4-Hydroxynonenal

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4-Hydroxynonenal
Skeletal formula of 4-hydroxynonenal ((2E)-2-en)
Skeletal formula of 4-hydroxynonenal ((2E)-2-en)
Names
Preferred IUPAC name
4-Hydroxynon-2-enal[1]
Other names
4-Hydroxy-2-nonenal
Identifiers
3D model (
JSmol
)
4660015 (2E,4R)
ChEBI
ChEMBL
ChemSpider
IUPHAR/BPS
MeSH 4-hydroxy-2-nonenal
UNII
  • InChI=1S/C9H16O2/c1-2-3-4-6-9(11)7-5-8-10/h5,7-9,11H,2-4,6H2,1H3/b7-5+ checkY
    Key: JVJFIQYAHPMBBX-FNORWQNLSA-N checkY
  • InChI=1/C9H16O2/c1-2-3-4-6-9(11)7-5-8-10/h5,7-9,11H,2-4,6H2,1H3/b7-5+
    Key: JVJFIQYAHPMBBX-FNORWQNLBE
SMILES
  • CCCCCC(O)C=CC=O
Properties
C9H16O2
Molar mass 156.225 g·mol−1
Density 0.944 g⋅cm−3
Boiling point 125–127 °C (257–261 °F; 398–400 K) 2 torr
log P 1.897
Acidity (pKa) 13.314
Basicity (pKb) 0.683
Related compounds
Related alkenals
 Glucic acid
Malondialdehyde
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE, (C9H16O2), is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues, and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction, due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.[2]

Early identification and characterization of 4-hydroxynonenal was reported by Esterbauer, et al.,[3] who also obtained the same compound synthetically.[4] The topic has since been often reviewed,[5] and one source describes the compound as "the most studied LPO (lipid peroxidation) product with pleiotropic capabilities".[6]

Synthesis

4-Hydroxynonenal is generated in the oxidation of

13-hydroperoxyoctadecadienoic acids.[7] Although they are the most studied ones, in the same process other oxygenated α,β-unsaturated aldehydes (OαβUAs) are generated also, which can also come from omega-3 fatty acids, such as 4-oxo-trans-2-nonenal, 4-hydroxy-trans-2-hexenal, 4-hydroperoxy-trans-2-nonenal and 4,5-epoxy-trans-2-decenal
.

Protein adducts

4-HNE can attach to proteins via a Michael addition reaction, which can target cysteine, histidine or lysine, or through the formation of a Schiff base, which can target arginine or lysine.[6]

The lysine adduct ((4-HNE)-lysine or 4-hydroxynonenallysine) has been referred to as an "oxidation-specific epitope" and a lipid oxidation "degradation product".[8][9] It is generated by the oxidative modification of low-density lipoprotein through the direct addition of carbonyl groups from 4-HNE onto lysine.[8][9]

Pathology

These compounds can be produced in cells and tissues of living organisms or in foods during processing or storage,

atherogenesis, diabetes and different types of cancer.[12]

There seems to be a dual and hormetic action of 4-HNE on the health of cells: lower intracellular concentrations (around 0.1-5

micromolar) seem to be beneficial to cells, promoting proliferation, differentiation, antioxidant defense and compensatory mechanism, while higher concentrations (around 10-20 micromolar) have been shown to trigger well-known toxic pathways such as the induction of caspase enzymes, the laddering of genomic DNA, the release of cytochrome c from mitochondria, with the eventual outcome of cell death (through both apoptosis and necrosis, depending on concentration)[citation needed]. HNE has been linked to the pathology of several diseases such as Alzheimer's disease, cataract, atherosclerosis, diabetes and cancer.[13]

The increasing trend to enrich foods with polyunsaturated

epidemiological and clinical researches have revealed possible effects of PUFA on brain development and curative and/or preventive effects on cardiovascular disease.[15][16] However, PUFA are very labile and easily oxidizable, thus the maximum beneficial effects of PUFA supplements may not be obtained if they contain significant amounts of toxic OαβUAs, which as commented on above, are being considered as possible causal agents of numerous diseases.[17]

Special attention must also be paid to cooking oils used repeatedly in catering and households because in those processes very high amounts of OαβUAs are generated and they can be easily absorbed through the diet.[18]

4-HNE has two reactive groups: the conjugated aldehyde and the C=C double-bond, and the hydroxy group at carbon 4. The

Michael acceptor
, adding thiols to give thioether adducts.

A small group of enzymes are specifically suited to the detoxification and removal of 4-HNE from cells. Within this group are the

Km
values for HNE catalysis and together are very efficient at controlling the intracellular concentration, up to a critical threshold amount, at which these enzymes are overwhelmed and cell death is inevitable.

Glutathione S-transferases hGSTA4-4 and hGST5.8 catalyze the conjugation of

heat shock
, cancer drugs, etc.), as the production of the more specific two isoforms is. This result strongly suggests that hGSTA4-4 and hGST5.8 are specifically adapted by human cells for the purpose of detoxifying 4-HNE to abrogate the downstream effects which such a buildup would cause.

Increased activity of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to have a protective effect against

cardiac ischemia in animal models, and the postulated mechanism given by the investigators was 4-hydroxynonenal metabolism.[19]

Export

GS-HNE is a potent inhibitor of the activity of glutathione S-transferase, and therefore must be shuttled out of the cell to allow conjugation to occur at a physiological rate.[20] Ral-interacting GTPase activating protein (RLIP76, also known as Ral-binding protein 1), is a membrane-bound protein which has high activity towards the transport of GS-HNE from the cytoplasm to the extracellular space. This protein accounts for approximately 70% of such transport in human cell lines, while the remainder appears to be accounted for by Multidrug Resistance Protein 1 (MRP1).[21][22]

References

  1. ^ "AC1L1C0X – Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 25 March 2005. Identification and Related Records. Retrieved 13 October 2011.
  2. PMID 15288119
    .
  3. PMID 6254573
    .
  4. doi:10.1007/BF01167162
    .
  5. PMID 24999379
    .
  6. ^
    PMID 37107229
    – via MDPI.
  7. S2CID 6062445
    .
  8. ^
    PMID 7511933
    .
  9. ^
    PMID 20521848
    .
  10. PMID 15713025
    .
  11. PMID 12207460
    .
  12. PMID 12893006
    .
  13. S2CID 18342164
    .
  14. S2CID 9185110
    .
  15. PMID 33918517
    .
  16. S2CID 1420490
    .
  17. ISBN 9780128018279
    . Retrieved 18 April 2018 – via Google Books.
  18. S2CID 85213700
    .
  19. PMID 18787169
    .
  20. PMID 26476300
    .
  21. PMID 18983828
    .
  22. PMID 20696399
    .


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