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Two Distinct Pathways of Formation of 4-Hydroxynonenal
Open accessAbstract
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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“The abundant diffusible products of lipid peroxidation are chemically reactive aldehydes including malondialdehyde (MDA), acrolein, 4-hydroxy-2-hexenal (4-HHE), and 4-hydroxy-2-nonenal (4-HNE) [57,58].”
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Metadata
- 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
- hybrid
- doi.org
- Licence
- 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 (medical) › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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