Topoisomerases structure

Finally, the composite helicase-topoisomerase structure of reverse gyrase suggests that this unusual enzyme could also be involved in any one of the mechanisms which requires the concerted action of such activities [Duguet, M., personal communication]. 

Champoux JJ. DNA topoisomerases Structure, function, and mechanism. Annu Rev Biochem 2001 70 369-413. 

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

Topoisomerase Type Structure Gene Predominant function in cell... 

Quantitative Structure-Activity Reiationships of Heterocyciic Topoisomerase i and ii inhibitors... 

Identification of proteins that bind to Z-DNA added one further step to the establishment of the presence of Z-DNA in vivo and its possible biological role. Herbert and Rich [22] demonstrated an in vitro assay system where one type of double-stranded RNA adenosine deaminase, called DRAD-binding Z-DNA. There are evidences that topoisomerase II from Drosophila, hiunan and calf thymus recognizes a number of DNA shapes, including Z-DNA [34,35]. Bloomfield and coworkers [36] have found that the condensation of plasmids is enhanced by Z-DNA conformation in d(CG)n repeats. The information related to B-Z transition [31], the effect of ligands on it [28,29] and X-ray crystal structure data [37,38] appear to suggest that the possible biological role of this polymorphic form of DNA will be soon established. 

The most important aspect of coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumour alkaloid camptothecin, which is known to exert this property [242], Presumably, the most notable biological action of these alkaloids appears to be topoisomerase inhibition [238-242], which has direct relevance to their DNA intercalating property. In this context. Pilch et al. [167] described a mixed binding mode model (Fig. 16) in which the protoberberine structure constitutes portions that can intercalate or bind to the minor groove of DNA. Wang et al. [240] demonstrated that coralyne (Ci) and several of its derivatives (Ce to Ch) (Scheme 5), including the partial saturated... 

Scheme 5 Structure of several coralyne analogues tested for inhibition of DNA topoisomerase I...

Scheme 6 Structure of coralyne derivatives and a substituent in 8-position tested for cytotoxicity and topoisomerase 1 and II poisons...

Hansch C, Verma RP (2007) Quantitative Structure-Activity Relationships of Heterocyclic Topoisomerase I and II Inhibitors. 10 43-74 Herncindez-Mateo F, see Santoyo-Gonzdlez F (2007) 7 133-177 Holt H Jr, see Brown T (2006) 2 1-51... 

Hansch and Verma contribute to the quantitative structure-activity relationship (QSAR) analysis of heterocyclic topoisomerase I and II inhibitors. These inhibitors, known to inhibit either enzyme, act as antitumor agents and are currently used in chemotherapy and in clinical trials. 

Quantitative Structure-Activity Relationships of Heterocyclic Topoisomerase 1 and 11 Inhibitors... 

Topoisomerase is responsible for relieving the pressure on the DNA structure during unwinding by producing strand breaks. Topoisomerase I produces single-strand breaks, whereas topoisomerase II produces double-strand breaks. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

However, there are a number of other miscellaneous biological roles played by this complex. The [Co(NH3)6]3+ ion has been shown to inhibit the hammerhead ribozyme by displacing a Mn2+ ion from the active site.576 However, [Co(NH3)6]3+ does not inhibit ribonuclease H (RNase),577 topoisomerase I,578 or hairpin ribozyme,579 which require activation by Mg2+ ions. The conclusions from these studies were that an outer sphere complex formation between the enzyme and Mgaq2+ is occuring rather than specific coordination of the divalent ion to the protein. These results are in contrast to DNase I inhibition by the same hexaammine complex. Inhibition of glucose-induced insulin secretion from pancreatic cells by [Co(NH3)6]3+ has been found.580 Intracellular injection of [Co(NH3)6]3+ into a neurone has been found to cause characteristic changes to the structure of its mitochondria, and this offers a simple technique to label neuronal profiles for examination of their ultrastructures.581... 

Taxonomically close to the Annonaceae, the Lauraceae family abounds with apor-phinoid alkaloids. A remarkable advance in the search for topoisomerase inhibitors from Lauraceae has been provided by Woo et al. (6). Using DNA-unwinding assay and structural modeling, they showed that dicentrine can attain a relatively planar conformation and molecular bulk which allow it to occupy the active site of topoisomerase II which becomes inactive. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine less potent against topoisomerase II than the... 

An other example of Salvia quinone is salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, which is cytotoxic against multidrug-resistant cancer cell lines of topoisomerase II inhibition by trapping the DNA-topoisomerase II complex (49). 

Wang and coworkers143 described a rapid and sensitive LC/MS/MS method for the determination of a novel topoisomerase I inhibitor (an indolocarbazole derivative) in human plasma, following SLE on 96-well diatomaceous earth plates. The structures of this inhibitor and the IS used are shown in Figure 1.26. Clinical, QC, and standard plasma samples were thawed at room temperature, vortexed for 30 sec, centrifuged at 3000 g for 10 min 250 fiL aliquots were transferred to... 

Schultz P, Olland S, Oudet P, Hancock R. Structure and conformational changes of DNA topoisomerase II visualized by electron microscopy. Proc Natl Acad Sci USA 1996 93 5936-5940. 

These observations, together with those on supercoiled DNAs relaxed by intercalating dyes and by topoisomerase I, indicate that complete conversion from the prevalent secondary structures in supercoiled DNAs to the normal B-helix must be severely hindered kinetically. It is also clear that the free energies per base pair of the secondary structure states a and b must be nearly identical in order for these states to be interconverted by such a small environmental perturbation. 

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