Effect of ring size on conformations of aromatic amine-DNA adducts

The aniline-C8 guanine adduct resides in the B-DNA major groove

Robert Shapiro, Stephen Ellis, Brian E. Hingerty, Suse Broyde

Research output: Contribution to journalArticle

Abstract

While the one-ring amine aniline (AN) has only slight genetic activity, the polycyclic aromatic amines 2-aminofluorene (AF) and 1-aminopyrene (AP) are significant mutagens and carcinogens. Moreover, the bulkier AP is more mutagenic per adduct than AF in the tetracycline-resistance gene of plasmid pBR322 [Melchior et al. (1994) Carcinogenesis 15, 889]. To elucidate possible conformational origins of the differing mutagenic effects of these three adducts, which may stem from their differing ring sizes, we have examined their conformations in two mutation-susceptible sequences from the above gene: TTGAG*GCCG (sequence I) and GAATG*GTGC (sequence II), where G* = C8- modified guanine. No experimental high-resolution NMR data are yet available for the aniline adduct in a DNA duplex. Minimized potential energy calculations were carried out, using the molecular mechanics program DUPLEX to explore the conformation space of these adducts. In the case of AN, a relatively unperturbed B-DNA helix with the amine in the major groove was strongly favored in both sequences. In the case of AF- and AP-modified DNA, however, several differing conformations were competitive in energy. They included major groove structures, as well as conformations with syn-modified guanine and the polycyclic amine in the minor groove, or the amine rings intercalated into the helix with displacement of the modified guanine, in overall harmony with high-resolution NMR solution structures. Thus, aniline distorts DNA structure to a lesser extent than larger aromatic amine ring systems, since a number of different conformations are energetically feasible and have been observed for the larger systems. This result may be relevant to their enhanced mutagenicity and their repair propensity, in contrast to aniline's low mutagenic effect.

Original languageEnglish (US)
Pages (from-to)335-341
Number of pages7
JournalChemical Research in Toxicology
Volume11
Issue number4
DOIs
StatePublished - 1998

Fingerprint

B-Form DNA
DNA Adducts
Guanine
Amines
Conformations
DNA
Genes
Nuclear magnetic resonance
Tetracycline Resistance
Molecular mechanics
Mutagens
Aniline
Potential energy
Tetracycline
Mechanics
Carcinogens
aniline
Carcinogenesis
Plasmids
Repair

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Effect of ring size on conformations of aromatic amine-DNA adducts : The aniline-C8 guanine adduct resides in the B-DNA major groove. / Shapiro, Robert; Ellis, Stephen; Hingerty, Brian E.; Broyde, Suse.

In: Chemical Research in Toxicology, Vol. 11, No. 4, 1998, p. 335-341.

Research output: Contribution to journalArticle

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