Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals.
The mechanism of formation of 4-hydroxy-2E-nonenal (4-HNE) has been a matter of debate since it was discovered as a major cytotoxic product of lipid peroxidation in 1980. Recent evidence points to 4-hydroperoxy-2E-nonenal (4-HPNE) as the immediate precursor of 4-HNE (Lee, S. H., and Blair, I. A. (2000) Chem. Res. Toxicol. 13, 698-702; Noordermeer, M. A., Feussner, I., Kolbe, A., Veldink, G. A., and Vliegenthart, J. F. G. (2000) Biochem. Biophys. Res. Commun. 277, 112-116), and a pathway via 9-hydroperoxylinoleic acid and 3Z-nonenal is recognized in plant extracts. Using the 9- and 13-hydroperoxides of linoleic acid as starting material, we find that two distinct mechanisms lead to the formation of 4-H(P)NE and the corresponding 4-hydro(pero)xyalkenal that retains the original carboxyl group (9-hydroperoxy-12-oxo-10E-dodecenoic acid). Chiral analysis revealed that 4-HPNE formed from 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13S-HPODE) retains >90% S configuration, whereas it is nearly racemic from 9S-hydroperoxy-10E,12Z-octadecadienoic acid (9S-HPODE). 9-Hydroperoxy-12-oxo-10E-dodecenoic acid is >90% S when derived from 9S-HPODE and almost racemic from 13S-HPODE. Through analysis of intermediates and products, we provide evidence that (i) allylic hydrogen abstraction at C-8 of 13S-HPODE leads to a 10,13-dihydroperoxide that undergoes cleavage between C-9 and C-10 to give 4S-HPNE, whereas direct Hock cleavage of the 13S-HPODE gives 12-oxo-9Z-dodecenoic acid, which oxygenates to racemic 9-hydroperoxy-12-oxo-10E-dodecenoic acid; by contrast, (ii) 9S-HPODE cleaves directly to 3Z-nonenal as a precursor of racemic 4-HPNE, whereas allylic hydrogen abstraction at C-14 and oxygenation to a 9,12-dihydroperoxide leads to chiral 9S-hydroperoxy-12-oxo-10E-dodecenoic acid. Our results distinguish two major pathways to the formation of 4-HNE that should apply also to other fatty acid hydroperoxides. Slight ( approximately 10%) differences in the observed chiralities from those predicted in the above mechanisms suggest the existence of additional routes to the 4-hydroxyalkenals.
Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
C
C
Schneider
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Tallman
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Porter
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Brash
D000446:Aldehyde-Lyases / Q000378:metabolism; D000447:Aldehydes / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D019662:Cucurbitaceae / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007700:Kinetics; D008041:Linoleic Acids / Q000737:chemistry* / Q000378:metabolism*; D008054:Lipid Peroxides / Q000737:chemistry* / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013025:Glycine max / Q000201:enzymology; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014810:Vitamin E / Q000737:chemistry
D000447:Aldehydes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D011994:Recombinant Proteins; D014810:Vitamin E; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C049606:9-hydroperoxy-11,12-octadecadienoic acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D000446:Aldehyde-Lyases; C054540:hydroperoxide lyase; C027576:4-hydroxy-2-nonenal