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.
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).
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.
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.
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.
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
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.
Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is a bifunctional enzyme which converts leukotriene A4 to leukotriene B4 and acts as an aminopeptidase.
In enzymology, a microsomal epoxide hydrolase (mEH) is an enzyme that catalyzes the hydrolysis reaction between an epoxide and water to form a diol.
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.
Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 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.
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.
Ubenimex (INN), also known more commonly as bestatin, is a competitive, reversible protease inhibitor. It is an inhibitor of arginyl aminopeptidase (aminopeptidase B), leukotriene A4 hydrolase (a zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities), alanyl aminopeptidase (aminopeptidase M/N), leucyl/cystinyl aminopeptidase (oxytocinase/vasopressinase), and membrane dipeptidase (leukotriene D4 hydrolase). It is being studied for use in the treatment of acute myelocytic leukemia and lymphedema. It is derived from Streptomyces olivoreticuli. Ubenimex has been found to inhibit the enzymatic degradation of oxytocin, vasopressin, enkephalins, and various other peptides and compounds.
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.
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.
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 acids (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 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.
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.
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.
