Epoxyeicosatetraenoic acid

Last updated
Epoxyeicosatetraenoic acid
17,18-epoxyeicosatetraenoic acid.svg
17,18-EEQ
Identifiers
3D model (JSmol)
ChEBI
PubChem CID
  • 5,6-EEQ:InChI=1S/C20H30O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-15-18-19(23-18)16-14-17-20(21)22/h3-4,6-7,9-10,12-13,18-19H,2,5,8,11,14-17H2,1H3,(H,21,22)/b4-3-,7-6-,10-9-,13-12-
    Key: AKBOADNSBQNXRS-LTKCOYKYSA-N
  • 8,9-EEQ:InChI=1S/C20H30O3/c1-2-3-4-5-6-7-8-9-12-15-18-19(23-18)16-13-10-11-14-17-20(21)22/h3-4,6-7,9-10,12-13,18-19H,2,5,8,11,14-17H2,1H3,(H,21,22)/b4-3-,7-6-,12-9-,13-10-
    Key: YKIOHMXLFWMWKD-JJUYGIQRSA-N
  • 11,12-EEQ:InChI=1S/C20H30O3/c1-2-3-4-5-9-12-15-18-19(23-18)16-13-10-7-6-8-11-14-17-20(21)22/h3-4,6,8-10,12-13,18-19H,2,5,7,11,14-17H2,1H3,(H,21,22)/b4-3-,8-6-,12-9-,13-10-
    Key: QHOKDYBJJBDJGY-BVILWSOJSA-N
  • 14,15-EEQ:InChI=1S/C20H30O3/c1-2-3-12-15-18-19(23-18)16-13-10-8-6-4-5-7-9-11-14-17-20(21)22/h3-4,6-7,9-10,12-13,18-19H,2,5,8,11,14-17H2,1H3,(H,21,22)/b6-4-,9-7-,12-3-,13-10-
    Key: RGZIXZYRGZWDMI-QXBXTPPVSA-N
  • 17,18-EEQ:InChI=1S/C20H30O3/c1-2-18-19(23-18)16-14-12-10-8-6-4-3-5-7-9-11-13-15-17-20(21)22/h3,5-6,8-9,11-12,14,18-19H,2,4,7,10,13,15-17H2,1H3,(H,21,22)/b5-3-,8-6-,11-9-,14-12-
    Key: GPQVVJQEBXAKBJ-JPURVOHMSA-N
  • 5,6-EEQ:CC/C=C\C/C=C\C/C=C\C/C=C\CC1C(O1)CCCC(=O)O
  • 8,9-EEQ:CC/C=C\C/C=C\C/C=C\CC1C(O1)C/C=C\CCCC(=O)O
  • 11,12-EEQ:CC/C=C\C/C=C\CC1C(O1)C/C=C\C/C=C\CCCC(=O)O
  • 14,15-EEQ:CC/C=C\CC1C(O1)C/C=C\C/C=C\C/C=C\CCCC(=O)O
  • 17,18-EEQ:CCC1C(O1)C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Properties
C20H30O3
Molar mass 318.457 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Epoxyeicosatetraenoic acids (EEQs or EpETEs) 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. [1] [2]

Contents

Structure

EPA is a straight-chain, 20 carbon omega-3 fatty acid containing cis (see Cis–trans isomerism) double bonds between carbons 5 and 6, 8 and 9, 11 and 12, 14 and 15, and 17 and 18; each of these double bonds is designated with the notation Z to indicate its cis configuration in the IUPAC Chemical nomenclature used here. EPA is therefore 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid. Certain cytochrome P450 epoxygenases metabolize EPA by converting one of these double bounds to an epoxide thereby forming one of 5 possible eicosatetraenoic acid epoxide regioisomers (see Structural isomer, section on position isomerism (regioisomerism)). These regioisomers are: 5,6-EEQ (i.e. 5,6-epoxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid), 8,9-EEQ (i.e. 8,9-epoxy-5Z,11Z,14Z,17Z-eicosatetraenoic acid), 11,12-EEQ (i.e. 11,12-epoxy-5Z,8Z,14Z,17Z-eicosatetraenoic acid), 14,15-EEQ (i.e. 14,15-epoxy-5Z,8Z,11Z,17Z-eicosatetraenoic acid, and 17,18-EEQ (i.e. 17,18-epoxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid. The epoxydases typically make both R/S enantiomers of each epoxide. For example, they metabolize EPA at its 17,18 double bond to a mixture of 17R,18S-EEQ and 17S,18R-EEQ. [3] [4] The EEQ products therefore consist of as many as ten isomers.

Production

Cellular cytochrome P450 epoxygenases metabolize various polyunsaturated fatty acids to epoxide-containing products. They metabolize the omega-6 fatty acids arachidonic acid, which possess four double bonds, to 8 different epoxide isomers which are termed epoxyeicosatrienoic acids or EETs and linoleic acid, which possess two double bonds, to 4 different epoxide isomers, i.e. two different 9,10-epoxide isomers termed vernolic acids or leukotoxins and two different 12,13-epoxides isomers termed coronaric acids or isoleukotoxins. They metabolize the omega-3 fatty acid, docosahexaenoic acid, which possesses six double bonds, to twelve different epoxydocosapentaenoic acid (EDPs) isomers. In general, the same epoxygenases that accomplish these metabolic conversions also metabolize the omega-6 fatty acid, EPA, to 10 epoxide isomers, the EEQs. These epoxygenases fall into several subfamilies including the cytochrome P4501A (i.e.CYP1A), CYP2B, CYP2C, CYP2E, and CYP2J subfamilies, and within the CYP3A subfamily, CYP3A4. In humans, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, CYP3A4, and CYP2S1 metabolize EPA to EEQs, in most cases forming principally 17,18-EEQ with smaller amounts of 5,6-EEQ, 8,9-EEQ, 11,12-EEQ, and 14,15-EEQ isomers. [5] [6] [7] However, CYP2C11, CYP2C18, and CYP2S1 also form 14,15-EEQ isomers while CYP2C19 also forms 11,12-EEQ isomers. [7] [8] The isomers formed by these CYPs vary greatly with, for example, the 17,18-EEQs made by CYP1A2 consisting of 17R,18S-EEQ but no detectable 17S,18R-EEQ and those made by CYP2D6 consisting principally of 17R,18S-EEQ with far smaller amounts of 17S,18R-EEQ. [9] In addition to the cited CYP's, CYP4A11, CYP4F8, CYP4F12, CYP1A1, CYP1A2, and CYP2E1, which are classified as CYP monooxygenase rather than CYP epoxygeanses because they metabolize arachidonic acid to monohydroxy eicosatetraenoic acid products (see 20-Hydroxyeicosatetraenoic acid), i.e. 19-hydroxyhydroxyeicosatetraenoic acid and/or 20-hydroxyeicosatetranoic acid, take on epoxygease activity in converting EPA primarily to 17,18-EEQ isomers (see epoxyeicosatrienoic acid). [7] 5,6-EEQ isomers are generally either not formed or formed in undetectable amounts while 8,9-EEQ isomers are formed in relatively small amounts by the cited CYPs. [5] The EET-forming CYP epoxygenases often metabolize EPA to EEQs (as well as DHA to EDPs) at rates that exceed their rates in metabolizing arachidonic acid to EETs; that is, EPA (and DHA) appear to be preferred over arachidonic acid as substrates for many CYP epoxygenases. [6]

The EEQ-forming cytochromes are widely distributed in the tissues of humans and other mammals, including blood vessel endothelium, blood vessel atheroma plaques, heart muscle, kidneys, pancreas, intestine, lung, brain, monocytes, and macrophages. [1] [6] [10] [11] These tissues are known to metabolize arachidonic acid to EETs; it has been shown or is presumed that they also metabolize EPA to EEQs. Note, however, that the CYP epoxygenases, similar to essentially all CYP450 enzymes, are involved in the metabolism of xenobiotics as well as endogenously-formed compounds; since many of these same compounds also induce increases in the levels of the epoxygenases, CYP oxygenase levels and consequently EEQ levels in humans vary widely and are highly dependent on recent consumption history; numerous other factors, including individual genetic differences, also contribute to the variability in CYP450 epoxygenase expression. [12]

EEQ metabolism

In cells, EEQs are rapidly metabolized by the same enzyme that similarly metabolizes other epoxy fatty acids including the EETs viz., cytosolic soluble epoxide hydrolase [EC 3.2.2.10.] (also termed sEH or the EPHX2), to form their corresponding Vicinal (chemistry) diol dihydroxyeicosatetraenoic acids (diHETEs). The omega-3 fatty acid epoxides, EEQs and EPAs, appear to be preferred over EETs as substates for sEH. [6] sEH converts 17,18-EEQ isomers to 17,18-dihydroxy-eicosatrienoic acid isomers (17,18-diHETEs), 14,15-EEQ isomers to 14,15-diHETE isomers, 11,12-EEQ isomers to 11,12-diHETE isomers, 8,9-EEQ isomers to 8,9-diHETE isomers, and 5,6-EEQ isomers to 5,6-diHETE isomers. [13] The product diHETEs, like their epoxy precursors, are enantiomer mixtures; for instance, sEH converts 17,18-EEQ to a mixture of 17(S),19(R)-diHETE and 17(R),18(S)-diHETE. [4] Since the diHETE products are as a rule generally far less active than their epoxide precursors, the sEH pathway of EET metabolism is regarded as a critical EEQ-inactivating pathway. [13] [14] [15]

Membrane-bound Microsomal epoxide hydrolase (mEH or Epoxide hydrolase 2 [EC 3.2.2.9.]) can metabolize EEQs to their dihydroxy products but is regarded as not contributing significantly to EEQ inactivation in vivo except possibly in rare tissues where the sEH level is exceptionally low while the mEH level is high. [2]

In addition to the sEH pathway, EETs may be acylated into phospholipids in an Acylation-like reaction. This pathway may serve to limit the action of EETs or store them for future release. [4] EETs are also inactivated by being further metabolized though three other pathways: Beta oxidation, Omega oxidation, and elongation by enzymes involved in Fatty acid synthesis. [2] [16]

Clinical significance

EEQS, similar to EDPs, have not be studied nearly as well as the EETs. In comparison to the many activities attributed to the EETs in animal model studies (see Epoxyeicosatrienoic acid), a limited set of studies indicate that EEQs (and EPAs) mimic EETS in their abilities to dilate arterioles, reduce hypertension, inhibit inflammation (the anti-inflammatory actions of EEQ are less potent than those of the EETs) and thereby reduce occlusion of arteries to protect the heart and prevent and strokes (see Epoxyeicosatrienoic acid#Clinical significance sections on a) Regulation of blood pressure, b) Heart disease, c) Strokes and seizures, and d) inflammation); they also mimic EETs in possessing analgesia properties in relieving certain types of pain (see Epoxyeicosatrienoic acid#Clinical significance). [6] Often, the EEQs (and EPAs) exhibit greater potency and/or effectiveness than EET in these actions. [17] [6] [18] In human studies potentially relevant to one or more of these activities, consumption of long chain omega-3 fatty acid (i.e. EPA- and DHA-rich) diet produced significant reductions in systolic blood pressure and increased peripheral arteriole blood flow and reactivity in patients at high to intermediate risk for cardiovascular events; an EPA/DHA-rich diet also reduced the risk while high serum levels of DHA and EPA were associated with a low risk of neovascular age-related macular degeneration. [19] [20] Since such diets lead to large increases in the serum and urine levels of EPAs, EEQs, and the dihydoxy metabolites of these epoxides but relatively little or no increases in EETs or lipoxygenase/cyclooxygenase-producing metabolites of arachidonic acid, DHA, and/or EEQs, it is suggested that the diet-induced increases in EPAs and/or EEQs are responsible for this beneficial effects. [6] [21] [22] In direct contrast to the EETs which have stimulating effects in the following activities (see Epoxyeicosatrienoic acid#Cancer, EEQs (and EPAs) inhibit new blood vessel formation (i.e. angiogenesis), human tumor cell growth, and human tumor metastasis in animal models implanted with certain types of human cancer cells. [6] The possible beneficial effects of omega-3 fatty acid-rich diets in pathological states involving inflammation, hypertension, blood clotting, heart attacks and other cardiac diseases, strokes, brain seizures, pain perception, acute kidney injury, and cancer are suggested to result, at least in part, from the conversion of dietary EPA and DHA to EEQs and EPAs, respectively, and the cited subsequent actions of these metabolites. [7] [23] [24] [2] [25] [17]

Related Research Articles

<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. Eicosanoids may also act as endocrine agents to control the function of distant cells.

<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">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

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">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">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

Eoxins are proposed to be a family of proinflammatory eicosanoids. They are produced by human eosinophils, mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes. That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.

<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.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

John Russell “Camille” Falck is an American chemist, Professor of Biochemistry, and holder of the Robert A. Welch Distinguish Chair in Chemistry at the University of Texas Southwestern Medical Center. In 1996 he was awarded the Wilfred T. Doherty Recognition Award from the Dallas-Forth Worth Section of the American Chemical Society and a Recognition Award at the March 10, 2002, Winter Eicosanoid Conference in appreciation of his significant contributions to the chemistry of natural products, and to the identification and functional characterization of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase metabolic pathway and its metabolites.

References

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  11. ↑ Xu M, Ju W, Hao H, Wang G, Li P (2013). "Cytochrome P450 2J2: Distribution, function, regulation, genetic polymorphisms and clinical significance". Drug Metabolism Reviews. 45 (3): 311–52. doi:10.3109/03602532.2013.806537. PMID   23865864. S2CID   22721300.
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  20. ↑ Merle BM, Benlian P, Puche N, Bassols A, Delcourt C, Souied EH, Nutritional AMD Treatment 2 Study Group (2014). "Circulating omega-3 Fatty acids and neovascular age-related macular degeneration". Investigative Ophthalmology & Visual Science. 55 (3): 2010–9. doi:10.1167/iovs.14-13916. PMID   24557349.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  21. ↑ Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH (2014). "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". The Journal of Lipid Research. 55 (6): 1150–1164. doi: 10.1194/jlr.M047357 . PMC   4031946 . PMID   24634501.
  22. ↑ Merino J, Sala-Vila A, Kones R, Ferre R, Plana N, Girona J, Ibarretxe D, Heras M, Ros E, Masana L (2014). "Increasing long-chain n-3PUFA consumption improves small peripheral artery function in patients at intermediate-high cardiovascular risk". The Journal of Nutritional Biochemistry. 25 (6): 642–6. doi:10.1016/j.jnutbio.2014.02.004. PMID   24746829.
  23. ↑ Iliff JJ, Jia J, Nelson J, Goyagi T, Klaus J, Alkayed NJ (2010). "Epoxyeicosanoid signaling in CNS function and disease". Prostaglandins & Other Lipid Mediators. 91 (3–4): 68–84. doi:10.1016/j.prostaglandins.2009.06.004. PMC   2844927 . PMID   19545642.
  24. ↑ Westphal C, Konkel A, Schunck WH (2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID   21945326.
  25. ↑ Wang W, Zhu J, Lyu F, Panigrahy D, Ferrara KW, Hammock B, Zhang G (2014). "Ω-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer". Prostaglandins & Other Lipid Mediators. 113–115: 13–20. doi:10.1016/j.prostaglandins.2014.07.002. PMC   4306447 . PMID   25019221.
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