Abstract
Clerocidin (CL), a diterpenoid natural product, alkylates DNA through its epoxide moiety and exhibits both anticancer and antibacterial activities. We have examined CL action in the presence of topoisomerase IV from Streptococcus pneumoniae. CL promoted irreversible enzyme-mediated DNA cleavage leading to single- and double-stranded DNA breaks at specific sites. Reaction required the diterpenoid function: no cleavage was seen using a naphthalene-substituted analogue. Moreover, drug-induced DNA breakage was not observed using a mutant topoisomerase IV (ParC Y118F) unable to form a cleavage complex with DNA. Sequence analysis of 102 single-stranded DNA breaks and 79 double-stranded breaks revealed an overwhelming preference for G at the -1 position, i.e. immediately 5' of the enzyme DNA scission site. This specificity contrasts with that of topoisomerase IV cleavage with antibacterial quinolones. Indeed, CL stimulated DNA breakage by a quinolone-resistant topoisomerase IV (ParC S79F). Overall, the results indicate that topoisomerase IV facilitates selective irreversible CL attack at guanine and that its cleavage complex differs markedly from that of mammalian topoisomerase II which promotes both irreversible and reversible CL att...Continue Reading
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Citations
Sep 10, 2011·Applied Microbiology and Biotechnology·Frédéric CollinAnthony Maxwell
Sep 4, 2007·Nucleic Acids Research·Sara N RichterManlio Palumbo
Aug 30, 2008·Nucleic Acids Research·Xiao Su PanL Mark Fisher
Mar 22, 2007·PloS One·Ivan LaponogovMark R Sanderson
Dec 4, 2014·Journal of Pharmaceutical Sciences·John F Valliere-DouglassShan Jiang
Sep 25, 2007·Experimental Gerontology·Torsten Richter, Carole Proctor
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Sep 9, 2016·Journal of Proteome Research·Siting LiFeng Ge
Feb 20, 2009·Organic & Biomolecular Chemistry·Sara N RichterManlio Palumbo
Aug 1, 2009·EcoSal Plus·Katherine Evans-Roberts, Anthony Maxwell
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