Macrostatin, a novel macromolecular inhibitor of topoisomerases produced by Streptomyces avermitilis no. C-127.
A novel inhibitor of topoisomerases designated as Macrostatin has been isolated from the culture filtrate of Streptomyces avermitilis strain No. C-127 and purified by successive chromatography on Dowex, activated charcoal, gel filtration and cellulose. It is an acidic macromolecule having 45 kD molecular weight as determined by gel filtration. Macrostatin inhibited topoisomerase I and II in a noncompetitive manner with Ki = 3.7 and 1.3 nM respectively. Macrostatin differed from well-known inhibitors of topoisomerase such as camptothecin, etoposide and doxorubicin which induce topoisomerase-mediated DNA cleavage by stabilizing the cleavable complex or intercalation into DNA strands. Macrostatin had neither ability to stabilize the cleavable complex nor ability to intercalate into DNA strands. It was suggested that Macrostatin inhibits topoisomerase by a direct action on the enzyme.
Suzuki
K
K
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Sekimoto
J
J
Siddique
T
T
Kamiya
A
A
Uyeda
M
M
D001667:Binding, Competitive; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D004996:Ethidium; D005047:Etoposide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007364:Intercalating Agents / Q000494:pharmacology; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D013302:Streptomyces / Q000201:enzymology / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D004247:DNA; D004996:Ethidium; D002166:Camptothecin