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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New details of the molecular interactions of quinolones with their target DNA gyrase and DNA have come from the nucleotide sequences of the gyrA genes from resistant mutants of Escherichia coli and wild-type strains of other bacteria and studies of gyrase A tryptic fragments, all suggesting the importance of an amino-terminal domain in quinolone action. Alterations in DNA supertwisting were also associated with altered quinolone susceptibility, possibly by indirect effects on DNA gyrase expression. Specific binding of relevant concentrations of norfloxacin to a complex of DNA gyrase and DNA in the presence of ATP, the cooperativity of DNA binding, and the crystalline structure of nalidixic acid have led to a model in which quinolones bind cooperatively to a pocket of single-strand DNA created by DNA gyrase. Quinolones vary in their relative activity against DNA gyrase and its eukaryotic homolog topoisomerase II, and in some assays increased action against the eukaryotic enzyme was associated with genotoxicity. Inhibition of bacterial DNA synthesis by quinolones may correlate with MICs in some species, but comparisons of drug accumulation and inhibition of DNA synthesis in permeabilized cells among species have been difficult to interpret. The specific factors necessary for bacterial killing by quinolones in addition to interaction with DNA gyrase have remained elusive, but include oxygen and new protein synthesis. The coordinate expression of the SOS proteins appears not to be necessary for quinolone lethality. Two independent mutants with selective reduced killing by quinolones and beta-lactams indicate overlap in the pathways of bactericidal activity of these classes of agents with distinct targets.
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PMID:Mode of action of the new quinolones: new data. 165 Jun 98

In the presence of a molar excess of eukaryotic DNA topoisomerase II and an appropriate concentration of dextran sulfate, relaxed closed circular DNA is converted to a negatively supercoiled form. The reaction is dependent on ATP. Neither adenosine 5'-[beta,gamma-imido]-triphosphate nor adenosine 5'-[gamma-thio]triphosphate can substitute for ATP. The negative supercoils formed are relaxed by subsequent addition of DNA topoisomerase I to the supercoiling reaction mixture. Covalent closure of a nicked circular DNA in the presence of DNA topoisomerase II and dextran sulfate but in the absence of ATP causes a small decrease in the linking number. These results suggest that when an appropriate concentration of dextran sulfate is present, the binding of a molar excess of eukaryotic DNA topoisomerase II constrains a small number of negative supercoils in DNA, which in turn generate unconstrained negative supercoils at the expense of ATP.
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PMID:Negative supercoiling of DNA by eukaryotic DNA topoisomerase II and dextran sulfate. 165 Jul 78

Nuclear extracts from teniposide (VM-26)-resistant sublines of the human leukemic cell line CCRF-CEM have decreased levels of DNA topoisomerase II catalytic activity and decreased capacity to form drug-stabilized covalent protein-DNA complexes. The ATP concentration required for equivalent activity in a DNA-unknotting assay is 2- to 8-fold higher in nuclear extracts from drug-resistant cell lines as compared with the parental line. When adenosine 5'-[beta,gamma-imido]triphosphate is substituted for ATP in complex-formation assays, no significant change is seen with drug-sensitive cells, but a 50-65% reduction is seen with VM-26-resistant cells. Collectively, these results indicate that an alteration in ATP binding may be involved in the resistance phenotype. Therefore, we identified regions of the topoisomerase II sequence that conform to previously identified nucleotide-binding sites. Starting with cDNA as the template we determined the sequence of the topoisomerase II mRNA surrounding these sites by sequencing DNA fragments produced by the polymerase chain reaction. In the region corresponding to the consensus B ATP-binding sequence described by Walker et al. [Walker, J. E., Saraste, M., Runswick, M. J. & Gay, N. J. (1982) EMBO J. 1, 945-951], the cDNA from the two VM-26-resistant sublines contained an altered sequence having a G----A base change. This base substitution results in the replacement of the conserved arginine at position 449 with a glutamine. Hybridization with allele-specific oligonucleotides confirmed the presence of both the normal and the altered sequence in the resistant cell lines, whereas only the normal sequence was found in the sensitive CEM cells. A chemical mismatch cleavage procedure for the detection of mispaired bases in DNA duplexes identified no other alterations in the 5' third of the mRNA coding sequence, which contains the complete ATP-binding domain of topoisomerase II. The presence of mRNA encoding topoisomerase II with Gln449 correlates both with the presence of a topoisomerase II protein whose interaction with ATP is altered and with increased resistance to the cytotoxicity of VM-26.
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PMID:Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide. 165 58

We have characterized the topoisomerase I and II activities in nuclear extracts from immature embryos of Zea mays and the effect of the treatment with 2,4-dichlorophenoxyacetic acid (2,4-D) and abscisic acid (ABA). These extracts were shown to be essentially devoid of protease and nuclease activities and they were tested for their ability to relax supercoiled DNA, unknotting P4 DNA and catenate circular duplex DNA under catalytic conditions. Unknotting and catenation reactions are strictly magnesium- and ATP-dependent, but not the relaxation of circular supercoiled DNA allowing the detection of both topoisomerase I and II activities. Two cytotoxic drugs, camptothecin, a plant alkaloid that inhibits eukaryotic topoisomerase I, and epipodophyllotoxin VM-26 (teniposide) that inhibits topoisomerase II, have been assayed in our extracts showing similar inhibitory effects on topoisomerase enzymes. Alkaline phosphatase treatment of nuclear extracts abolishes both topoisomerase activities. Nuclear extracts from embryos treated with 2,4-D showed 200% increase on topoisomerase II activity as compared with untreated ones, but only residual activity was detected in ABA-treated embryos. Nuclear extracts from hormone-treated and untreated embryos showed similar topoisomerase I activity with deviations of less than 25%. These differences are discussed in terms of possible post-translational modifications of the enzymes associated with the increase in proliferation activity of calli.
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PMID:Characterization of topoisomerase I and II activities in nuclear extracts during callogenesis in immature embryos of Zea mays. 165 30

An enzyme from Leishmania donovani that catenates monomeric pBR322 into huge catenanes has been isolated and characterized. The enzyme also decatenates kinetoplast DNA networks into covalently closed monomeric circles and relaxes supercoiled pBR322. The catenation, decatenation and relaxation reactions do not require ATP. The formation of topological isomers of unique linking numbers suggest that the enzyme is a type II DNA topoisomerase.
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PMID:An ATP-independent catenating enzyme from the kinetoplast hemoflagellate Leishmania donovani. 165 69

In this work some aspects of carcinogenesis are given. The importance of the emergence of Z or H DNA structure in the gene, or in the flanking gene sequences for the gene deletion and unusual gene recombination, is discussed. Some considerations on the role of selective pressure (of polyamines, of Mg2+, of the various levels of topoisomerase II, and of ATP) in the process of oncogene amplification, are given too.
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PMID:The importance of the specific Z-DNA structure and polyamines in carcinogenesis: fact or fiction. 165 80

DNA topoisomerase II was isolated from mouse leukemia L1210 cells and the activity was determined by using P4 phage knotted DNA and pBR 322 DNA as the substrates. Based on these results, a method for screening antitumor agents by using DNA topoisomerase II as a target was established. The experiments showed that DNA topoisomerase II catalyzed pBR 322 DNA breaking and relaxing which were reversible and dependent on ATP. The activity was increased 2-4 times in the presence of ATP 1 mmol.L-1. In contrast with type II enzyme, the activity of DNA topoisomerase I was completely inhibited in the presence of ATP 1 mmol.L-1 and had full activity in the absence of ATP. Type II enzyme also showed the unknotting activity by using p4 phage knotted DNA as a substrate. DNA cleavage and relaxing reaction induced by type II enzyme increased 5-fold in the presence of Doxorubicin (Dox) 1 microgram.ml-1 or daunorubicin (Dau). Etoposide (Eto) and aclarubicin B (Acl B) also stimulated the reaction at 100 micrograms.ml-1. The cleavage reaction resulted from topoisomerase II was inhibited by other agents, such as frankincense extracts, terpenic compounds (BC series).
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PMID:Determination of DNA topoisomerase II activity from L1210 cells--a target for screening antitumor agents. 166 90

Pentamidine and related derivatives inhibit an ATP-dependent topoisomerase activity from Pneumocystis carinii extracts. Since it would be extremely difficult to purify ample quantities of the organisms to allow characterization of the enzyme and carry out drug binding experiments, we have begun the cloning of the topoisomerase genes with a goal towards expression of each gene in a heterologous system. Following construction of genomic libraries in the vectors lambda DASH and lambda ZAP, oligonucleotides corresponding to conserved regions of both topoisomerases I and II were used in the polymerase chain reaction (PCR) of P. carinii DNA to generate probes. Candidate clones for both genes have been identified. Partial DNA sequence of the topoisomerase II gene has been determined.
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PMID:Inhibition of topoisomerases from Pneumocystis carinii by aromatic dicationic molecules. 166 35

We have initiated the characterization of the DNA helicases from HeLa cells, and we have observed at least 4 molecular species as judged by their different fractionation properties. One of these only, DNA helicase I, has been purified to homogeneity and characterized. Helicase activity was measured by assaying the unwinding of a radioactively labelled oligodeoxynucleotide (17 mer) annealed to M13 DNA. The apparent molecular weight of helicase I on SDS polyacrylamide gel electrophoresis is 65 kDa. Helicase I reaction requires a divalent cation for activity (Mg2+ greater than Mn2+ greater than Ca2+) and is dependent on hydrolysis of ATP or dATP. CTP, GTP, UTP, dCTP, dGTP, dTTP, ADP, AMP and non-hydrolyzable ATP analogues such as ATP gamma S are unable to sustain helicase activity. The helicase activity has an optimal pH range between pH8.0 to pH9.0, is stimulated by KCl or NaCl up to 200mM, is inhibited by potassium phosphate (100mM) and by EDTA (5mM), and is abolished by trypsin. The unwinding is also inhibited competitively by the coaddition of single stranded DNA. The purified fraction was free of DNA topoisomerase, DNA ligase and nuclease activities. The direction of unwinding reaction is 3' to 5' with respect to the strand of DNA on which the enzyme is bound. The enzyme also catalyses the ATP-dependent unwinding of a DNA:RNA hybrid consisting of a radioactively labelled single stranded oligodeoxynucleotide (18 mer) annealed on a longer RNA strand. The enzyme does not require a single stranded DNA tail on the displaced strand at the border of duplex regions; i.e. a replication fork-like structure is not required to perform DNA unwinding. The purification of the other helicases is in progress.
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PMID:A DNA helicase from human cells. 170 1

A cloned yeast TOP2 gene was modified to produce yeast DNA topoisomerase II (EC 5.99.1.3) epitopically labeled at its amino or carboxyl terminus. Limited digestion with SV8 endoprotease shows three distinct protease-sensitive sites in each polypeptide of the dimeric enzyme. These sites were mapped by immunostaining of the end-labeled proteolytic fragments resolved by SDS/polyacrylamide gel electrophoresis; two of the mapped locations were confirmed by sequencing the amino ends of two unlabeled peptic fragments. Proteolytic cleavage by SV8 endoprotease at a pair of sites corresponding to the carboxyl sides of Glu-411 and Glu-680 is modulated by the binding of the nonhydrolyzable ATP analogs adenosine 5'-[beta, gamma-imido]triphosphate (5'-adenylyl imidodiphosphate) and adenosine 5'-[gamma-thio]triphosphate: in their absence cleavage occurs predominantly at Glu-411; in the presence of either analog, cleavage occurs predominantly at Glu-680. These results are interpreted in terms of allosteric interdomainal movements in the type II DNA topoisomerase following the binding of ATP.
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PMID:Proteolysis patterns of epitopically labeled yeast DNA topoisomerase II suggest an allosteric transition in the enzyme induced by ATP binding. 172 May 43


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