Saintopin, a dual inhibitor of DNA topoisomerases I and II, as a probe for drug-enzyme interactions.
1994; Elsevier BV; Volume: 269; Issue: 46 Linguagem: Inglês
10.1016/s0021-9258(19)61962-9
ISSN1083-351X
AutoresFrançois Leteurtre, A. Fujimori, Akihiko Tanizawa, A. K. Chhabra, Abhijit Mazumder, Glenda Kohlhagen, Hiroyuki Nakano, Yves Pommier,
Tópico(s)Synthesis and Biological Evaluation
ResumoStabilization of the topoisomerase-cleavable complexes is the common initial event leading to the cytotoxicity of topoisomerase I and II (top1 and top2) inhibitors. Using saintopin (STP), a poison of both topoisomerases, we studied top1- and top2-cleavable complexes (Yamashita, Y., Kawada, S.-Z., Fujii, N., and Nakano, H. (1991) Biochemistry 30, 5838-5845). top1 and top2 sites induced in the presence of STP showed the same preferences for the base located 3' to the topoisomerase-induced DNA break (position +1): preference for G and not C. A camptothecin-resistant top1 with a mutation (Asn722-->Ser) next to the catalytic tyrosine (Tyr723) was cross-resistant to STP, suggesting that both STP and camptothecin interact with the protein near the catalytic tyrosine. These results are consistent with a dual interaction of the drug with the enzyme and the DNA and provide further evidence for the drug-stacking model. This model proposes that topoisomerase inhibitors bind, possibly through hydrogen bonding and/or stacking, with one of the bases flanking the DNA termini (guanine at position +1 in the case of STP) and within the enzyme catalytic pocket, most likely by stacking with the catalytic tyrosine.
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