Formation and structure of a novel enediyne-RNA base covalent adduct.
The structure of an unusual covalent adduct formed by thiol-activated neocarzinostatin chromophore (NCS-chrom) and a RNA-DNA hybrid having an overhang of four unpaired residues at the 3'-end of the RNA strand has been elucidated by MS and NMR spectroscopic analyses. Unlike previously characterized adducts formed by NCS-chrom on the sugar residue of the DNA target, this adduct has been found to be on one of the uracil bases in the RNA overhang. Covalent linkage is between C-6 of the post-activated NCS-chrom and C-5 of the uracil. A novel mechanism involving adduction of the NCS-chrom C-6 radical, generated by 2-mercaptoethanol activation, to C-5 of the uracil at the U9 position of the RNA 11-mer, oxidation by dioxygen, reduction by the thiol, and subsequent dehydration is proposed for adduct formation.
Jiang
Zhi-Hong
ZH
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Hwang
Geum-Sook
GS
Xi
Zhen
Z
Goldberg
Irving H
IH
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D008623:Mercaptoethanol / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011743:Pyrimidines / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*; D014542:Uridine Monophosphate / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D011743:Pyrimidines; D008623:Mercaptoethanol; D012313:RNA; D014542:Uridine Monophosphate