ABSTRACT
The bleomycins (BLMs) are a family of antitumor antibiotics œrst isolated from Streptomyces verticillus by Umezawa and colleagues.1,2 As illustrated (Figure 19.1), the BLMs are glycosylated oligopeptides, having extensively modiœed amino acid constituents. Some of these are derived biosynthetically from proteinogenic amino acids such as the bithiazole moiety, which is formed by dehydrative cyclization and oxidation of β-alanylcysteinylcysteine.3 However, more recent studies have revealed that the biosynthesis also depends in part on transformations used to assemble polyketide antibiotics,4 and the biosyntheses of the BLM group antibiotics tallysomycin (TLM) and zorbamycin have also been reported recently.5-9
19.1 Introduction .......................................................................................................................... 451 19.2 Mechanism of Action............................................................................................................ 453
19.2.1 BLM Activation ........................................................................................................ 453 19.2.2 DNA Binding and Degradation ................................................................................ 453
19.2.2.1 Chemistry of DNA Degradation ................................................................ 453 19.2.2.2 Modes of DNA Binding ............................................................................. 455 19.2.2.3 DNAs Strongly Bound by BLM ................................................................. 456
19.2.3 RNA Degradation ..................................................................................................... 458 19.2.3.1 Transfer RNAs and tRNA Precursor Transcripts ...................................... 458 19.2.3.2 Other RNA Substrates for BLM ................................................................ 459 19.2.3.3 Chemistry of RNA Cleavage .....................................................................460
