An oxidized sugar phosphate and free base other

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an oxidized sugar phosphate, and free base. Other metals such as copper and cobalt can also activate bleomycins, al- though their mechanistic pathways for strand scission are clearly different from that of Fe(II)-bleomycin. Whether other natural products that bind DNA also chelate metal ions and exploit them for oxidative strand cleavage is not known, but several systems provide hints that they do. Furthermore, such a fact would not be surprising given our understanding of the utility of metal ions in promot- ing this chemistry. An even more detailed understanding of this chemistry might lead to the development of second-generation synthetic transition-metal phar- maceuticals that specifically and efficiently target and cleave DNA sites. D. A Catalytic Role In addition to serving structural and modulating roles in proteins which bind nucleic acids, metal ions also appear to be essential to the functioning of various complex enzymes that act on nucleic acids. At this stage our understanding of the participation of the metal ion in the catalytic chemistry of these enzymes is somewhat sketchy, and we are relying more on our current understanding of the
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(A) 0~NH2 ~H /NH 2 H NH 2 N H 0 1:t / n H /CH 3 ~ro ~o H2 N' ~ 1 0 0 HO : NH S~N I NH S(~~3)2 CH f; 0 I I"" U 3 HN N: CH HO : CH ~ N S H H 3 H 3 N o H \ » ,1oJ N HOV'Fto~g~ OH ~ OH I 0~NH2 bleomycin (C) BLM-Fe(lI) + O 2 (B) NH 2 CO ,H ~N-HN~H H f::1 \\'~C ~ ,-----t--N II O-L-alanine ~C/' ,/'" \ /' u " I':) rU{N H NH 2 CO __ H o NH 2 H I BLM-Fe(III)-OO· Ie Fe(II)-BLM Fe(III)-BLM BLM-Fe(III)-0-02- BLM-Fe(lIl) + HP2 I ~ BLM-Fe(V) = 0 + H 2 0 "activated bleomycin"
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(D) o II N ROP0)(:j I -0 0-0 " H s ----+ o H R I O=P-O I OR' y o II R~rvO~ ">--fH s o H R I O=P-O- I OR' ~ ~ CRt:;jH) 0 N ROPOy -~ cg "H s ----+ o'J H R I _ O=P-O I , OR o 0 II II "'\ N R~r~::i°~) H H s f ',,\ o 'H~ ~ H H~N o H s ~ 0 ROPOJ O - 0 I I -0 O=P-O- I OR' o II ROiO~N) -0 U N CH(j "H s -L o H R I O=P-O- I OR' o II ROiOUO H -0 00 "H~ o H R I O=P-O- I OR' ow ----+ o II 0 ROloJr=!H H H 0- I O=P-O- I OR' Figure 8.19 (A) The structure of bleomycin A 2 . (B) The crystallographically determined structure 98 of a copper derivative of bleomycin, P3A. (C) A scheme to generate "activated bleomycin." (D) The proposed mechanism of action of activated Fe-bleomycin. [499]
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500 8/ METAUNUCLEIC-ACID INTERACTIONS possible roles where metal ions may prove advantageous. These remain areas of biochemical focus where the inorganic chemist could make a major contribu- tion. For example, zinc ion appears to be essential to the functioning of both RNA polymerases and DNA topoisomerases. 1 00-102 These multisubunit en- zymes perform quite complex tasks. RNA polymerase must bind site-specifi- cally to its DNA template, bind its nucleotide and primer substrates, and form a new phosphodiester bond in elongating the growing RNA. Two zinc ions appear to be involved. One may be involved in orienting the nucleotide sub- strate, and the other structurally in template recognition. It would not be sur- prising, however-indeed, it might be advantageous-if one or both metal ions also participated in the polymerization step. Our mechanistic understanding of how topoisomerases function is even more cursory. These complex enzymes
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