title: DNA cleavage by copper-ATCUN complexes. Factors influencing cleavage mechanism and linearization of dsDNA.
abstract: The reactivity of two [peptide-Cu] complexes ([GGH-Cu](-) and [KGHK-Cu](+)) toward DNA cleavage has been quantitatively investigated. Neither complex promoted hydrolytic cleavage, but efficient oxidative cleavage was observed in the presence of a mild reducing agent (ascorbate) and dioxygen. Studies with scavengers of ROS confirmed hydrogen peroxide to be an obligatory diffusible intermediate. While oxidative cleavage of DNA was observed for Cu(2+)(aq) under the conditions used, the kinetics of cleavage and reaction products/pathway were distinct from those displayed by [peptide-Cu] complexes. DNA cleavage chemistry is mediated by the H(2)O-dependent pathway following C-4'H abstraction from the minor groove. Such a cleavage path also provides a ready explanation for the linearization reaction promoted by [KGHK-Cu](+). Kinetic activities and reaction pathways are compared to published results on other chemical nucleases. Both [peptide-Cu] complexes were found to display second-order kinetics, with rate constants k(2) approximately 39 and 93 M(-1) s(-1) for [GGH-Cu](-) and [KGHK-Cu](+), respectively. Neither complex displayed enzyme-like saturation behavior, consistent with the relatively low binding affinity and residence time expected for association with dsDNA, and the absence of a prereaction complex. However, the intrinsic activity of each is superior to other catalyst systems, as determined from relative k(2) or k(cat)/K(m) values. Linearization of DNA was observed for [KGHK-Cu](+) relative to [GGH-Cu](-), consistent with the increased positive charge and longer residency time on dsDNA.
authors.affiliation: Evans Laboratory of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: J A
authors.initials: JA
authors.lastname: Cowan
mesh_terms: D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004355:Drug Stability; D007700:Kinetics; D008667:Metalloproteins / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction
chemical_list: D008667:Metalloproteins; D009842:Oligopeptides; D003300:Copper; D004247:DNA