title: A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4.
abstract: Previous studies have established that 4-hydroxy-2-nonenal is a lipid hydroperoxide-derived aldehydic bifunctional electrophile that reacts with DNA and proteins. However, it has now been recognized that 4-oxo-2-nonenal is also a major product of lipid hydroperoxide decomposition. Furthermore, 4-oxo-2-nonenal is more reactive than 4-hydroxy-2-nonenal toward the DNA-bases 2'-deoxyguanosine, 2'-deoxyadenosine, and 2'-deoxycytidine and proteins. The formation of 4-oxo-2-nonenal can be induced through vitamin C-mediated or transition metal ion-mediated homolytic decomposition of polyunsaturated omega-3 lipid hydroperoxides such as 13(S)-hydroperoxyoctadecadienoic acid. We have discovered that synthetic 4-oxo-nonenal or 4-oxo-2-nonenal-generated from 13(S)-hydroperoxyoctadecadienoic acid recognizes the specific amino acid motifs of His75, Ala76, and Lys77 in bovine histone H4. Reaction of the histidine and lysine residues with 4-oxo-2-nonenal results in the formation of a novel cyclic structure within the protein. The cyclic structure incorporates the histidine imidazole ring and a newly formed pyrrole derived from the lysine. The cyclic imidazole-pyrrole derivative that is formed from the small Nalpha-acetyl-His-Ala-Lys peptide exists as a mixture of two atropisomers that inter-convert upon heating. Such lipid hydroperoxide-derived modifications could potentially modulate transcriptional activation in vivo. Furthermore, the ability to synthesize cyclic peptides using 4-oxo-2-nonenal will facilitate the preparation of novel structural analogs with potential biological activity.
authors.affiliation: Center for Cancer Pharmacology, 1254 BRB II/III, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oe
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Arora
authors.forename: Seon Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D002247:Carbon Isotopes; D002417:Cattle; D003500:Cyclization; D003903:Deuterium; D006639:Histidine / Q000737:chemistry; D006657:Histones / Q000737:chemistry*; D008054:Lipid Peroxides / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D002247:Carbon Isotopes; D006657:Histones; D008054:Lipid Peroxides; D010456:Peptides, Cyclic; D006639:Histidine; D003903:Deuterium; D008239:Lysine