DefinitionThis section has been translated automatically.
Topisomerases are a class of nuclear enzymes that are involved in the regulation of DNA supercoiling. They belong to the isomerases. DNA molecules are able to coil and bend in space, which due to their helical structure leads to changes in topology and the formation of negative or positive supercoils.
General informationThis section has been translated automatically.
There are two superordinate classes:
- Type I topoisomerases (subclasses topoisomerase I & III)
- Type II topoisomerase (for eukaryotes = topoisomerases II & IV; for bacteria the TYPE II topoisomerase corresponds to the enzyme gyrase).
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PathophysiologyThis section has been translated automatically.
Topisomerases control and maintain the spatial arrangement (topology) of DNA double strands during replication. They convert superhelical DNA into relaxed DNA by temporarily cleaving one (type I topoisomerase) or both DNA strands (type II topisomerases) and thus create the prerequisite for reading, i.e. transcription, of the DNA.
During DNA replication (S phase), a strong twisting(supercoiling) of the DNA double strand and the associated tension in front of the replication fork (superhelical DNA), prevents the attachment of the DNA polymerases, which is necessary for the synthesis of the daughter strand.
Type I topoisomerases (subclasses topoisomerase I & III) relax DNA, convert a superhelical DNA into a relaxed DNA by reversibly cleaving one strand of duplex DNA. This creates the prerequisite for reading, i.e. transcription of the DNA. After successful DNA replication, the DNA break is closed again. Afterwards, the topoisomerases I & IV remove the negative deviations of the twisting state and thus restore the physiological original state.
Type I topisomerases reversibly cleave only one strand of DNA at a time. In contrast, the type II topisomerases are able to separate both DNA strands in an ATP-dependent manner.
Note(s)This section has been translated automatically.
Antibiotic effect of toposiomerase inhibitors
- Topoisomerases are the target of some drugs. The bacterial type I topoisomerases (prokaryotic topoisomerases I) can exclusively relax negative supercoiling of DNA. They require magnesium ions for their activity. Type I prokaryotic topoisomerases bind covalently to the 5' end of the strand break by means of a phosphotyrosine bond. This conserves the energy of the cleaved bond and allows the two ends to reconnect after topoisomerization. The enzyme does not require energy in the form of ATP for its activity. Type I topoisomerases are blocked by quinolones(gyrase inhibitors). This explains the antibacterial effect of this group of substances.
Cytostatic effect of toposiomerase inhibitors
- Various tumors are characterized by increased topisomerase activity, which is why topisomerase inhib itors can be effective as cytostatic agents. In this context, they show a certain tumor selectivity (e.g. in ovarian carcinoma, small cell lung carcinoma, colorectal carcinoma, etc.). Type I topomerase inhibitors include, for example, the drugs:
- Type II topomerase inhibitors are:
LiteratureThis section has been translated automatically.
- Lima CD et al (1994) Three-dimensional structure of the 67K N-terminal fragment of E. coli DNA topoisomerase I. Nature 367:138-145.
- Wang JC (1991). DNA topoisomerases: why so many? Journal of Biological Chemistry 266:6659-6662.
- Yu L et al (1995) Solution structure of the C-terminal single-stranded DNA-binding domain of E. coli topoisomerase I. Biochemistry 34:7622-7628.