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Enzymatic Activation of DNA Cleavage by Dynemicin A and Synthetic Analogs

Myers, Andrew G. and Kort, Michael E. and Cohen, Scott B. and Tom, Norma J. (1997) Enzymatic Activation of DNA Cleavage by Dynemicin A and Synthetic Analogs. Biochemistry, 36 (13). pp. 3903-3908. ISSN 0006-2960. https://resolver.caltech.edu/CaltechAUTHORS:20170919-145628362

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Abstract

Dynemicin A (1), a member of the enediyne family of natural products, binds to double-stranded DNA (K_B ∼ 10^4 M^(-1)) and in the presence of millimolar concentrations of a reducing cofactor such as NADPH or GSH reacts to cleave DNA. In this work, we show that the two flavin-based enzymes ferredoxin−NADP^+ reductase and xanthine oxidase catalyze the reductive activation of 1 by NADPH and NADH, respectively. The enzyme-catalyzed reductive activation of 1 leads to more rapid and efficient cleavage of DNA, even with 10−20-fold lower concentrations of the stoichiometric reductant. Significantly, the enzymatic systems are also found to activate the tight-binding (K_B ≥ 10^6 M^(-1)) synthetic dynemicin analogs 3 and 5 toward DNA cleavage. These same analogs do not undergo reductive activation with NADPH or NADH alone, where evidence has been obtained to support the proposal that the DNA-bound drugs are protected from reductive activation. The new enzymatic activation processes described may have important implications for chemistry occurring with 1 and synthetic analogs in vivo, as well as for the future development of dynemicin-based anticancer agents.


Item Type:Article
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https://doi.org/10.1021/bi962976nDOIArticle
http://pubs.acs.org/doi/abs/10.1021/bi962976nPublisherArticle
Additional Information:© 1997 American Chemical Society. Received December 4, 1996; Revised Manuscript Received January 28, 1997. Publication Date (Web): April 1, 1997. This research was supported by National Institutes of Health Grant CA47148 and a National Science Foundation postdoctoral fellowship to M.E.K. We thank William A. Greenberg, Susanne E. Swalley, Jason W. Szewczyk, and John W. Trauger of the Dervan research group for helpful discussions during the course of this work.
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Funding AgencyGrant Number
NIHCA47148
NSF Postdoctoral FellowshipUNSPECIFIED
Issue or Number:13
Record Number:CaltechAUTHORS:20170919-145628362
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170919-145628362
Official Citation:Enzymatic Activation of DNA Cleavage by Dynemicin A and Synthetic Analogs. Andrew G. Myers, Michael E. Kort, Scott B. Cohen, and Norma J. Tom. Biochemistry 1997 36 (13), 3903-3908. DOI: 10.1021/bi962976n
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:81586
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:19 Sep 2017 22:04
Last Modified:03 Oct 2019 18:44

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