pyrimidines and purines. The crystal structure of PDE4 contains magnesium and zinc cations as well as catalytic water molecule but no ligand. Several docking experiments of cAMP and rolipram were performed and the results showed clear-cut dependence between the ligand orientation and the presence of metals in the active site. All three cases show specific problems of the docking methodology, depending on the character of the active site.
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PMID:Methodology and problems of protein-ligand docking: case study of dihydroorotate dehydrogenase, thymidine kinase, and phosphodiesterase 4. 1250 12

Cytochrome P450scc catalyzes the important first step in the steroid synthesis pathway; however, it is clear that additional factors regulating the temporal and spacial specific expression of the CYP11A1 gene remain to be identified. To isolate novel transcription factors that regulate this gene, a cis-acting element of the 5'-flanking region from nucleotides -155 to -131 (-155/-131) was used to screen a human placental lambda gt11 cDNA expression library, and an interacting clone was isolated. The open reading frame of the cDNA encodes several domains that are characteristic of transcription factors including an acidic region, a region rich in prolines and three zinc-finger motifs. Expression of the cDNA by in vitro transcription/translation and by transient transfection in HeLa cells yielded a protein of 132 kDa, which concurs with the predicted size. Transfection of the cDNA in placental JEG-3 and adrenal NCI-H295 cells, stimulate expression of a reporter construct controlled by the P450scc gene 5'-flanking region from nucleotides -1676 to +49. This transcriptional regulating protein of 132kDa (TReP-132) when expressed in HeLa cells was demonstrated to interact with the -155/-131 region in bandshift analysis, and tandem copies of this region was shown to confer activation of the heterologous HSV thymidine kinase minimal promoter. Coexpression of CBP/p300 with TReP-132 further increased promoter activity, and the proteins were demonstrated to interact physically. RNA analysis demonstrated the highest levels of expression in the adrenal cortex and testis; and transcript expression is also found in the steroidogenic JEG-3, NCI-H295, and MCF-7 cell lines, but not in non-steroidogenic HepG2 and HK293 cells. Subsequently it has been shown that TReP-132 interacts with steroidogenic factor-1 (SF-1) through specific domains; and along with the interaction with CBP/p300 these factors are postulated to form a complex to regulate expression of the P450scc gene.
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PMID:Function of the transcriptional regulating protein of 132 kDa (TReP-132) on human P450scc gene expression. 1253 Jun 63

Cytosolic thymidine kinase 1, TK1, is a well known cell-cycle-regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs such as 3'-azido-3'-deoxythymidine (AZT). We have now determined the structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP. The TK1s have a tetrameric structure in which each subunit contains an alpha/beta-domain that is similar to ATPase domains of members of the RecA structural family and a domain containing a structural zinc. The zinc ion connects beta-structures at the root of a beta-ribbon that forms a stem that widens to a lasso-type loop. The thymidine of dTTP is hydrogen-bonded to main-chain atoms predominantly coming from the lasso loop. This binding is in contrast to other deoxyribonucleoside kinases where specific interactions occur with side chains. The TK1 structure differs fundamentally from the structures of the other deoxyribonucleoside kinases, indicating a different evolutionary origin.
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PMID:Structures of thymidine kinase 1 of human and mycoplasmic origin. 1561 77

The structure of human cytosolic thymidine kinase in complex with its feedback inhibitor 2'-deoxythymidine-5'-triphosphate was determined. This structure is the first representative of the type II thymidine kinases found in several pathogens. The structure deviates strongly from the known structures of type I thymidine kinases such as the Herpes simplex enzyme. It contains a zinc-binding domain with four cysteines complexing a structural zinc ion. Interestingly, the backbone atoms of the type II enzyme bind thymine via hydrogen-bonds, in contrast to type I, where side chains are involved. This results in a specificity difference exploited for antiviral therapy. The presented structure will foster the development of new drugs and prodrugs for numerous therapeutic applications.
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PMID:Structure of a type II thymidine kinase with bound dTTP. 1573 44

The effect ofin utero zinc deficiency on fetal development in rats is reviewed. Attention is paid to the primary biochemical lesion associated with zinc-related teratogenesis and special consideration is given to the central nervous system. Evidence is presented that the thymidine kinase salvage pathway, used for the synthesis of thymidine monophosphate in DNA synthesis, is depressed more in fetal brain tissue than in the liver. In addition, greater reliance appears to be placed on this pathway than onde novo synthesis in the fetal brain than in other tissues. Some consideration is given to the use of in vitro embryo culture in studies relating to neurogenesis, but evidence is presented of a greater capacity of explanted rat embryos to obtain zinc from maternal serum than occurs in vivo.The rapid onset of a teratogenic zinc deficiency following dietary zinc restriction is again highlighted and further studies are described which demonstrate the critical impact of a single feeding cycle, of 4 d duration, on maternal plasma zinc levels and on the extent and nature of the observed fetal abnormalities. Evidence is presented that by shifting the timing of the high dietary intake/low plasma zinc peak to coincide with a particular 48 h period between days 6 and 10 of pregnancy, the pattern of malformations thus obtained reflected the coincidence of the high dietary intake of zinc-deficient diet and the critical time of morphogenesis of several organ systems.Whereas diminished plasma zinc levels at term in zinc-deficient animals are generally well correlated with reduced growth and dysmorphogenesis of the offspring, the same is not always found in human studies. In some cases, elevated plasma zinc levels at parturition are found in mothers with growth-retarded children, or vice versa. Experimental studies with rats are reported that suggest that maternal zinc status at term may be higher in dams bearing pups stunted by exposure to a transient zinc deficiency early in pregnancy, which in turn may have reduced the demand for maternal zinc in the later stages of gestation.The protective effect of zinc on cadmium-induced teratogenesis is discussed, particularly in relation to findings concerning an interaction of these metals in the embryonic yolk sac and thus on preplacental embryonic nutrition. Possible interactions between alcohol and zinc deficiency are also considered and data are presented pointing to increased fetotoxicity and teratogenesis in the presence of both treatments and to a more specific interaction with respect to reduced cell numbers in the developing rat hippocampus. Malondialdehyde levels, which reflect the extent of lipid peroxidation in tissue, are reported to be substantially higher in microsomes from fetal rat livers whenin utero deficiency and gestational alcoholism are combined. The suggestion is made that alcohol and zinc deficiency act independently in the body, but overlap to some extent at the common biochemical locus of membrane lipid peroxidation.
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PMID:Zinc deficiency and the developing embryo. 2425 40

The incorporation of(3)H-thymidine into DNA in the brains of the 17-day and 20-day old rat fetuses was significantly reduced by maternal zinc restriction during pregnancy. The activity of the enzyme thymidine kinase (EC 2.7.1.21) was similarly reduced in the zine-deprived fetal brains on days 14 and 20 of gestation, but not on day 17. Fetal brain alkaline phosphatase (EC 3.1.3.1) was significantly depressed by maternal zinc deprivation on days 17 and 20 of pregnancy.The data suggest an association between thymidine kinase and the reduced incorporation of(3)H-thymidine into DNA in the brains of 20-day old fetuses but not in animals on day 17. Alkaline phosphatase was however depressed at this stage.The suggestion is made that because of the complexity of brain development, future biochemical studies in this area should concern specific structures in the brain at particular critical stages during neurogenesis.
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PMID:Incorporation of(3)H-thymidine into DNA and the activity of alkaline phosphatase in zinc-deficient fetal rat brains. 2427 50

The nutritional requirement for zinc in the proliferation of normal and malignant cells has been demonstrated in a number of animal studies. A distinction is made between the effect of zinc status upon the host during carcinogenesis and tumor growth. The present studies focus on the Ehrlich ascites tumor in mice fed a semipurified zinc-deficient diet along with defined concentration of zinc in the drinking water. This model of zinc deficiency is compared with others in which chelating agents are used to create zinc-deficient conditions or the microorganismEuglena gracilis is examined in a defined zinc-deficient medium. It is reported here that Ehrlich cells remain quiescent for several weeks in severely deficient mice, suggesting their restriction to a G1 or G0 state of the cell cycle. The kinetics of thymidine and uridine uptake and incorporation into DNA and RNA in Zn-normal and Zn-deficient tumors is consistent with the inhibition of thymidine kinase and DNA polymerase in the Zn-deprived system, but with little effect on RNA synthesis. The concentration of metabolites of these labeled nucleosides in Ehrlich cells is also consistent with a primary effect upon thymidine kinase. Although the ascites fluid Zn is depressed in Zn deficiency, total cellular zinc and its distribution among cell fractions is not significantly affected. It is suggested that these effects are specific in nature and not the result of a general lack of zinc for zinc metalloproteins and other binding sites in the cell.
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PMID:Control of Ehrlich cell division by zinc. 2427 64


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