title: DNA cross-link induced by trans-4-hydroxynonenal.
abstract: Trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1,N(2)-dG adducts. The adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence. It has been compared with the (6R,8S,11R) 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 (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals are located within the minor groove. However, the (6S,8R,11S) cyclic hemiacetal orients in the 5'-direction, while the (6R,8S,11R) 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 (6S,8R,11S) aldehyde orients in the 5'-direction, while the (6R,8S,11R) aldehyde orients in the 3'-direction. This suggests a kinetic basis to explain, in part, why the (6S,8R,11S) HNE adduct forms interchain cross-links in the 5'-CpG-3' sequence, whereas (6R,8S,11R) 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.
authors.affiliation: Department of Chemistry, Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Kozekov
authors.forename: Albena
authors.initials: A
authors.lastname: Kozekova
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure
chemical_list: D000447:Aldehydes; D003432:Cross-Linking Reagents; D004247:DNA; C027576:4-hydroxy-2-nonenal