Unraveling the aflatoxin-FAPY conundrum: Structural basis for differential replicative processing of isomeric forms of the formamidopyrimidine-type DNA adduct of aflatoxin B1

TOXI 94

Thomas M. Harris, thomas.m.harris@vanderbilt.edu1, Kyle L. Brown, kyle.l.brown@vanderbilt.edu1, James Z. Deng2, Rajkumar S. Iyer, raji@gen-probe.com3, Lalitha G. Iyer, lalithai@gen-probe.com3, Markus W. Voehler, m.voehler@vanderbilt.edu4, Michael P. Stone, michael.p.stone@vanderbilt.edu5, and Constance M. Harris, constance.m.harris@vanderbilt.edu5. (1) Department of Chemistry, Center in Molecular Toxicology and Vanderbilt Institute of Chemical Biology, Vanderbilt University, P.O. Box 1822, Station B, Nashville, TN 37235, (2) Merck Research Laboratories, West Point, PA 19486, (3) Gen-Probe, Inc, 110120 Genetic Center Drive, San Diego, CA 92121, (4) Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, TN, (5) Department of Chemistry, Center in Molecular Toxicology and the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37235
The formamidopyrimidine (FAPY) derived from the guanine N7 adduct of aflatoxin B1 (AFB) epoxide is a highly persistent lesion in DNA and is probably the basis of the potent mutagenicity and carcinogenicity of this mycotoxin. It exists as two separable but interconvertible forms that have been assigned by various workers as functional, positional, or conformational isomers. One of them is potently mutagenic and the other a complete block to replication. Structural studies carried out on AFB-FAPY base, nucleoside, and oligonucleotides define equilibria involving geometrical isomers of the formamide, diastereomers at the congested pyrimidine C5-N5 bond, and anomers of the deoxyribose. In DNA, the chromatographically separable species are assigned as anomers. The beta anomer, which is the exclusive form in duplex DNA, is the mutagenic species. In single-stranded environments, both anomers are present with the alpha anomer predominating. The alpha form is the replication block.

 

General Papers
9:00 AM-11:30 AM, Wednesday, 13 September 2006 Moscone Center -- Room 308, Oral

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Chemical Toxicology

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006