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Topoisomerase I Inhibitors

Mechanism

TopI relaxes DNA supercoiling during replication and transcription.  Under normal circumstances, TopI attacks the backbone of DNA, forming a transient TopI-DNA intermediate that allows for the rotation of the cleaved strand around the helical axis.  TopI then re-ligates the cleaved strand to reestablish duplex DNA.  Treatment with TopI inhibitors stabilizes the intermediate cleavable complex, preventing DNA re-ligation, and inducing lethal DNA strand breaks. Camptothecin-derived TopI inhibitors function by forming a ternary complex with TopI-DNA and are able to stack between the base pairs that flank the cleavage site due to their planar structure. Normal cells have multiple DNA checkpoints that can initiate the removal of these stabilized complexes, preventing cell death. In cancer cells, however, these checkpoints are typically inactivated, making them selectively sensitive to TopI inhibitors. Noncamptothecins, such as indenoisoquinolines and indolocarbazoles, also associate with TopI itself, forming hydrogen bonds with residues that typically confer resistance to camptothecin. Indenosioquinolines and indolocarbazoles also lack the lactone ring present in camptothecin, making them more chemically stable and less prone to hydrolysis at biological pH.



Gram negative antibiotic activity among topoisomerase inhibitors is typically linked to the inhibition of DNA gyrase while gram positive antibiotic activity is associated with the inhibition of TopIV, a type of TopII. (citation http://www.sciencedirect.com/science/article/pii/0922338X92901128)

Topoisomerase II Inhibitors

Mechanism

TopII forms a homodimer that functions by cleaving double stranded DNA, winding a second DNA duplex through the gap, and re-ligating the strands.  TopII is necessary for cell proliferation and is abundant in cancer cells, which make TopoII inhibitors effective anti-cancer treatments. In addition, some inhibitors, such as quinalones, fluoroquinalones and coumarins, are specific only to bacterial type 2 topoisomerases (TopoIV and gyrase), making them effective antibiotics. Regardless of their clinical use, TopoII inhibitors are classified as either catalytic inhibitors or poisons. TopoII catalytic inhibitors bind the N-terminal ATPase subunit of TopoII, preventing the release of the separated DNA strands from the TopII dimer. The mechanisms of these inhibitors are diverse. For example, ICRF-187 binds non-competitively to the N-terminal ATPase of eukaryotic TopoII, while coumarins bind competitively to the B subunit ATPase of gyrase. Alternatively, TopoII poisons generate lethal DNA strand breaks by either promoting the formation of covalent TopII-DNA cleavage complexes, or by inhibiting re-ligation of the cleaved strand. Some poisons, such as doxorubicin, intercalate in the strand break between the base pairs that flank the TopII-DNA intermediate. Others, such as etoposide, interact with specific amino acids in TopII to from a stable ternary complex with the TopII-DNA intermediate.

POISONS VS INHIBITORS

CATALYTIC INHIBITORS - BLOCK ATPase (bind at n terminal atpase (or gyrase beta subunit atpase))

TopII poisons generate lethal DNA strand breaks in two ways: either by promoting the formation of covalent TopII-DNA cleavage complexes, or by inhibiting re-ligation of the cleaved strand.

BLOCK RELIGATION VS TRAP CC

INTERCALATING VS NONINTERCALATING (include throughout?)

Some of the inhibitors, like ellipticines and doxorubicin, intercalate in the strand break between the base pairs that flank the TopII-DNA intermediate. Alternatively, inhibitors such as etoposide and azatoxins interact with specific amino acids in TopII to from a stable ternary complex with the TopII-DNA intermediate.  ICRF-187 indirectly promotes the formation of the TopII-DNA intermediate by interfering with the activity of the ATPase region of TopII, which prevents the release of the religated DNA strands from the cleavage complex. The mechanism for others, like quinolones, have yet to be fully determined.  Interestingly, there is overlap between inhibitors’ mechanism types and forms of inhibition.  For example, while ellipticines and doxorubicin are both DNA intercalators, ellipticines trap the TopII-DNA intermediate, while doxorubicin blocks relegation.  The same is true of azotoxins, which are non-intercalating and trap the Top-DNA complex, and etoposide, which is also non-intercalating but prevents strand religation.  


Fluoroquinalones and coumarins, respectively inhibit bacterial