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J Biol Chem, Vol. 274, Issue 19, 13139-13146, May 7, 1999

Identification of Extremely Reactive -Ketoaldehydes (Isolevuglandins) as Products of the Isoprostane Pathway and Characterization of Their Lysyl Protein Adducts

Cynthia J. Brame, Robert G. Salomon^§, Jason D. Morrow, and L. Jackson Roberts II

From the  Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee 37232-6602 and the ^§ Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078

Isoprostanes are prostaglandin-like compounds produced by non-enzymatic peroxidation of arachidonic acid. The cyclooxygenase-derived endoperoxide, prostaglandin H₂, can undergo rearrangement to highly reactive -ketoaldehyde secoprostanoids (levuglandin E₂ and D₂). We explored whether isoprostane endoperoxide intermediates also rearrange to levuglandin-like compounds (isolevuglandins). Formation of a series of isolevuglandins during oxidation of arachidonic acid in vitro was established utilizing a number of mass spectrometric analyses. However, these compounds could not be detected in free form in protein-containing biological systems, which we hypothesized was due to extremely rapid adduction to amines. This was supported by the finding that >60% of levuglandin E₂ adducted to albumin within 20 s, whereas ~50% of 4-hydroxynonenal still remained unadducted after 1 h. By utilizing electrospray tandem mass spectrometry, we established that these compounds form oxidized pyrrole adducts (lactams and hydroxylactams) with lysine. Formation of isolevuglandin-lysine adducts on apolipoprotein B was readily detected during oxidation of low density lipoprotein following enzymatic digestion of the protein to single amino acids. These studies identify a novel series of extremely reactive products of the isoprostane pathway that rapidly form covalent adducts with lysine residues on proteins. This provides the basis to explore the formation of isolevuglandins in vivo to investigate the potential biological ramifications of their formation in settings of oxidant injury.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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