As a leading supplier of cytotoxin discovery and manufacture, BOC Sciences provides a wide range of specific products for DNA topoisomerase I. Topoisomerases are essential enzymes that widely exist in organisms and participate in critical intranuclear processes such as DNA replication, transcription, recombination and reparation. Usually, topoisomerases are divided into DNA Topoisomerase I (Topo I) and DNA Topoisomerase II (Topo II) according to a different mechanism of DNA topoisomerases catalyzing DNA topoisomer transformation. Topo I affects the DNA topological structure by regulating superhelical, linkage, delinkage and unknotting effects. With a broad application of Camptothecins (CPTs) in clinical, Topo I has become an essential novel target for the research of anti-tumor drugs. The three CPTs drugs listed here are Irinotecan (CPT-11), Topotecan (TPT) and Hydroxycamptothecin (HCPT), and they were used in clinical treatment for colon cancer, ovarian cancer and lung cancer, respectively.
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Topoisomerase I (Topo I) is a monomeric protein composed of 765 amino acids, including the N-terminal domain, core domain, linker domain, and carboxyl-terminal domain. The N-terminal domain is positively charged and contains minor hydrophobic amino acids. Thus it cannot form a stable spherical domain. The carboxyl-terminal domain, which includes a critical active site residue Tyr723, can be recombined with an independent core domain and achieve the activity that approximates the holoenzyme. Although the linker domain does not affect to the catalytic activity. It stabilizes the DNA downstream by forming hydrogen bonds with the nucleotides of DNA cleavage sites to slow down the reconnection process. The core domain contains all active site residues except Tyr723 (Arg488, Arg590, His632 and Lys532, etc.). Mechanistic research indicates that Topo I form a 3′-phosphotyrosine ester bond and 5′-hydroxy by nucleophilic attack on a single-stranded phosphodiester bond of DNA, and the broken single-stranded revolves around DNA to unlock the positive supercoil state and continue DNA replication.
Biochemistry 2009, 48, 14, 3176–3185.
Topoisomerase I (Topo I) inhibitors have become a vital target enzyme for designing new anti-cancer drugs. Such anti-cancer drugs have high efficacy and a broad anti-tumor spectrum. Moreover, the Topo I content of various tumor cells (especially colon cancer, cervical cancer, ovarian cancer) is much higher than that of normal tissues, especially in S-stage tumor cells. Therefore, drugs that inhibit Topo I can selectively inhibit DNA replication in proliferating tumor cells. The Topo I inhibitors are usually divided into Topo I poison and Topo I suppressor, which inhibit Topo I activity and prevent DNA relaxation. Topo I poison, which includes DNA intercalating agent, groove binders (minor-groove binders and major groove binders) and inhibitors that combine DNA with Topo I, can capture the Topo I-DNA cleavable complex and form a barrier that prevents DNA replication and leads to cell death. Topo I suppressor damage cells by inhibiting the catalytic activity of enzymes, so it contains higher activity in cells with low Topo I expression. Both Topo1 poison and Topo1 suppressor revealed potentials in anti-tumor therapy.