Cited by 313Antioxidant Activity and Oxidative StressRedox biology and oxidative stressEicosanoids and Hypertension Pharmacology

Two Distinct Pathways of Formation of 4-Hydroxynonenal

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Schneider, Claus, Tallman, Keri A., Porter, Ned A., Brash, Alan R.·2001·Journal of Biological Chemistry

Abstract

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.

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Authors
Schneider, C., Tallman, K. A., Porter, N. A., & Brash, A. R.
Affiliations
Vanderbilt University (US)
Corresponding author
Brash, Alan R.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-06
Volume
276
Issue
24
Pages
20831-20838
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2050057935
Cited by
313
References
30
Citations by year
2026: 8 · 2025: 8 · 2024: 3 · 2023: 10 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 4 · 2017: 12 · 2016: 16 · 2015: 12 · 2014: 12 · 2013: 13 · 2012: 10
FWCI
10.34
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (GM 15431)
  • National Institute of General Medical Sciences (GM 15431, GM-53638, R01GM053638)
Topics
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
4-hydroxynonenal, lipid peroxidation, linoleic acid hydroperoxide, allylic hydrogen abstraction, chiral analysis, 4-hydroxyalkenals
MeSH terms
Aldehyde-Lyases, Aldehydes, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Kinetics, Linoleic Acids, Lipid Peroxides, Lipoxygenase, Recombinant Proteins, Glycine max, Spectrophotometry, Ultraviolet, Stereoisomerism, Vitamin E, Cucurbitaceae

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