Characterization of Bis(levuglandinyl) Urea Derivatives as Products of the Reaction between Prostaglandin H2 and Arginine

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Abstract
Levuglandins are γ-keto aldehydes formed by rearrangement of prostaglandin (PG) H2 in aqueous solution. Levuglandins are highly reactive with primary amines. We had previously characterized adducts formed after reaction of levuglandin E2 (LGE2) or PGH2 with lysine. In this study, we assessed whether reaction of PGH2 with arginine yielded covalent adducts. Using Nα-acetylarginine and both PGH2 and synthetic LGE2, we discovered a novel series of levuglandinyl adducts derived from reaction of two levuglandin moieties with the guanidino group of arginine. Subsequent spontaneous hydrolysis of the adducted amino acid yields bis(levuglandinyl) urea and the corresponding ornithine residue. Using liquid chromatography tandem mass spectrometry, we characterized the molecular structure of these novel adducts and demonstrated their formation after coincubation of PGH2 with synthetic peptides and proteins. The soluble characteristic of these molecules provides a potential strategy for development of biological markers of lipid modification of proteins following cyclooxygenase activity or lipid peroxidation.