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-ketoaldehydes (isolevuglandins) and characterization of their protein adducts
* Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee, 37232-6602, USA; and
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
1Correspondence: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA. E-mail: jack.roberts{at}mcmail.vanderbilt.edu
The bicyclic endoperoxide prostaglandin (PG) H2
undergoes nonenzymatic rearrangement not only to PGE2 and
PGD2, but also to levuglandins (LG) E2 and
D2, which are highly reactive 
-ketoaldehydes.
Isoprostanes (IsoPs) are PG-like compounds that are produced by
nonenzymatic peroxidation of arachidonic acid. PGH2-like
endoperoxides are intermediates in this pathway. Therefore, we explored
whether the IsoP endoperoxides also undergo rearrangement to form
IsoLGs. Oxidation of arachidonic acid in vitro resulted
in the formation of abundant quantities of compounds that were
established to be IsoLGs by using mass spectrometric analyses. However,
the formation of IsoLGs could not be detected in biological systems
subjected to an oxidant stress. We hypothesized that this was due to
extremely rapid adduction of IsoLGs to proteins. This notion was
supported by the finding that LGE2 adducted to albumin at a
rate that exceeded that of 4-hydroxynonenal by several orders of
magnitude: >50% of LGE2 had adducted within 20 s. We
therefore undertook to characterize the nature of LG adducts. Using
liquid chromatography electrospray tandem mass spectrometry, we
established that LGs form oxidized pyrrole adducts (lactams and
hydroxylactams) with the 
-amino group of lysine. Oxidation of low
density lipoprotein resulted in readily detectable IsoLG adducts on
apolipoprotein B after enzymatic digestion of the protein to individual
amino acids. These studies identify a novel class of ketoaldehydes
produced by the IsoP pathway that form covalent protein adducts at a
rate that greatly exceeds that of other known aldehyde products of
lipid peroxidation. Elucidation of the nature of the adducts formed by
IsoLGs provides the basis to explore the formation of IsoLGs in
vivo and investigate the potential biological ramifications of
their formation in settings of oxidant injury.—Roberts, L. J.,
II, Salomon, R. G., Morrow, J. D., Brame, C. J. New
developments in the isoprostane pathway: identification of novel highly
reactive -ketoaldehydes (isolevuglandins) and characterization of
their protein adducts.
Key Words: free radical • oxidant injury • lipid peroxidation • aldehyde
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  E. POLIAKOV, M.-L. BRENNAN, J. MACPHERSON, R. ZHANG, W. SHA, L. NARINE, R. G. SALOMON, and S. L. HAZEN Isolevuglandins, a novel class of isoprostenoid derivatives, function as integrated sensors of oxidant stress and are generated by myeloperoxidase in vivo FASEB J, December 1, 2003; 17(15): 2209 - 2220. [Abstract] [Full Text] [PDF]
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