3'-Formyl phosphate-ended DNA: high-energy intermediate in antibiotic-induced DNA sugar damage
Under anaerobic conditions where the nitroaromatic radiation-sensitizer misonidazole substitutes for dioxygen, DNA strand breakage (gaps with phosphate residues at each end) by the nonprotein chromophore of the antitumor antibiotic neocarzinostatin (NCS-Chrom) is associated with the generation of a reactive form of formate from the C-5' of deoxyribose of thymidylate residues. Such lesions account for a minority (10-15%) of the strand breakage found in the aerobic reaction without misonidazole. Amino-containing nucleophiles such as tris(hydroxymethyl)aminomethane (Tris) and hydroxylamine act as acceptors for the activated formate. The amount of (/sup 3/H)formyl hydroxamate produced from DNA labeled with (5'-/sup 3/H)thymidine is comparable to the spontaneously released thymine. During the course of the reaction, misonidazole undergoes a DNA-dependent reduction and subsequent conjugation with glutathione used to activate NCS-Chrom. From these and earlier results, the authors propose a possible mechanism in which the carbon-centered radical formed at C-5' by hydrogen atom abstraction by thiol-activated NCS-Chrom reacts anaerobically with misonidazole to form a nitroxyl-radical-adduct intermediate, which fragments to produce an oxy radical at C-5'. ..beta..-fragmentation results in cleavage between C-5' and C-4' with the generation of 3'-formyl phosphate-ended DNA. A similar mechanism, involving dioxygen addition, is probably responsible for the 10-15% DNA gap formation in the aerobic reaction.
- Research Organization:
- Harvard Medical School, Boston, MA (USA)
- OSTI ID:
- 6936091
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 84:20; ISSN PNASA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
AZINES
AZOLES
BIOLOGICAL EFFECTS
CARBON 14 COMPOUNDS
CHROMATOGRAPHY
DNA
DRUGS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
MISONIDAZOLE
MOLECULAR STRUCTURE
NEOCARCINOSTATIN
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIMIDINES
RADIOMIMETIC DRUGS
RADIOSENSITIZERS
RIBOSIDES
SEPARATION PROCESSES
STRAND BREAKS
THIN-LAYER CHROMATOGRAPHY
THYMIDINE
TRACER TECHNIQUES
TRITIUM COMPOUNDS