4-Hydroxynonenal

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4-Hydroxynonenal


Systematic name	(E)-4-Hydroxy-2-nonenal
Chemical formula	C₉H₁₆O₂
Molecular mass	156.22 g/mol
Density	0.944 g/cm³
Melting point	? °C
Boiling point	? °C
CAS number	[75899–68–2]
SMILES	CCCCCC(O)/C=C/C=O
Disclaimer and references

4-Hydroxynonenal, or trans-4-hydroxy-2-nonenal or 4-HNE or HNE, (C₉H₁₆O₂), is an α,β-unsaturated hydroxyalkenal which is produced by lipid peroxidation in cells. 4-HNE is the primary alpha,beta-unsaturated hydroxyalkenal formed in this process. 4-HNE has 3 reactive groups: an aldehyde, a double-bond at carbon 2, and a hydroxy group at carbon 4.

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.

The first characterization of 4-hydroxynonenal was reported by Esterbauer, et al. in 1991, and since then the amount of research involving this chemical has been steadily increasing, with entire issues of relatively high-impact journals such as Molecular Aspects of Medicine and Free Radical Biology and Medicine devoting volumes to 4-HNE-centered publications.

4-HNE has been hypothesized by several researchers to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.

1 Pathology
2 Detoxification
3 Export
4 References
5 External links

[edit] Pathology

There seems to be a dual influence of 4-HNE on the health of cells: lower intracellular concentrations (in the neighborhood of 0.1-5 micromolar) seem to be beneficial to cells, promoting proliferation, while higher concentrations (in the neighborhood of 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). HNE has been linked in the pathology of several diseases such as Alzheimer's disease, cataract, atherosclerosis, and cancer.

[edit] Detoxification

There are small group of enzymes which are specifically suited to the detoxification and removal of 4-HNE from cells. Within this group are the glutathione S-transferases (GSTs) such as hGSTA4-4 and hGST5.8, aldose reductase, and aldehyde dehydrogenase. These enzymes have low 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 glutathione peptides to 4-hydroxynonenal through a conjugate addition to the alpha-beta unsaturated carbonyl, forming a more water-soluble molecule, GS-HNE. While there are other GSTs capable of this conjugation reaction (notably in the alpha class), these other isoforms are much less efficient and their production is not induced by the stress events which cause the formation of 4-HNE (such as exposure to hydrogen peroxide, ultraviolet light, heat shock, cancer drugs, etc.), as the production of the more specific two isoforms is. This 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.

[edit] 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. 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).

[edit] References

Esterbauer, H., Schaur, R.J., Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Rad Biol Med. 1991 ;11:81-128.
Zarkovic N, Zarkovic K, Schaur R.J., Stolc S, Schlag G, Redl H, Waeg G, Borovic S, Loncaric I, Juric G, Hlavka V. 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor. Life Sci.1999;65:1901-1904.
Zarkovic N. 4-Hydroxynonenal as a bioactive marker of pathopysiological processes. Mol Asp Med, 2003 ; 24: 281-291.
Awasthi YC, Yang Y, Tiwari NK, Patrick B, Sharma A, Li J, Awasthi S. Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases. Free Rad Biol Med. 2004 Sep 1;37(5):607-19.
Sharma R, Brown D, Awasthi S, Yang Y, Sharma A, Patrick B, Saini MK, Singh SP, Zimniak P, Singh SV, Awasthi YC. Transfection with 4-hydroxynonenal-metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells. Eur J Biochem. 2004 May;271(9):1690-701.