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)

Inhibitors of the enzyme bacterial topoisomerase II (DNA gyrase) were evaluated for activity against Trypanosoma cruzi (Brazil strain), based on the theoretical need for a topoisomerase II in the replication of the kinetoplast DNA network. Novobiocin (500 micrograms/ml) antagonized amastigotes of T. cruzi growing in a cell-free medium at 37 degrees C, as manifested by inhibition of multiplication, abnormal morphology of Giemsa-stained organisms, and delayed or absent growth of cells upon subculturing in a drug-free medium. In contrast, novobiocin (1,000 micrograms/ml) essentially had no effect on the multiplication and motility of epimastigotes growing in a cell-free medium at 27 degrees C. This resistance of epimastigotes represented a difference in the physiology of this morphologic stage and not in the temperature of experimentation, because novobiocin inhibited multiplication of amastigotes at 27 degrees C as well and accelerated transformation to epimastigotes. With T. cruzi growing within cultured human fibroblasts, novobiocin (200 micrograms/ml) markedly inhibited transformation of intracellular amastigotes to trypomastigotes. Clorobiocin, a structural analog of novobiocin and likewise an inhibitor of the B subunit of bacterial topoisomerase II, was five times more potent on a molar basis than novobiocin was in antagonism of amastigotes growing in a cell-free medium and did not antagonize epimastigotes. Coumermycin A1, another analog of novobiocin, and five 4-quinolone antibacterial agents, antagonists of the A subunit of bacterial topoisomerase II, inhibited neither amastigotes nor epimastigotes. These experiments indicate that novobiocin and clorobiocin represent a new structural class of drugs with activity against T. cruzi. Whether the mechanism of action of these drugs involves antagonism of a T. cruzi topoisomerase II or an unrelated target is yet to be determined.
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PMID:Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium. 352 85

The results reported in this paper describe the effects produced by the antibiotic Coumermycin A1 (CA1) on survival and metabolism of chick embryo fibroblast cells (CEF), and give a clue to the understanding of its toxicity. The drug acts primarily at the level of DNA and RNA synthetic enzymes; no effect on DNA superstructure is detectable at doses at which cytotoxicity is pronounced. A spectroscopic approach produced evidence that CA1 binds to DNA, RNA, chromatin components such as histones and to a structurally unrelated protein such as bovine serum albumin. Furthermore, CA1 behaves like a pure non-competitive inhibitor of lactic dehydrogenase, a ubiquitous enzyme not involved in nucleic acid metabolism. The interaction of CA1 with a wide range of macromolecules playing different biological roles is certainly relevant to its activity and adds a new insight into the mechanism of action of this antibiotic. These observations are also discussed in the light of the alleged role of CA1 as a specific inhibitor of DNA topoisomerase in eukaryotic cells.
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PMID:Nature of toxicity for chick embryo fibroblast cells of coumermycin A1 and its physico-chemical interactions with protein and nucleic acid. 620 Jan 13

An activity from the yeast Saccharomyces cerevisiae, initially noted for its catalysis of aggregation of covalently closed double-stranded DNA rings in the presence of ATP, has been identified as a type II DNA topoisomerase and is designated yeast DNA topoisomerase II. The formation of the DNA aggregate, which has been shown to be a network of DNA rings that are topologically interlocked, requires the presence of a yeast DNA-binding protein in addition to the topoisomerase. In the absence of the binding protein, yeast DNA topoisomerase II catalyzes decatenation and unknotting of duplex DNA rings and the relaxation of negatively or positively supercoiled DNA. All reactions are ATP-dependent and require Mg(II). Similar to other eukaryotic and phage T4-type II DNA topoisomerases, the yeast enzyme does not catalyze DNA supercoiling under the assay conditions employed. The activity is not sensitive to the gyrase inhibitor nalidixic acid, oxolinic acid, or novobiocin. Coumermycin inhibits the activity, however, at a concentration as low as 5 microgram/ml.
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PMID:Yeast DNA topoisomerase II. An ATP-dependent type II topoisomerase that catalyzes the catenation, decatenation, unknotting, and relaxation of double-stranded DNA rings. 627 16

Several rifamycin derivatives inhibited the DNA-dependent RNA polymerase of African swine fever (ASF) virus particles. The inhibition was similar to that found with vaccinia virus RNA polymerase. Coumermycin A1, an inhibitor of type II DNA topoisomerases, inhibited strongly RNA synthesis in vitro by ASF virus particles. This suggests that transcription of ASF virus DNA requires a DNA topoisomerase.
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PMID:Effect of rifamycin derivatives and coumermycin A1 on in vitro RNA synthesis by African swine fever virus. Brief report. 662 87