Topoisomerase II enzymes

Antibiotic and Antimicrobial Drugs. The antimicrobial agents (119) flumequiae (160) and (161), and methylflumequiae (S-25930) (162) and (163) effectively eliminate a number of microbial pathogens via inhibition of the topoisomerase II enzyme of c-DNA containing bacteria (120) (see... 

II cleaves the two complementary strands of DNA four base pairs apart and the resulting 5 -phosphoryl groups become covalently linked to a pair of tyrosine groups, one in each half of the dimeric topoisomerase II enzyme. Several groups of drugs are known that selectively inhibit topoisomerases in bacteria (quino-lones) or mammalian cells (etoposide, tenoposide). Quinolones are used to treat bacterial infections inhibitors of mammalian topoisomerases are cytostatic drugs used for the treatment of cancer. 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

The mammalian topoisomerase II enzyme catalyzes the double-strand breakage of DNA to allow the second strand passage and thereby control the topology... 

Figure 7.11 Examples of topoisomerase inhibitors. Ellipticene acts by both intercalation and inhibition of topoisomerase II enzymes. It is active against nasopharyngeal carcinomas. Amsacrine is used to treat ovarian carcinomas, lymphomas and myelogenous leukaemias. Camptothecin is an antitumour agent...

The interaction of ellipticine derivatives with topoisomerase II enzymes in Plasmodium berghei (163), a parasite of mouse red blood cells, mouse lymphoma L5178Y cells (164), simian virus 40 CV-1 cells (165), Trypanosoma cruzi (166,167), and the human small-cell lung cancer cell line NCI N417 (168,169) has been studied. In the latter study, the highest in vitro activity in the topoisomerase II-DNA cleavage reaction and decatenation was observed for elliptinium (5) and datelliptium (384) (769). 

MOA Inhibits topoisomerase 1 enzyme blocks effective replication and transcription. Forms complex with topoisomerase II enzyme, which blocks DNA replication results in DMA strand breakage. 

Ferguson LR, Baguley BC. Topoisomerase II enzymes and mut nicity. Environ Mol Mutagen 1994 24 245-261. 

Gyrase is another term for bacterial topoisomerase II. The enzyme consists of two A and two B subunits and is responsible for the negative supercoiling of the bacterial DNA. Negative supercoiling makes the bacterial DNA more compact and also more readily accessible to enzymes that cause duplication and transcription of the DNA to RNA. 

I topoisomerase of mammals is a 100 kD monomeric protein whose activity is ATP-independent. This enzyme binds to double-stranded DNA and cleaves one of the DNA strands of the duplex, simultaneously forming an enzyme-DNA covalent bond between a tyrosine residue and the 3 -phosphate of the cleaved DNA. The type II topoisomerases are dimeric enzymes, which are ATP-dependant. Two isoforms of topoisomerase II exist, topoisomerase a and (3, with apparent molecular weights of 170 and 180 kD. Topoisomerase... 

Topoisomerase II is a nuclear enzyme involved in replication, transcription. 

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

Meng LH, Zhang JS, Ding J. Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage complexes. Biochem Pharmacol 2001 62 733-741. 

The scaffold contains several proteins, especially HI in the core and topoisomerase II. Both appear important to the compaction of the chromosome. In fact, the relationship between topoisomerase II and chromosome folding is so vital that inhibitors of this enzyme can kill rapidly dividing cells thus, several drugs used in the treatment of cancer are topoisomerase II inhibitors. 

Etoposide and teniposide are synthetic derivatives of the extract of the American mandragora plant (May Apple). The mechanism of their action has not been completely explained however, they act on the enzyme topoisomerase II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA synthesis, as well as transport of nucleotides to cells. Cytotoxic action on normal cells is observed only in very high doses. These drugs exhibit significant activity in lymphomas, leukemia, Kaposi s sarcomas, and in testicular cancer. 

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