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RESEARCH PRODUCT

Bleomycin, an Antibiotic That Removes Thymine from Double-Stranded DNA

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Publisher Summary This chapter reviews that bleomycins are members of a new class of DNA-modifying agents, the quasi-enzymes. In in vitro systems, bleomycin first removes thymines from native DNA by hydrolysis of the N-glycosidic bonds without modifying the deoxyribose moiety. In a second step, single-strand scissions occur at the sites of the nonglycosidic deoxyribose moieties, resulting in the formation of 3'-OH and 5'-P termini. It is suggested that bleomycin is bound to DNA by interaction of the positively charged terminal amine moiety with the negatively charged phosphate group in DNA; intercalation seems to be involved in binding. Bleomycin is inactivated by copper and zinc ions, probably by chelate formation, which might cause a contortion of the antibiotic. The chapter discusses that the action is enhanced by a coincubation with intercalating agents. A reaction mechanism is proposed by which the quasi-enzymic character of bleomycin as a nucleosidase is described, assuming that the carboxyl amide group of β-aminoalanine is the active site of the molecule. In isolated enzyme systems, it affects the activities of DNA-dependent DNA polymerases and DNA-dependent RNA polymerases as well as DNases in an indirect way; it first modifies DNA, which then affects the polymerases through its aldehyde groups and the DNases by reduction of their substrate affinity. The chapter also reviews that antitumor activity of bleomycin is dependent upon uptake, inactivation and activation, leading to tissue- and organ-specific actions. The observed antiviral activity of bleomycin does not seem to be specific, but to be due to an overall inhibition of DNA synthesis.