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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both biochemical and genetic experiments suggest that the type I DNA topoisomerase may participate in DNA replication, recombination, transcription, and other aspects of DNA metabolism. Despite its apparent importance, genetic studies in unicellular organisms including eubacteria and yeasts indicate that topoisomerase I is not essential for viability. We have previously isolated the cDNA clone encoding DNA topoisomerase I from Drosophila melanogaster. We report here the cytogenetic mapping of top1 to the X chromosome at 13C1 and isolation of top1 genomic DNA. Using P-element mutagenesis, we have isolated a mutant deficient in Drosophila topoisomerase I functions. Genetic studies of this mutant show that topoisomerase I is essential for the growth and development of the fruit fly, a multicellular organism. The biological functions of topoisomerase I are inferred from our analysis of the regulation of topoisomerase I expression during Drosophila development.
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PMID:DNA topoisomerase I is essential in Drosophila melanogaster. 839 72

Escherichia coli DNA topoisomerase I is a well-studied type I DNA topoisomerase that catalyzes the breakage and rejoining of one DNA strand to allow passage of the other strand. We have cloned and over-expressed a 67 kDa amino-terminal fragment of the protein, and shown that it retains the ability of the intact enzyme to cleave single-stranded DNA. High-quality crystals of the purified 67 kDa fragment have been obtained. The crystals belong to space group P2(1)2(1)2(1), with cell dimensions a = 64.0 A, b = 79.9 A and c = 142.3 A. They diffract to at least 2.8 A at low temperature and, when cooled to cryogenic temperatures, to at least 1.9 A in a synchrotron source. A complete native data set and two derivative data sets have been collected. A multiple isomorphous replacement map to 3 A resolution shows clear secondary structural elements. Final structure determination is in progress.
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PMID:Crystallization of a 67 kDa fragment of Escherichia coli DNA topoisomerase I. 839 51

The type I DNA topoisomerase isolated from bovine liver mitochondria is demonstrated here to be inhibited by camptothecin, a plant alkaloid previously shown to target the nuclear type I topoisomerase in mammalian cells. The antitumor drug reduces the ability of the mitochondrial enzyme to relax positive as well as negative supercoils although the inhibition of the former process requires more than 60-fold more drug than the latter process. A similar response is seen with the nuclear topoisomerase I. Camptothecin also stimulates the mitochondrial topoisomerase-induced cleavage of pUC19 at numerous, discrete sites. The antitumor drug 4'-(9-acridinylamino)-methanesulfon-m-anisidide, which has been shown to target the nuclear topoisomerase II, inhibited the mitochondrial type I topoisomerase relaxation activity, but this effect was found to be the result of the drug intercalating into the negatively supercoiled DNA rather than from a specific interaction with the mitochondrial enzyme. VM-26, a nonintercalating topoisomerase II poison, showed no inhibitory effect up to a concentration of 50 microM.
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PMID:Response of purified mitochondrial DNA topoisomerase I from bovine liver to camptothecin and m-AMSA. 855 21

Irinotecan (CPT-11) has been reported to be cytotoxic to tumor cells through its inhibitory activity on type I DNA topoisomerase. CPT-11 has also been shown to have several unique biological activities apart from direct cytotoxicity. We investigated the ability of CPT-11 to induce tumor necrosis factor (TNF) production. Human peripheral blood mononuclear cells (MNCs) were incubated with LPS, CPT-11, or with vinblastin sulfate as a control. The priming effect of CPT-11 on endogenous production of TNF was examined by injecting the drug intravenously into mice, followed 3 hours by the injection of OK432. At a dose of 200-400 micrograms/kg, CPT-11 showed a significant priming effect. A significant amount of TNF was released when MNCs were incubated with 100-300 microM of CPT-11 for more than 4 hours, but not with vinblastin sulfate, indicating a triggering effect of TNF production on MNCs in vitro. These effects may be advantageous in cancer therapy.
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PMID:Induction of tumor necrosis factor by a camptothecin derivative, irinotecan, in mice and human mononuclear cells. 891 43

The complete gene encoding Topoisomerase 1 (Topo I) from Mycobacterium tuberculosis (MTb), Erdman strain, has been isolated and sequenced. The coding region of this gene is 2700 nt encoding a polypeptide of 900 amino acids with a calculated molecular mass of 99353 Da. The amino-acid sequence identity compared to E. coli and Synechococcus Topo I is 22 and 30%, respectively. The gene was expressed in E. coli BL21(DE3) and purified to near homogeneity. Recombinant MTb Topo I is enzymatically active, relaxing negatively supercoiled DNA in a magnesium-dependent, ATP-independent reaction. Spermidine, a typical inhibitor of prokaryotic type I DNA topoisomerase, inhibits the activity. Unlike the more well-characterized E. coli Topo I, MTb Topo I does not contain a zinc-finger DNA-binding motif in the C-terminal domain of the protein.
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PMID:Cloning, expression, purification and characterization of DNA topoisomerase I of Mycobacterium tuberculosis. 892 93

We cloned and sequenced a DNA fragment from the thermophilic archaeal strain Sulfolobus shibatae B12 that includes the gene topR encoding the reverse gyrase. The RNA of the reverse gyrase gene was characterized indicating that the topR gene is fully functional in vivo. We showed by primer extension analysis that transcription of topR initiates 28 bp downstream from a consensus A-box promoter. In order to understand how this particular type I DNA topoisomerase introduces positive superturns into the DNA, we compared the amino acid sequence of reverse gyrase from S.shibatae with the two other known reverse gyrases. This comparison indicates a common organization of these proteins: the carboxy-terminal domain is related to the type I-5' topoisomerase family while the amino-terminal domain possesses some motifs of proteins described as RNA or DNA helicases. By using local alignments, we showed that (i) reverse gyrases constitute a new and rather homogenous group within the type I-5' DNA topoisomerase family; (ii) a careful sequence analysis of the amino-terminal domain allows us to relate the presence of some motifs with an ATP binding and hydrolysis reaction coupled to a DNA binding and unwinding activity.
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PMID:Reverse gyrase gene from Sulfolobus shibatae B12: gene structure, transcription unit and comparative sequence analysis of the two domains. 897 52

A MeOH extract of Swertia chirata found to inhibit the catalytic activity of topoisomerase I of Leishmania donovani was subjected to fractionation to yield three secoiridoid glycosides: amarogentin (1), amaroswerin (2), and sweroside (3). Amarogentin is a potent inhibitor of type I DNA topoisomerase from Leishmania and exerts its effect by interaction with the enzyme, preventing binary complex formation.
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PMID:Amarogentin, a naturally occurring secoiridoid glycoside and a newly recognized inhibitor of topoisomerase I from Leishmania donovani. 898 49

We investigated the effects of compounds with two covalently linked netropsin moieties (bis-netropsin) on the function of mammalian type I DNA topoisomerase (topo I) in vitro. We initiated these studies because earlier studies had shown that certain bis-netropsins possess a several-fold higher antitumor and antiviral activity than netropsin. We confirmed that the parent compound netropsin, but not its bifunctional derivatives, induce supercoils in closed DNA. We determined that bis-netropsins inhibit the binding of topo I to DNA more efficiently than netropsin and that bis-netropsins but not netropsin induce specific DNA strand cleavage in the presence of topo I. We discuss a model explaining the different effects of netropsin and bis-netropsins on topo I.
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PMID:Effects of bifunctional netropsin-related minor groove-binding ligands on mammalian type I DNA topoisomerase. 906 34

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the sensitivity of living organisms and the pharmacokinetics of the drug. ICR male mice were housed under standardized light-dark cycle conditions (lights on at 0700, off at 1900) with food and water ad libitum. The loss of body weight after an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late dark and the early light and milder in the late light and the early dark. The CPT-11-induced leukopenia was more serious in the late dark and milder in the late light. The lower toxicity of CPT-11 was observed when DNA synthesis and type I DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity was observed when these activities began to increase. There were circadian stage-dependent changes in the concentrations of CPT-11 and its major metabolite (SN-38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT-11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhythm-dependent processes.
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PMID:Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. 940 14

Previous results from our laboratory have demonstrated that type I DNA topoisomerase activity is required for the replication and gene expression of pseudorabies virus (PRV). In the present report, we further analyzed the expression of topoisomerase I in PRV-infected cells, and the western blot result showed that the expression of topoisomerase I was increased after virus infection. The increase sustained to late time of infection when the cytopathic effect was obvious and the synthesis of most host proteins was shut off by PRV. From transient expression assay, it was also found that the promoter of cellular topoisomerase I gene could be stimulated by immediate-early protein (IE180) and viral early protein 0 (EP0), and these two regulatory proteins appeared to work synergistically. Collectively, these findings provide evidence that PRV can stimulate the expression of topoisomerase I and that the stimulation is mediated at least by IE180 and EP0 proteins of PRV at the transcriptional level.
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PMID:Stimulation of type I DNA topoisomerase gene expression by pseudorabies virus. 941 19


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