Topoisomerase II mechanism

Eukaryotic topoisomerase II is a homodimeric enzyme that requires ATP to function. It makes a transient double strand break, where the tyrosines from the active sites of both monomers attack the phosphodiester bond to the 5'-side of the phosphate, leading to a covalent 5'-phosphotyrosyl linkage in each strand

After binding of the enzyme to DNA, a double strand DNA break is produced by nucleophilic attack of both tyrosine residues. These breaks between the strands are not directly opposite to each other; instead, they are separated by a four base pair overhang, generating a space through which another region of intact DNA can be passed. The final steps involve religation of the DNA break, dissociation, and release of DNA from the topoisomerase (Fig. 7.11). Several of these steps require the binding and hydrolysis of ATP.

The catalytic cycle of topoisomerase II is complex and is summarized in Fig. 7.12, together with the names of some drugs that have steps of this cycle as targets.42 The enzyme assumes two different conformations, resembling an open

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