Hepoxilin

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Hepoxilin A3
Hepoxilin A3.png
Names
IUPAC name
(5E,9E)-8-hydroxy-10-[3-[(E)-oct-2-enyl] -2-oxiranyl]deca-5,9-dienoic acid
Other names
HXA3
Identifiers
3D model (JSmol)
PubChem CID
UNII
  • CCCCCC=CCC1C(O1)C=CC(CC=CCCCC(=O)O)O
Properties
C20H32O4
Molar mass 336.47 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) 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 (including human) 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.

Contents

History

HxA3 and HxB3 were first identified, named, shown to have biological activity in stimulating insulin secretion in cultured rat pancreatic islets of Langerhans in Canada in 1984 by CR Pace-Asciak and JM Martin. [1] Shortly thereafter, Pace-Asciak identified, named, and showed to have insulin secretagogue activity HxA4 and HxB4. [2]

Nomenclature

HxA3, HxB3, and their isomers are distinguished from most other eicosanoids (i.e. signaling molecules made by oxidation of 20-carbon fatty acids) in that they contain both epoxide and hydroxyl residues; they are structurally differentiated in particular from two other classes of arachidonic acid-derived eicosanoids, the leukotrienes and lipoxins, in that they lack conjugated double bonds. HxA4 and HxB4 are distinguished from HxA3 and HxB3 by possessing four rather than three double bonds. The 14,15-HxA3 and 14,15-HxB3 non-classical eicosanoids are distinguished from the aforementioned hepoxilins in that they are formed by a different metabolic pathway and differ in the positioning of their epoxide and hydroxyl residues. Two other classes of epoxyalcohol fatty acids, those derived from the 22-carbon polyunsaturated fatty acid, docosahexaenoic acid, and the 18-carbon fatty acid, linoleic acid, are distinguished from the aforementioned hepoxilins by their carbon chain length; they are termed hepoxilin-like rather than hepoxilins. [3] [4] A hepoxilin-like derivative of linoleic acid is formed on linoleic acid that is esterified to a sphingosine in a complex lipid termed esterified omega-hydroxylacyl-sphingosin (EOS). [4]

Note on nomenclature ambiguities

The full structural identities of the hepoxilins and hepoxilin-like compounds in most studies are unclear in two important respects. First, the R versus S chirality of their hydroxy residue in the initial and most studies thereafter is undefined and therefore given with, for example, HxB3 as 10R/S-hydroxy or just 10-hydroxy. Second, the R,S versus S,R chirality of the epoxide residue in these earlier studies likewise goes undefined and given with, for example, HxB3 as 11,12-epoxide. While some later studies have defined the chirality of these residues for the products they isolated, [5] it is often not clear that the earlier studies dealt with products that had exactly the same or a different chirality at these residues.

Biochemistry

Hepoxilins, such as HxA3 and HxB3, are metabolic intermediates derived from the polyunsaturated fatty acid (PUFA), arachidonic acid. They possess both an epoxide and a hydroxyl residue. As metabolic intermediates, hepoxilins play several roles in human physiology and pathology. They have various biological activities in animal models and/or cultured mammalian (including human) tissues and cells. For example, they have been implicated in promoting the neutrophil-based inflammatory response to various bacteria in the intestines and lungs of rodents.

Production

Human HxA3 and HxB3 are formed in a two-step reaction. First, molecular oxygen (O2) is added to carbon 12 of arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) and concurrently the 8Z double bond in this arachidonate moves to the 9E position to form the intermediate product, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-hydroperoxyeicosatetraenoic acid or 12S-HpETE). Second, 12S-HpETE is converted to the hepoxilin products, HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid). [3] This two-step metabolic reaction is illustrated below:

5Z,8Z,11Z,14Z-eicosatetraenoic acid + O2 → 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid → 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid + 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid

The second step in this reaction, the conversion of 12(S)-HpETE to HxA3 and HxB3, may be catalyzed by ALOX12 as an intrinsic property of the enzyme. [6] Based on gene knockout studies, however, the epidermal lipoxygenase, ALOXE3, or more correctly, its mouse ortholog Aloxe3, appears responsible for converting 12(S)-HpETE to HxB3 in mouse skin and spinal tissue. [4] [7] [8] It is suggested that ALOXE3 contributes in part or whole to the production of HxB3 and perhaps other hepoxilins by tissues where it is expressed such as the skin. [4] [9] Furthermore, hydroperoxide-containing unsaturated fatty acids can rearrange non-enzymatically to form a variety of epoxyalcohol isomers. [10] The 12(S)-HpETE formed in tissues, it is suggested, may similar rearrange non-enzymatically to form HxA3 and HXB3. [4] Unlike the products made by ALOX12 and ALOXE3, which are stereospecific in forming only HxA3 and HxB3, however, this non-enzymatic production of hepoxilins may form a variety of hepoxilin isomers and occur as an artifact of tissue processing. [4] Finally, cellular peroxidases readily and rapidly reduce 12(S)-HpETE to its hydroxyl analog, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12S-HETE; see 12-hydroxyeicosatetraenoic acid; this reaction competes with the hepoxilin-forming reaction and in cells expressing very high peroxidase activity may be responsible for blocking the formation of the hepoxilins. [3]

ALOX15 is responsible for metabolizing arachidonic acid to 14,15-HxA3 and 14,15-HxB3 as indicated in the following two-step reaction which first forms 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15S-HpETE) and then two specific isomers of 11S/R-hydroxy-14S,15S-epoxy-5Z,8Z,12E-eicosatrienoic acid (i.e. 14,15-HxA3) and 13S/R)-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid (i.e. 14,15-HxB3):

5Z,8Z,11Z,14Z-eicosatetraenoic acid + O2 → 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid → 11R-hydroxy-14S,15 S-epoxy-5Z,8Z,12E-eicosatrienoic acid and 13R-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid

ALOX15 appears capable of conducting both steps in this reaction [11] although further studies may show that ALOXE3, non-enzymatic rearrangements, and the reduction of 15S-HpETE to 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (i.e. 15S-HETE; see 15-hydroxyicosatetraenoic acid) may be involved in the production of 14,15-HxA3 and 14,15-HxB3 as they are in that of HxA3 and HxB3.

Production of the hepoxilin-like metabolites of docosahexaenoic acid, 7R/S-hydroxy-10,11-epoxy-4Z,7E,13Z,16Z,19Z-docosapentaenoic acid (i.e. 7-hydroxy-bis-α-dihomo-HxA5) and 10-hydroxy-13,14-epoxy-4Z,7EZ,11E,16Z,19Z-docosapentaenoic acid (i.e. 10-hydroxy-bis-α-dihomo-HxA5) was formed (or inferred to be formed based on the formation of their tihydroxy metabolites (see trioxilins, below) as a result of adding docosahexaenoic acid to the pineal gland or hippocampus isolated from rats; the pathway(s) making these products has not been described. [3] [12]

A hepoxilin-like metabolite of linoleic acid forms in the skin of humans and rodents. This hepoxilin is esterified to sphinganine in a lipid complex termed EOS (i.e. esterified omega-hydroxyacyl-sphingosine, see Lipoxygenase#Biological function and classification#Human lipoxygenases) that also contains a very long chain fatty acid. In this pathway, ALOX12B metabolizes the esterified linoleic acid to its 9R-hydroperoxy derivative and then ALOXE3 metabolizes this intermediate to its 13R-hydroxy-9R,10R-epoxy product. The pathway functions to deliver very long chain fatty acids to the cornified lipid envelope of the skin surface. [9]

Further metabolism

HxA3 is extremely unstable and HxB3 is moderately unstable, rapidly decomposing to their tri-hydroxy products, for example, during isolation procedures that use an even mildly acidic methods; they are also rapidly metabolized enzymatically in cells to these same tri-hydroxy products, termed trioxilins (TrX's) or trihydroxyeicoxatrienoic acids (THETA's); HxA3 is converted to 8,11,12-trihydroxy-5Z,9E,14Z-eicosatrienoic acid (trioxilin A3 or TrXA3) while HxB3 is converted to 10,11,12-trihydroxy-5Z,8Z,14Z-eicosatrienoic acid (trioxilin B3 or TrXB3). [3] [13] A third trihydroxy acid, 8,9,12-trihydroxy-5Z,10E,14Z eicosatrienoic acid (trioxilin C3 or TrXC3), has been detected in rabbit and mouse aorta tissue incubated with arachidonic acid. [5] [14] The metabolism of HxA3 to TrXA3 and HXB3 to TrX is accomplished by soluble epoxide hydrolase in mouse liver; since it is widely distributed in various tissues of various mammalian species, including humans, soluble epoxide hydrolase may be the principal enzyme responsible for metabolizing these and perhaps other hepoxilin compounds. [3] [15] It seems possible, however, that other similarly acting epoxide hydrolases such as microsomal epoxide hydrolase or epoxide hydrolase 2 may prove to hepoxilin hydrolase activity. While the trihydroxy products of hepoxilin synthesis are generally considered to be inactive and the sEH pathway therefore considered as functioning to limiting the actions of the hepoxilins, [3] [16] some studies found that TrXA3, TrXB3, and TrXC3 were more powerful than HxA3 in relaxing pre-contracted mouse arteries [5] and that TrXC3 was a relatively potent relaxer of rabbit pre-contracted aorta. [14]

HxA3 was converted through a Michael addition catalyzed by glutathione transferase to its glutathione conjugate, HxA3-C, i.e., 11-glutathionyl-HxA3, in a cell-free system or in homogenates of rat brain hippocampus tissue; HxA3-C proved to be a potent stimulator of membrane hyperpolarization in rat hippocampal CA1 neurons. [17] This formation of hepoxilin A3-C appears analogous to the formation of leukotriene C4 by the conjugation of glutathione to leukotriene A4. Glutathione conjugates of 14,15-HxA3 and 14,15-HxB3 have also been detected the human Hodgkin disease Reed–Sternberg cell line, L1236. [11]

HxB3 and TrX3 are found esterified into the sn-2 position of phospholipid in human psoriasis lesions and samples of human psoriatic skin acylate HxBw and TrX2 into these phospholipids in vitro. [3] [18]

Physiological effects

Virtually all of the biological studies on hepoxilins have been conducted in animals or in vitro on animal and human tissues, However, these studies give species-specific different results which complicate their relevancy to humans. The useful translation of these studies to human physiology, pathology, and clinical medicine and therapies requires much further study.

Inflammation

HxA3 and HxB3 possess pro-inflammatory actions in, for example, stimulating human neutrophil chemotaxis and increasing the permeability of skin capillaries. [3] [19] Studies in humans have found that the amount of HxB3 is >16-fold higher in psoriatic lesions than normal epidermis. It is present in psoriatic scales at ~10 micromolar, a concentration which is able to exert biologic effects; HxB3 was not detected in these tissues although its present was strongly indicated by the presence of its metabolite, TrXB3, at relatively high levels in psoriatic scales but not normal epidermal tissue. [13] These results suggest that the pro-inflammatory effects of HxA3 and HxB3 may contribute to the inflammatory response that accompanies psoriasis and perhaps other inflammatory skin conditions. [3] [13] [20] [21] HxA3 has also been implicating in promoting the neutrophil-based inflammatory response to various bacteria in the intestines and lungs of rodents.; [22] [23] this allows that this hepoxilin may also promote the inflammatory response of humans in other tissues, particularly those with a mucosa surface, besides the skin. In addition, HxA3 and a synthetic analog of HxB3, PBT-3, induce human neutrophils to produce neutrophil extracellular traps, i.e. DNA-rich extracellular fibril matrixes able to kill extracellular pathogens while minimizing tissue; hence these hepoxilins may contribute to innate immunity by being responsible of the direct killing of pathogens. [24]

Circulation

In addition to 12S-HETE and 12R-HETE (see 12-HETE#Blood pressure), HxA3, TrXA3, and TrXC3 but neither HxB3 nor TrXB3 relax mouse mesentery arteries pre-contracted by thromboxane A2)(TXA2). Mechanistically, these metabolites form in the vascular endothelium, move to the underlining smooth muscle, and reverse the smooth muscle contraction caused by TXA2 by functioning as a Receptor antagonist, i.e. they competitively inhibit the binding of TXA2 to its thromboxane receptor, α isoform. [5] In contrast, 15-lipoxygenase-derived epoxyalcohol and trihydroxy metabolites of arachidonic acid viz., 15-hydroxy-11,12-epoxyeicosatrienoic acid, 13-hydroxy-14,15-epoxy-eicosatrienoic acid (a 14,15-HxA4 isomer), and 11,12,15-trihydroxyeicosatrienoic acid dilate rabbit aorta by an Endothelium-derived hyperpolarizing factor (EDHF) mechanism, i.e. they form in the vessels endothelium, move to underlying smooth muscles, and trigger a response of Hyperpolarization (biology)-induced relaxation by binding to and thereby opening their apamin-sensitive small conductance (SK) Calcium-activated potassium channel#SK channels. [5] [25] [26] The cited metabolites may use one or the other of these two mechanisms in different vascular beds and in different animal species to contribute in regulating regional blood flow and blood pressure. While the role of these metabolites in the human vasculature has not been studied, 12S-HETE, 12R-HETE, HxA3, TrXA3, and TrXC3 do inhibit the binding of TXA2 to the human thromboxane receptor. [5] [27]

Pain perception

HXA3 and HXB3 appear responsible for hyperalgesia and tactile allodynia (pain caused by a normally non-painful stimulus) response of mice to skin inflammation. In this model, the hepoxilins are released in spinal cord and directly activate TRPV1 and TRPA1 receptors to augment the perception of pain. [3] [28] [29] TRPV1 (the transient receptor potential cation channel subfamily V member 1 (TrpV1), also termed the capsaicin receptor or vanilloid receptor) and TRPA1 (Transient receptor potential cation channel, member A1) are plasma membrane ion channels on cells; these channels are known to be involved in the perception of pain caused by exogenous and endogenous physical and chemical stimuli in a wide range of animal species including humans.

Oxidative stress

Cultured rat RINm5F pancreatic islet cells undergoing oxidative stress secrete HxB3; HxB3 (and HxA3) in turn upregulates peroxidase enzymes which act to decrease this stress; it is proposed that this HxB3-triggered induction of oxidases constitutes a general compensatory defense response used by a variety of cells to protect their vitality and functionality. [30] [31]

Insulin secretion

The insulin-secreting actions of HxA3 and HxB3 on isolate rat pancreatic islet cells involves their ability to increase or potentiate the insulin-secreting activity of glucose, requires very high concentrations (e.g. 2 micromolar) of the hepoxilins, and has not been extended to intact animals or humans. [3] [32]

Hepoxilins are also produced in the brain. [33]

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. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<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.

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

<span class="mw-page-title-main">TRPA1</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

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

Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid de novo. Its elevated presence in the blood is an indication of essential fatty acid deficiency. Mead acid is found in large quantities in cartilage.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">ALOX12</span> Protein-coding gene in the species Homo sapiens

ALOX12, also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12S-Lipoxygenase, 12-LOX, and 12S-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ALOX12 gene which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75 kilodalton protein composed of 663 amino acids.

In enzymology, a hepoxilin-epoxide hydrolase is an enzyme that catalyzes the conversion of the epoxyalcohol metabolites arachidonic acid, hepoxilin A3 and hepoxilin B3 to their tri-hydroxyl products, trioxolin A3 and trioxilin B3, respectively. These reactions in general inactivate the two biologically active hepoxilins.

<span class="mw-page-title-main">Oxoeicosanoid receptor 1</span> Protein-coding gene in the species Homo sapiens

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

<span class="mw-page-title-main">ALOX12B</span> Protein-coding gene in the species Homo sapiens

Arachidonate 12-lipoxygenase, 12R type, also known as ALOX12B, 12R-LOX, and arachidonate lipoxygenase 3, is a lipoxygenase-type enzyme composed of 701 amino acids and encoded by the ALOX12B gene. The gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lipoxygenases, ALOXE3 and ALOX15B. Among the human lipoxygenases, ALOX12B is most closely related in amino acid sequence to ALOXE3

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">12-Hydroxyeicosatetraenoic acid</span> Chemical compound

12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5Z,8Z,10E,14Z Cis–trans isomerism configuration (Z=cis, E=trans) in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s). However, the term 12-HETE is ambiguous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE or 12S-HETE), made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (also termed 12(R)-HETE or 12R-HETE) made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as Endocrine signalling agents, these arachidonic acid metabolites act locally as Autocrine signalling and/or Paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

<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">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.

<span class="mw-page-title-main">Eoxin</span> Family of proinflammatory eicosanoids

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">5-Oxo-eicosatetraenoic acid</span> Chemical compound

5-Oxo-eicosatetraenoic acid is a nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.

5-Hydroxyeicosanoid dehydrogenase (5-HEDH) or more formally, nicotinamide adenine dinucleotide phosphate (NADP+)-dependent dehydrogenase, is an enzyme that metabolizes an eicosanoid product of arachidonate 5-lipoxygenase (5-LOX), 5(S)-hydroxy-6S,8Z,11Z,14Z-eicosatetraenoic acid (i.e. 5-(S)-HETE; see 5-HETE) to its 5-keto analog, 5-oxo-eicosatetraenoic acid (i.e. 5-oxo-6S,8Z,11Z,14Z-eicosatetraenoic acid or 5-oxo-ETE). It also acts in the reverse direction, metabolizing 5-oxo-ETE to 5(S)-HETE. Since 5-oxo-ETE is 30–100-fold more potent than 5(S)-HETE in stimulating various cell types, 5-HEDH is regarded as a regulator and promoter of 5(S)HETE's and thereby 5-LOX's influences on cell function. Although 5-HEDH has been evaluated in a wide range of intact cells and in crude microsome preparations, it has not yet been evaluated for its structure, for its gene, of in pure form; furthermore, most studies on it have been conducted in human tissues.

<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.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

References

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