Coronaric acid

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Coronaric acid
Coronaric acid.svg
Names
IUPAC name
8-[3-[(Z)-Oct-2-enyl]oxiran-2-yl]octanoic acid
Other names
9,10-Epoxy-12Z-octadecenoic acid; 9(10)-EpOME
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C18H32O3/c1-2-3-4-5-7-10-13-16-17(21-16)14-11-8-6-9-12-15-18(19)20/h7,10,16-17H,2-6,8-9,11-15H2,1H3,(H,19,20)/b10-7-
    Key: FBUKMFOXMZRGRB-YFHOEESVSA-N
  • CCCCC/C=C\CC1C(O1)CCCCCCCC(=O)O
Properties
C18H32O3
Molar mass 296.451 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Coronaric acid (leukotoxin or leukotoxin A) is a mono-unsaturated, epoxide derivative of the di-saturated fatty acid, linoleic acid (i.e. 9(Z),12(Z) octadecadienoic acid). It is a mixture of the two optically active isomers of 12(Z) 9,10-epoxy-octadecenoic acid. This mixture is also termed 9,10-epoxy-12Z-octadecenoic acid or 9(10)-EpOME [1] and when formed by or studied in mammalians, leukotoxin.

Contents

Occurrence

Coronaric acid is found in the seed oils derived from plants in the sunflower family, such as Helianthus annuus [2] and Xeranthemum annuum. [3]

Coronaric acid is also formed by the cells and tissues of various mammalian (including human) species through the metabolism of linoleic acid by cytochrome P450 (CYP) epoxygenase enzymes. These CYPs (CYP2C9 and probably other CYPs that metabolize polyunsaturated fatty acids to epoxides) metabolize linoleic acid to (+)12S,13R-epoxy-9(Z)-octadecenoic acid and (-)12R,13S-epoxy-9(Z)-octadecenoic acid, i.e. the (+) and (-) epoxy optical isomers of coronaric acid. [4] [5] [6] When studied in this context, the optical isomer mixture is often termed isoleukotoxin. This same CYP epoxygenases concurrently attack linoleic acid at the carbon 9,10 rather than 12,13 double bond of linoleic acid to form a mixture of (+) and (-) epoxy optical isomers viz., 9S,10R-epoxy-12(Z)-octadecenoic and 9R,10S-epoxy-12(Z)-octadecenoic acids. This (+) and (-) optical mixture is often termed vernolic acid when studied in plants and leukotoxin when studied in mammals. [4] [5] [6]

Coronaric acid is found in urine samples from healthy human subjects and increases 3- to 4-fold when these subjects are treated with a salt-loading diet. [5]

Coronaric and vernolic acids also form non-enzymatically when linoleic acid is exposed to oxygen and/or UV radiation as a result of the spontaneous process of autoxidation. [7] This autoxidation complicates studies in that it is often difficult to determine if these epoxy fatty acids identified in linoleic acid-rich plant and mammalian tissues represent actual tissue contents or are artifacts formed during their isolation and detection.

Metabolism

In mammalian tissue, coronaric acid is metabolized to its two corresponding dihydroxy stereoisomers, 12S,13R-dihydroxy-9(Z)-octadecenoic and 12R,13S-dihydroxy-9(Z)-octadecenoic acids, by soluble epoxide hydrolase within minutes of its formation. [8] The metabolism of coronaric acid to these two products, collectively termed isoleukotoxin diols, appears to be critical to coronaric acid's toxicity, i.e. the diols are the toxic metabolites of the non-toxic or far less toxic coronaric acid. [8] [9] [6]

Activities

Toxicities

At very high concentrations, the linoleic acid-derived set of optical isomers, coronaric acid (i.e. isoleukotoxin) possesses toxicity similar to that of other structurally unrelated leukotoxins. It is toxic to leukocytes and other cell types, and when injected into rodents produces multiple organ failure and respiratory distress. [10] [11] [12] [6] These effects appear to be due to its conversion to its dihydroxy counterparts, 9S,10R- and 9R,10S-dihydroxy-12(Z)-octadecenoic acids by soluble epoxide hydrolase. [8] Some studies suggest, but have not yet proven, that isoleukotoxin, acting primarily if not exclusively through its dihydroxy counterparts, is responsible for or contributes to multiple organ failure, the acute respiratory distress syndrome, and certain other cataclysmic diseases in humans (see epoxygenase section on linoleic acid). [11] [13] [9] Vernolic acid (i.e. leukotoxin) shares a similar metabolic fate in being converted by soluble epoxide hydrolase to its dihydroxide counterparts, resluting in the toxic actions of those counterparts.

Other activities

At lower concentrations, isoleukotoxin and its dihydroxy counterparts can protect from the toxic actions cited above that occur at higher concentrations of isoleukotoxin and leukotoxin; they may also share with the epoxides of arachidonic acid, i.e. the epoxyeicosatreienoates (see Epoxyeicosatrienoic acids), anti-hypertension activities. [5]

Related Research Articles

Linoleic acid (LA) is an organic compound with the formula HOOC(CH
2)
7CH=CHCH
2CH=CH(CH
2)
4CH
3. Both alkene groups are cis. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 cis-9,12. A linoleate is a salt or ester of this acid.

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

<span class="mw-page-title-main">Epoxide hydrolase</span> Enzyme that metabolizes compounds containing epoxides

Epoxide hydrolases (EHs), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. Several enzymes possess EH activity. Microsomal epoxide hydrolase, soluble epoxide hydrolase, and the more recently discovered but not as yet well defined functionally, epoxide hydrolase 3 (EH3) and epoxide hydrolase 4 (EH4) are structurally closely related isozymes. Other enzymes with epoxide hydrolase activity include leukotriene A4 hydrolase, Cholesterol-5,6-oxide hydrolase, MEST (gene) (Peg1/MEST), and Hepoxilin-epoxide hydrolase. The hydrolases are distinguished from each other by their substrate preferences and, directly related to this, their functions.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, Soluble epoxide hydrolase (sEH), also termed Epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">CYP1A1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.

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

Vernolic acid is a long chain fatty acid that is monounsaturated and contains an epoxide. It is the R,R-cis epoxide derived from the C12–C13 alkene of linoleic acid. Vernolic acid was first definitively characterized in 1954. It is a major component in vernonia oil, which is produced in abundance by the genera Vernonia and Euphorbia and is a potentially useful biofeedstock.

<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.

<span class="mw-page-title-main">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP2S1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2S1 is a protein that in humans is encoded by the CYP2S1 gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substrate of the CYP epoxylgenases is arachidonic acid. This polyunsaturated fatty acid is metabolized by cyclooxygenases to various prostaglandin, thromboxane, and prostacyclin metabolites in what has been termed the first pathway of eicosanoid production; it is also metabolized by various lipoxygenases to hydroxyeicosatetraenoic acids and leukotrienes in what has been termed the second pathway of eicosanoid production. The metabolism of arachidonic acid to epoxyeicosatrienoic acids by the CYP epoxygenases has been termed the third pathway of eicosanoid metabolism. Like the first two pathways of eicosanoid production, this third pathway acts as a signaling pathway wherein a set of enzymes metabolize arachidonic acid to a set of products that act as secondary signals to work in activating their parent or nearby cells and thereby orchestrate functional responses. However, none of these three pathways is limited to metabolizing arachidonic acid to eicosanoids. Rather, they also metabolize other polyunsaturated fatty acids to products that are structurally analogous to the eicosanoids but often have different bioactivity profiles. This is particularly true for the CYP epoxygenases which in general act on a broader range of polyunsaturated fatty acids to form a broader range of metabolites than the first and second pathways of eicosanoid production. Furthermore, the latter pathways form metabolites many of which act on cells by binding with and thereby activating specific and well-characterized receptor proteins; no such receptors have been fully characterized for the epoxide metabolites. Finally, there are relatively few metabolite-forming lipoxygenases and cyclooxygenases in the first and second pathways and these oxygenase enzymes share similarity between humans and other mammalian animal models. The third pathway consists of a large number of metabolite-forming CYP epoxygenases and the human epoxygenases have important differences from those of animal models. Partly because of these differences, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.

<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acid's (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, Vicinal (chemistry) dihydroxy fatty acids by ubiquitous cellular Soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

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

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

<span class="mw-page-title-main">Epoxide hydrolase 3</span> Protein-coding gene in the species Homo sapiens

Epoxide hydrolase 3 is a protein that in humans is encoded by the EPHX3 gene. It is the third defined isozyme in a set of epoxide hydrolase isozymes, the epoxide hydrolases. This set includes the Microsomal epoxide hydrolase ; the epoxide hydrolase 2 ; and the far less well defined enzymatically, epoxide hydrolase 4. All four enzyme contain an Alpha/beta hydrolase fold suggesting that they have Hydrolysis activity. EH1, EH2, and EH3 have been shown to have such activity in that they add water to epoxides of unsaturated fatty acids to form vicinal cis products; the activity of EH4 has not been reported. The former three EH's differ in subcellular location, tissue expression patterns, substrate preferences, and thereby functions. These functions include limiting the biologically actions of certain fatty acid epoxides, increasing the toxicity of other fatty acid epoxides, and contributing to the metabolism of drugs and other xenobiotics.

References

  1. ↑ "Coronaric acid".
  2. ↑ Mikolajczak, K. L.; Freidinger, R. M.; Smith Jr, C. R.; Wolff, I. A. (1968). "Oxygenated fatty acids of oil from sunflower seeds after prolonged storage". Lipids. 3 (6): 489–94. doi:10.1007/BF02530891. PMID   17805802. S2CID   4028426.
  3. ↑ Powell, R. G.; Smith Jr, C. R.; Wolff, I. A. (1967). "Cis-5,cis-9,cis-12-octadecatrienoic and some unusual oxygenated acids in Xeranthemum annuum seed oil". Lipids. 2 (2): 172–7. doi:10.1007/BF02530918. PMID   17805745. S2CID   3994480.
  4. 1 2 Draper, A. J.; Hammock, B. D. (2000). "Identification of CYP2C9 as a human liver microsomal linoleic acid epoxygenase" (PDF). Archives of Biochemistry and Biophysics. 376 (1): 199–205. doi:10.1006/abbi.2000.1705. PMID   10729206. S2CID   21213904. Archived from the original (PDF) on 2020-01-01.
  5. 1 2 3 4 Konkel, A; Schunck, W. H. (2011). "Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 210–22. doi:10.1016/j.bbapap.2010.09.009. PMID   20869469.
  6. 1 2 3 4 Spector, A. A.; Kim, H. Y. (2015). "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 356–65. doi:10.1016/j.bbalip.2014.07.020. PMC   4314516 . PMID   25093613.
  7. ↑ Sevanian, A; Mead, J. F.; Stein, R. A. (1979). "Epoxides as products of lipid autoxidation in rat lungs". Lipids. 14 (7): 634–43. doi:10.1007/bf02533449. PMID   481136. S2CID   4036806.
  8. 1 2 3 Greene, J. F.; Newman, J. W.; Williamson, K. C.; Hammock, B. D. (2000). "Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase". Chemical Research in Toxicology. 13 (4): 217–26. doi:10.1021/tx990162c. PMID   10775319.
  9. 1 2 Edwards, L. M.; Lawler, N. G.; Nikolic, S. B.; Peters, J. M.; Horne, J; Wilson, R; Davies, N. W.; Sharman, J. E. (2012). "Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion". The Journal of Lipid Research. 53 (9): 1979–86. doi: 10.1194/jlr.P027706 . PMC   3413237 . PMID   22715155.
  10. ↑ Moran, J. H.; Weise, R; Schnellmann, R. G.; Freeman, J. P.; Grant, D. F. (1997). "Cytotoxicity of linoleic acid diols to renal proximal tubular cells". Toxicology and Applied Pharmacology. 146 (1): 53–9. doi:10.1006/taap.1997.8197. PMID   9299596.
  11. 1 2 Greene, J. F.; Hammock, B. D. (1999). "Toxicity of Linoleic Acid Metabolites". Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 4. Advances in Experimental Medicine and Biology. Vol. 469. pp. 471–7. doi:10.1007/978-1-4615-4793-8_69. ISBN   978-1-4613-7171-7. PMID   10667370.
  12. ↑ Linhartová, I; Bumba, L; Mašín, J; Basler, M; Osička, R; Kamanová, J; Procházková, K; Adkins, I; Hejnová-Holubová, J; Sadílková, L; Morová, J; Sebo, P (2010). "RTX proteins: A highly diverse family secreted by a common mechanism". FEMS Microbiology Reviews. 34 (6): 1076–112. doi:10.1111/j.1574-6976.2010.00231.x. PMC   3034196 . PMID   20528947.
  13. ↑ Zheng, J; Plopper, C. G.; Lakritz, J; Storms, D. H.; Hammock, B. D. (2001). "Leukotoxin-diol: A putative toxic mediator involved in acute respiratory distress syndrome". American Journal of Respiratory Cell and Molecular Biology. 25 (4): 434–8. doi:10.1165/ajrcmb.25.4.4104. PMID   11694448. S2CID   27194509.
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