A Novel Lipid Hydroperoxide-derived Cyclic Covalent Modification

In this paper we learn that that 4-hydroxy-2- nonenal (a lipid hydroperoxide-derived aldehydic bifunctional electrophile) reacts with DNA and proteins and furthermore the authors observe that 4-oxo- 2-nonenal is also a major product of lipid hydroperoxide decomposition. Moreover, 4-oxo-2-nonenal appears to be more reactive than 4-hydroxy-2-nonenal toward the DNAbases 2’-deoxyguanosine, 2’-deoxyadenosine, and 2’-deoxycytidine it is pointed out that homolytic decomposition of polyunsaturated lipid hydroperoxides such as 13(S)-hydroperoxyoctadecadienoic acid, can lead to formation of 4-oxo-2-nonenal. Very importantly the authors report that either synthetic 4-oxo-nonenal or 4-oxo-2-nonenal- generated from 13(S)-hydroperoxyoctadecadienoic can interact and recognize with His75, Ala76, and Lys77 of bovine histone H4. The amino acid residues histidine and lysine react with 4-oxo-2-nonenal to form a new cyclic structure within the protein. Such cyclic structures integrate the histidine imidazole ring with the pyrrole ring derived from lysine. This cyclic imidazole-pyrrole derivative formed from N-acetyl-His-Ala-Lys peptide can be found as a mixture of two atropisomers that interchange upon heating. It is conceived that this lipid hydroperoxide moeities may be able to modulate transcriptional activation in vivo. Novel chemical synthesis of structural analogs of these cyclic peptides could generate new compounds with improved biological activity.