Topoisomerases

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... 

Fig. 5. Structures of topoisomerase interactive drugs given in Table 4.

Batcho indole synthesis is a useful tool for synthesis of naniral products. As oudined in Scheme 10.6, the Batcho indole synthesis is used for total synthesis of the slime mold alkaloid arcyriacyanin. Such indolocarbazole alkaloids represent a growing number of naniral products isolated from soil organism, slime molds, and marine sources. They are important as andnimor compounds and protein kinase C and topoisomerase inhibitors. 

Anthracyclins. Figure 2 Mechanisms of anthracycline-induced apoptosis of tumor cells. ROS, reactive oxygen species topo II, topoisomerase II cyt c, cytochrome c. 

Some are mitosis inhibitors which affect microtubule function and hence the formation of the mitotic spindle, others are topoisomerase I and II inhibitors. 

Epipodophyllotoxins (etoposide, teniposide) are derived from mandrake root (Podophyllum peltatum). They inhibit topoisomerase H thus causing double strand breaks. Cells in S- and G2-phases are most sensitive. Unwanted effects include nausea and vomiting, myelosuppression, and hair loss. 

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

Camptothecin is a plant alkaloid that selectively targets topoisomerase I (Topi). It produces DNA damage leading to the destruction of eukaryotic cells. Because... 

Pommier Y (2006) Topoisomerase I inhibitors camp-tothecins and beyond. Nat Rev Cancer 6(10) 789-802... 

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. 

The enzymes gyrase and topoisomerase IV can be protected from fluoroquinolone inhibition by a small protein belonging to the pentapeptide-repeat family of... 

Quinolones. Table 1 Quinolones - Classification of bacterial topoisomerases... 

Topoisomerase Type Structure Gene Predominant function in cell... 

Gootz TD, Osheroff N (1993) Quinolones and eukaryotic topoisomerases. In Hooper DC and Wolfson JS (eds) Quinolone antimicrobial agents, 2nd edn. American Society for Microbiology, Washington, DC, pp 139-160... 

Bacterial as well as eukaryotic chromosomes contain too much DNA to fit easily into a cell. Therefore, the DNA must be condensed (compacted) to fit into the cell or nucleus. This is accomplished by supercoiling the DNA into a highly condensed form. When relaxed circular DNA is twisted in the direction that the helix turns, the DNA becomes positively supercoiled, if it is twisted in the opposite direction, it is called negatively supercoiled. Bacterial DNA is normally found in a negatively supercoiled state. Supercoiling reactions are catalyzed by topoisomerases. 

Topoisomerase enzymes control and modify the topologic states of DNA. The mechanisms of these enzymes involve DNA cleavage and strand passage through the break, followed by religation of the cleaved DNA. Two main forms of topoisomerase exist. The type... 

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... 

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. 

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