Drugs Targeting Topoisomerase

Unwinding of the DNA helix generates a torsional strain from supercoiling of the helix above and below the region of ongoing nucleic acid during DNA replication, transcription, or recombination. DNA topoisomerase I is a ubiquitous nuclear enzyme that relaxes this torsional strain by catalyzing a transient single-stranded nick in the DNA. This results in covalent linkage of the enzyme to the 3'-terminus of the cleaved DNA. It also reanneals the strand break after passage of the intact single strand through the gap in the cleaved DNA strand. Topoisomerase I is expressed in both mitotic and non-mitotic cells alike throughout the cell cycle, with higher levels of its mRNA and the topoisomerase protein found in malignant tumors than in their normal tissue counterparts.99,100

Topoisomerase II exists in two isoforms in mammalian cells. Although topoisomerase IIP is expressed throughout the cell cycle, expression of topoisomerase IIa is cell cycle specific, highest during G2-M phases of the cell cycle, and its concentrations are higher in rapidly proliferating cells. The a-isoenzyme is preferentially targeted by the topoisomerase II inhibitors at drug concentrations reached with standard doses. Unlike topoisomerase I, topoisomerase II is energy cofactor dependent, requiring ATP and magnesium for its catalytic activity. It becomes covalently attached to the 5'-terminus of the cleaved DNA. It then facilitates strand passage through another and thereafter religates the strand break. Furthermore, it can create double-stranded DNA gaps, orchestrate concerted strand passage, and can catalyze "unknotting" or decatenation of intertwined DNA, attesting to its role in mitosis.

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