4-Hydroxynonenal

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4-Hydroxynonenal
4-hydroxynonenal-Line-Structure.png
4-Hydroxynonenal 3D Balls.png
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
MeSH 4-hydroxy-2-nonenal
PubChem CID
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+ Yes check.svgY
    Key: JVJFIQYAHPMBBX-FNORWQNLSA-N Yes check.svgY
  • 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
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE, ( C 9 H 16 O 2), 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]

Contents

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 lipids containing polyunsaturated omega-6 fatty acids, such as arachidonic and linoleic acids, and of their 15-lipoxygenase metabolites, namely 15-hydroperoxyeicosatetraenoic and 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, [10] [11] and from these latter can be absorbed through the diet. Since 1991, OαβUAs are receiving a great deal of attention because they are being considered as possible causal agents of numerous diseases, such as chronic inflammation, neurodegenerative diseases, adult respiratory distress syndrome, 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 acyl groups entails the potential risk of enriching the food with some OαβUAs at the same time, as has already been detected in some studies carried out in 2007. [14] PUFA-fortified foods available on the market have been increasing since 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 α,β-unsaturated ketone serves as a 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 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 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]

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol, or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives. It occurs when free radicals, specifically reactive oxygen species (ROS), interact with lipids within cell membranes, typically polyunsaturated fatty acids (PUFAs) as they have carbon–carbon double bonds. This reaction leads to the formation of lipid radicals, collectively referred to as lipid peroxides or lipid oxidation products (LOPs), which in turn react with other oxidizing agents, leading to a chain reaction that results in oxidative stress and cell damage.

Glutathione <i>S</i>-transferase Family of enzymes

Glutathione S-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification. The GST family consists of three superfamilies: the cytosolic, mitochondrial, and microsomal—also known as MAPEG—proteins. Members of the GST superfamily are extremely diverse in amino acid sequence, and a large fraction of the sequences deposited in public databases are of unknown function. The Enzyme Function Initiative (EFI) is using GSTs as a model superfamily to identify new GST functions.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

<span class="mw-page-title-main">Malondialdehyde</span> Chemical compound

Malondialdehyde belong to the class of β-dicarbonyls. A colorless liquid, malondialdehyde is a highly reactive compound that occurs as the enol. It is a physiological metabolite, and a marker for oxidative stress.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

Glutamate–cysteine ligase (GCL) EC 6.3.2.2), previously known as γ-glutamylcysteine synthetase (GCS), is the first enzyme of the cellular glutathione (GSH) biosynthetic pathway that catalyzes the chemical reaction:

<span class="mw-page-title-main">GSTA2</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase A2 is an enzyme that in humans is encoded by the GSTA2 gene.

<span class="mw-page-title-main">Aldehyde dehydrogenase 3 family, member A1</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.

<span class="mw-page-title-main">GSTA4</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase A4, also known as GSTA4, is an enzyme which in humans is encoded by the GSTA4 gene.

<span class="mw-page-title-main">Bacterial glutathione transferase</span>

Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification. The primary role of GSTs is to catalyze the conjugation of glutathione (GSH) with the electrophilic centers of a wide variety of molecules. The most commonly known substrates of GSTs are xenobiotic synthetic chemicals. There are also classes of GSTs that utilize glutathione as a cofactor rather than a substrate. Often these GSTs are involved in reduction of reactive oxidative species toxic to the bacterium. Conjugation with glutathione receptors renders toxic substances more soluble, and therefore more readily exocytosed from the cell.

Oxytosis/ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Oxytosis/ferroptosis is initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death. Although the connection between iron and lipid peroxidation has been appreciated for years, it was not until 2012 that Brent Stockwell and Scott J. Dixon coined the term ferroptosis and described several of its key features. Pamela Maher and David Schubert discovered the process in 2001 and called it oxytosis. While they did not describe the involvement of iron at the time, oxytosis and ferroptosis are today thought to be the same cell death mechanism.

<span class="mw-page-title-main">13-Hydroxyoctadecadienoic acid</span> Chemical compound

13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE). The production of 13(S)-HODE is often accompanied by the production of its stereoisomer, 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE). The adjacent figure gives the structure for the (S) stereoisomer of 13-HODE. Two other naturally occurring 13-HODEs that may accompany the production of 13(S)-HODE are its cis-trans (i.e., 9E,11E) isomers viz., 13(S)-hydroxy-9E,11E-octadecadienoic acid (13(S)-EE-HODE) and 13(R)-hydroxy-9E,11E-octadecadienoic acid (13(R)-EE-HODE). Studies credit 13(S)-HODE with a range of clinically relevant bioactivities; recent studies have assigned activities to 13(R)-HODE that differ from those of 13(S)-HODE; and other studies have proposed that one or more of these HODEs mediate physiological and pathological responses, are markers of various human diseases, and/or contribute to the progression of certain diseases in humans. Since, however, many studies on the identification, quantification, and actions of 13(S)-HODE in cells and tissues have employed methods that did not distinguish between these isomers, 13-HODE is used here when the actual isomer studied is unclear.

<span class="mw-page-title-main">Reactive carbonyl species</span>

Reactive carbonyl species (RCS) are molecules with highly reactive carbonyl groups, and often known for their damaging effects on proteins, nucleic acids, and lipids. They are often generated as metabolic products. Important RCSs include 3-deoxyglucosone, glyoxal, and methylglyoxal. RCSs react with amines and thiol groups leading to advanced glycation endproducts (AGEs). AGE's are indicators of diabetes.

Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes protect living cells by making bonds within the delicate molecules inside and around cells harder to break. This makes the cells less prone to damage caused by reactive oxygen species (ROS), one of the principal causes of ageing and age-associated diseases. Founded in 2006 by entrepreneurs and scientists with seed funding from private investors, Retrotope is developing a non-antioxidant approach to preventing lipid peroxidation, a detrimental factor in mitochondrial, neuronal, and retinal diseases. The company employs the virtual business model and works in scientific collaboration with more than 80 research groups in universities worldwide.

<span class="mw-page-title-main">Reactive aldehyde species</span>

Reactive aldehyde species (RASP), also known as reactive aldehydes, refer to a class of electrophilic organic aldehyde molecules that are generally toxic or facilitate inflammation. RASP covalently react with amine groups and thiol groups, particularly in proteins. Following threshold amounts of binding to the electrophile-responsive proteome, RASP modify protein function, as has been described with MAP kinase, protein kinase C, and other proteins that potentiate cytokine release and other aspects of inflammation. Binding of RASP to proteins can also lead to NF-kB activation, autoantibody formation, inflammasome activation, and activation of Scavenger Receptor A. RASP are formed via a variety of processes, including oxidation of alcohols, polyamine metabolism and lipid peroxidation. In addition to binding to proteins and other amine or thiol-containing molecules such as glutathione, RASP are metabolized by aldehyde dehydrogenases or aldehyde reductases. Due to the toxicity of RASP, only a small number of genetic mutations in aldehyde dehydrogenases allow for viable offspring, resulting in Sjögren-Larsson Syndrome, Succinic Semi-Aldehyde Dehydrogenase Deficiency, and other rare diseases.

<span class="mw-page-title-main">Isotope effect on lipid peroxidation</span>

Isotope effect is observed when molecules containing heavier isotopes of the same atoms are engaged in a chemical reaction at a slower rate. Deuterium-reinforced lipids can be used for the protection of living cells by slowing the chain reaction of lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, drugs that stop the chain reaction of lipid peroxidation have preventive and therapeutic potential.

References

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  3. ↑ Benedetti, Angelo; Comporti, Mario; Esterbauer, Hermann (1980). "Identification of 4-Hydroxynonenal as a Cytotoxic Product Originating from the Peroxidation of Liver Microsomal Lipids". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 620 (2): 281–296. doi:10.1016/0005-2760(80)90209-X. PMID   6254573.
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  10. ↑ Guillén, M. A. D.; Cabo, N.; Ibargoitia, M. A. L.; Ruiz, A. (2005). "Study of both Sunflower Oil and Its Headspace throughout the Oxidation Process. Occurrence in the Headspace of Toxic Oxygenated Aldehydes". Journal of Agricultural and Food Chemistry. 53 (4): 1093–1101. doi:10.1021/jf0489062. PMID   15713025.
  11. ↑ Zanardi, E.; Jagersma, C. G.; Ghidini, S.; Chizzolini, R. (2002). "Solid Phase Extraction and Liquid Chromatography−Tandem Mass Spectrometry for the Evaluation of 4-Hydroxy-2-nonenal in Pork Products". Journal of Agricultural and Food Chemistry. 50 (19): 5268–5272. doi:10.1021/jf020201h. PMID   12207460.
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  13. ↑ Negre-Salvayre, A.; Auge, N.; Ayala, V.; Basaga, H.; Boada, J.; Brenke, R.; Chapple, S.; Cohen, G.; Feher, J.; Grune, T.; Lengyel, G.; Mann, G. E.; Pamplona, R.; Poli, G.; Portero-Otin, M.; Riahi, Y.; Salvayre, R.; Sasson, S.; Serrano, J.; Shamni, O.; Siems, W.; Siow, R. C. M.; Wiswedel, I.; Zarkovic, K.; Zarkovic, N. (2010). "Pathological aspects of lipid peroxidation". Free Radical Research. 44 (10): 1125–1171. doi:10.3109/10715762.2010.498478. PMID   20836660. S2CID   18342164.
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  20. ↑ Singhal, Sharad S.; Singh, Sharda P.; Singhal, Preeti; Horne, David; Singhal, Jyotsana; Awasthi, Sanjay (2015-12-15). "Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling". Toxicology and Applied Pharmacology . 289 (3): 361–370. doi:10.1016/j.taap.2015.10.006. PMC   4852854 . PMID   26476300.
  21. ↑ Singhal, Sharad S.; Yadav, Sushma; Roth, Cherice; Singhal, Jyotsana (2009-03-01). "RLIP76: A novel glutathione-conjugate and multi-drug transporter". Biochemical Pharmacology . 77 (5): 761–769. doi:10.1016/j.bcp.2008.10.006. PMC   2664079 . PMID   18983828.
  22. ↑ Fenwick, R. Brynmor; Campbell, Louise J.; Rajasekar, Karthik; Prasannan, Sunil; Nietlispach, Daniel; Camonis, Jacques; Owen, Darerca; Mott, Helen R. (2010-08-11). "The RalB-RLIP76 Complex Reveals a Novel Mode of Ral-Effector Interaction". Structure. 18 (8): 985–995. doi:10.1016/j.str.2010.05.013. PMC   4214634 . PMID   20696399.


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