Unraveling the Aflatoxin-FAPY Conundrum: Structural Basis for Differential Replicative Processing of Isomeric Forms of the Formamidopyrimidine-Type DNA Adduct of Aflatoxin B1
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- 作者：Kyle L. Brown ; James Z. Deng ; Rajkumar S. Iyer ; Lalitha G. Iyer ; Markus W. Voehler ; Michael P. Stone ; Constance M. Harris ; Thomas M. Harris
- 刊名：Journal of the American Chemical Society
- 出版年：2006
- 出版时间：November 29, 2006
- 年：2006
- 卷：128
- 期：47
- 页码：15188 - 15199
- 全文大小：291K
- 年卷期：v.128,no.47(November 29, 2006)
- ISSN：1520-5126
文摘
Aflatoxin B1 (AFB) epoxide forms an unstable N7 guanine adduct in DNA. The adduct undergoesbase-catalyzed ring opening to give a highly persistent formamidopyrimidine (FAPY) adduct which existsas a mixture of forms. Acid hydrolysis of the FAPY adduct gives the FAPY base which exists in two separablebut interconvertible forms that have been assigned by various workers as functional, positional, orconformational isomers. Recently, this structural question became important when one of the two majorFAPY species in DNA was found to be potently mutagenic and the other a block to replication [Smela, M.E.; Hamm, M. L.; Henderson, P. T.; Harris, C. M.; Harris, T. M.; Essigmann, J. M. Proc. Natl. Acad. Sci.U.S.A. 2002, 99, 6655-6660]. NMR studies carried out on the AFB-FAPY bases and deoxynucleoside3',5'-dibutyrates now establish that the separable FAPY bases and nucleosides are diastereomeric N5formyl derivatives involving axial asymmetry around the congested pyrimidine C5-N5 bond. Anomerizationof the protected 
hars/beta2.gif" BORDER=0 ALIGN="middle">-deoxyriboside was not observed, but in the absence of acyl protection, both anomerizationand furanosyl 
pyranosyl ring expansion occurred. In oligodeoxynucleotides, two equilibrating FAPYspecies, separable by HPLC, are assigned as anomers. The form normally present in duplex DNA is themutagenic species. It has previously been assigned as the hars/beta2.gif" BORDER=0 ALIGN="middle"> anomer by NMR (Mao, H.; Deng, Z. W.;Wang, F.; Harris, T. M.; Stone, M. P. Biochemistry 1998, 37, 4374-4387). In single-stranded environmentsthe dominant species is the hars/alpha.gif" BORDER=0> anomer; it is a block to replication.
hars/beta2.gif" BORDER=0 ALIGN="middle">-deoxyriboside was not observed, but in the absence of acyl protection, both anomerizationand furanosyl pyranosyl ring expansion occurred. In oligodeoxynucleotides, two equilibrating FAPYspecies, separable by HPLC, are assigned as anomers. The form normally present in duplex DNA is themutagenic species. It has previously been assigned as the hars/beta2.gif" BORDER=0 ALIGN="middle"> anomer by NMR (Mao, H.; Deng, Z. W.;Wang, F.; Harris, T. M.; Stone, M. P. Biochemistry 1998, 37, 4374-4387). In single-stranded environmentsthe dominant species is the hars/alpha.gif" BORDER=0> anomer; it is a block to replication.