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DNA cross‐link induced by trans ‐4‐hydroxynonenal
Author(s) -
Huang Hai,
Kozekov Ivan D.,
Kozekova Albena,
Wang Hao,
Lloyd R. Stephen,
Rizzo Carmelo J.,
Stone Michael P.
Publication year - 2010
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20599
Subject(s) - diastereomer , chemistry , adduct , hemiacetal , stereochemistry , aldehyde , dna , deoxyguanosine , dna adduct , biochemistry , organic chemistry , catalysis
Trans −4‐Hydroxynonenal (HNE) is a peroxidation product of ω−6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1, N 2 ‐dG adducts. The adduct of (6 S ,8 R ,11 S ) stereochemistry forms interstrand N 2 ‐dG: N 2 ‐dG cross‐links in the 5′‐CpG‐3′ sequence. It has been compared with the (6 R ,8 S ,11 R ) adduct, incorporated into 5′‐d(GCTAGCXAGTCC)‐3' · 5'‐d(GGACTCGCTAGC)‐3′, containing the 5′‐CpG‐3′ sequence (X = HNE‐dG). Both adducts rearrange in DNA to N 2 ‐dG aldehydes. These aldehydes exist in equilibrium with diastereomeric cyclic hemiacetals, in which the latter predominate at equilibrium. These cyclic hemiacetals mask the aldehydes, explaining why DNA cross‐linking is slow compared to related 1, N 2 ‐dG adducts formed by acrolein and crotonaldehyde. Both the (6 S ,8 R ,11 S ) and (6 R ,8 S ,11 R ) cyclic hemiacetals are located within the minor groove. However, the (6 S ,8 R ,11 S ) cyclic hemiacetal orients in the 5′‐direction, while the (6 R ,8 S ,11 R ) cyclic hemiacetal orients in the 3′‐direction. The conformations of the diastereomeric N 2 ‐dG aldehydes, which are the reactive species involved in DNA cross‐link formation, have been calculated using molecular mechanics methods. The (6 S ,8 R ,11 S ) aldehyde orients in the 5′‐direction, while the (6 R ,8 S ,11 R ) aldehyde orients in the 3′‐direction. This suggests a kinetic basis to explain, in part, why the (6 S ,8 R ,11 S ) HNE adduct forms interchain cross‐links in the 5′‐CpG‐3′ sequence, whereas (6 R ,8 S ,11 R ) HNE adduct does not. The presence of these cross‐links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease. Environ. Mol. Mutagen., 2010. © 2010 Wiley‐Liss, Inc.