ALOX12 (EC 1.13.11.31), 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. [5] [6] ALOX12 is 75 kilodalton protein composed of 663 amino acids.
| arachidonate 12-lipoxygenase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.13.11.31 | ||||||||
| CAS no. | 82391-43-3 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Other systematic names for ALOX12 include 12S-Lipoxygenase, platelet-type 12-lipoxygenase, arachidonate:oxygen 12-oxidoreductase, Delta12-lipoxygenase, 12Delta-lipoxygenase, and C-12 lipoxygenase. ALOX12, often termed plate platelet-type 12-lipoxygenase, is distinguished from leukocyte-type 12-lipoxygenase which is found in mice, rats, cows, and pigs but not humans. Leukocyte-type 12-lipoxygenase in these animal species shares 73-86% amino acid identity with human ALOX15 but only 57-66% identity with human platelet-type 12-lipoxygenase and, like ALOX15, metabolizes arachidonic acid primarily to 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (i.e. 15(S)-HpETE; see 15-Hydroxyeicosatetraenoic acid). [7] Accordingly, rodent leukocyte 12-lipoxygenase is deemed an ortholog of ALOX15 and is designated as Alox15. [8]
Human ALOX12 and ALOX15 along with rodent leukocyte-type Alox12 and Alox15 are commonly termed 12/15-lipoxygenases based on their ability to metabolize arachidonic acid to both 12(S)-HpETE and 15(S)-HpETE and to conduct this same metabolism on arachidonic acid that is esterified to membrane phospholipids; human ALOX15B makes 15(S)-HpETE but not 12(S)-HpETE and therefore is not regarded as a 12/15-lipoxygenase. [9] Studies on the role of ALOX12 in pathophysiology using the main models for such functional studies, rats and mice, are complicated because neither species possesses a lipoxygenase that makes a predominance of 12(S)-HETE and therefore is metabolically equivalent to ALOX12. [7] [9] For example, the functions inferred for Alox12 in mice made deficient in Alox12 using knockout methods may not indicate a similar function for ALOX12 in humans due to differences in these two enzymes' metabolic activities. The function of ALOX12 is further clouded by human ALOX15 which metabolizes arachidonic acid primarily to 15(S)-HpETE but also makes lesser but still significant amounts of 12(S)-HpETE (see ALOX15).
ALOX12 is also distinguished from arachidonate 12-lipoxygenase, 12R type (ALOX12B), which metabolizes arachidonic acid to the R stereoisomer of 12(S)-HpETE viz., 12(R)-hydroperoxy-5Z,8Z,10E,14Z-icosatetraenoic acid (12(R)-HpETE), a product with very different pathophysiological roles than that of 12(S)-HpETE (see ALOX12B).
ALOX12, originally called arachidonate 12-lipoxygenase, was first characterized by the Nobel Laureate, Bengt I. Samuelsson, and his famed colleague, Mats Hamberg, in 1974 by showing that human platelets metabolize arachidonic acid not only by the well-known cyclooxygenase pathway into prostaglandins and 12-hydroxyheptadecatrienoic acid but also by a cyclooxygenase-independent pathway to 12(S)-hydroperoxy-5,8,10,14-eicosatetraenoic acid; this activity was the first mammalian lipoxygenase activity to be characterized. [10] In 1975, the first biological activity was attached to this metabolite in studies showing that it simulated the chemotaxis of human neutrophils. [11] During the several years thereafter, human ALOX12 was purified, characterized biochemically, and had its gene molecularly cloned. [7] [12]
Based predominantly on the presence of its mRNA, human ALOX12 is distributed predominantly in blood platelets and leukocytes and at lower levels in the basal layer of the epidermis (particularly in the skin lesions of psoriasis), islets of Langerhans within the pancreas, and certain cancers. [13]
The control of ALOX12 activity appears to rest principally on the availability of its polyunsaturated fatty acid (PUFA) substrates which are released from storage in membrane phospholipids by cell stimulation. [14] The enzyme participates in arachidonic acid metabolism by conducting the following chemical reaction wherein its substrates are arachidonic acid (also termed as arachidonate or, chemically, as 5Z,8Z,11Z,14Z-eicosatetraenoic acid) and O2 (i.e. oxygen) and its product is 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-hydroperoxyeicosatetraenoic acid or 12S-HpETE): [10] [15]
In cells, 12SHpETE may be further metabolized by ALOX12 itself, by ALOXE3 or possibly other, as yet not fully identified, hepoxilin syntheses to hepoxilin A3 (8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and B3 (10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid): [16] [17] [18]
Hepoxilins can promote certain inflammation responses, increase pain perception (i.e. tactile allodynia), regulate regional blood flow, and contribute to the regulation of blood pressure in animal models (see Hepoxilins). Far more commonly, however, 12S-HpETE is rapidly reduced to its hydroxyl product by ubiquitous cellular peroxidase activities thereby forming 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid, i.e. 12-hydroxyeicosatetraenoic acid or 12S-HETE: [19]
12S-HETE promotes inflammation responses, may be involved in the perception of puritis (i.e. itching) in the skin, and regulates regional blood flow in animal models; it also promotes the malignant behavior of cultured human cancer cells as well as the growth of certain cancers in animal models (see 12-HETE). While arachidonate and 12(S)-HETE are the predominant substrates and products, respectively, of ALOX12, the enzyme also metabolizes other PUFA. It metabolizes the omega-3 fatty acid, docosahexaenoic acid (DHA i.e., 4(Z),7(Z),10(Z),13(Z),16(Z),19(Z)-docosahexaenoic acid to 14(R)-hydroperoxy-4(Z),8(Z),10(Z),12(E),16(Z),19(Z)-docosahexaenoic acid)(i.e. 17-hydroperoxy-DHA); then, ALOX12 or an unidentified epoxidase-type enzyme may metabolize this intermediate to an epoxide, 13,14-epoxy-4(Z),7(Z),9(E),11(E),16(Z),19(Z)-docosahexaenoic acid (i.e. 13,14-e-maresin) which metabolized to 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (i.e. Maresin 1), by an unidentified epoxide hydrolase-type enzyme:
Maresin 1 has a set of activities that may oppose those of 12(S)-HETE and the hepoxilins; it is a member of a class of PUFA metabolites termed Specialized pro-resolution mediators (SPMs) which possess anti-inflammatory, pain-alleviating, and other defensive activities. [20] ALOX12 also acts on leukotriene A4 (LTA4) in a two cellular reaction termed transcellular metabolism: human neutrophils metabolize arachidonic acid to its 5,6-epoxide, LTA4, and releases this intermediate to nearby neutrophils which metabolize it to lipoxin A4 (5S,6R,15S-trihydroxy-7E,9E,11Z,13Z-eicosatetraenoic acid) and lipoxin B4 (5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid); both lipoxins are SPMs with many SPM-like activities (see lipoxin). [21] ALOX12 may also metabolize lesser amounts of DHA to secondary products including 17-hydroperoxy-DHA, 11-hydroperoxy-DHA, and 8,14-dihydroxy-DHA [20] ALOX12 may likewise metabolize 5(S)-HETE to 5S,12S-dihydroxyeicosatetraenoic acid (12,15-diHETE) and 15S-HETE to 14,15S-diETE. [14] While these compounds have not been thoroughly evaluated for bioactivity, 17-hydroperoxy-HDHA and the reduced product to which it is rapidly converted in cells, 17-hydroxy-HDHA, have been shown to inhibit the growth of cultured human prostate cancer cell by causing them to enter apoptosis. [22]
Studies on rodents lacking or made deficient in the leukocyte-type 12-lipoxygenase, Alox12 (which is most closely related to human ALOX15) implicate this enzyme in: a) preventing the development and complications of dietary-induced and/or genetically induced diabetes, adipose cell/tissue dysfunction, and obesity; b) the development of atherosclerosis and Steatohepatitis; b) regulating blood vessel contraction, dilation, pressure, remodeling, and angiogenesis; c) maintaining normal renal, neurological, and brain function; and d) the development of Alzheimer's disease. [8] [9] [23] In these studies, it is usually unclear which, if any metabolite(s) of Alox12 was implicated.
The metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose (or overt diabetes), high serum triglycerides, and low high-density lipoprotein (HDL) levels. ALOX12 and its metabolite, 12(S)-HETE, are elevated in the islets of Langerhans of patients with type 1 diabetes or type 2 diabetes as well as in the fat cells of white adipose tissue of morbidly obese type 2 diabetic patients. [8] The PP cells (i.e. gamma cells) of the pancreas islets appear to be the major if not only site where ALOX12 is expressed in these patients. [8] The studies propose that in the islets of Langerhans ALOX12 and its 12(S)-HETE product cause excessive production of reactive oxygen species and inflammation which lead to losses in insulin-secreting beta cells and thereby types 1 and 2 diabetes and that in adipose tissue the excess in AlOX12, 12(S)-HETE, reactive oxygen species, and inflammation lead to fat cell dysfunction (also see 12-HETE#Inflammation and inflammatory diseases and 12-HETE#Diabetes). Indeed, in one study a Single-nucleotide polymorphism, rs2073438, [24] located in an intron region of the ALOX12 gene was significantly associated with total and percentage fat mass of obese compared to non-obese young Chinese men. [8] [13] [18] ALOX12 and 12(S)-HETE are likewise implicated in essential hypertension (see next section). Hence, ALOX12 and its metabolite(s) may contribute to the development and/or progression of obesity, diabetes, hypertension, and/or the metabolic syndrome.
A selective but not totally specific inhibitor of ALOX12 reduced the growth response of cultured human endothelial cells to basic fibroblast growth factor and vascular endothelial growth factor (VEGF); this reduction was partially reversed by 12(S)-HETE; 12(S)-HETE also stimulates human prostate cell lines to produce VEGF. [19] These results suggest that growth responses to the two growth factors involves their stimulation of 12(S)-HETE production by endothelial cells and therefore that ALOX12 may be a target for reducing the neo-vascularization that promotes arthritic and cancer diseases. 12(S)-HETE also dilates human coronary microcirculation arteries by activating these vessels' smooth muscle BKca Potassium channels and is therefore suggested to be an Endothelium-derived hyperpolarizing factor. [9] [19] Finally, a single nucleotide variant in the ALOX12 gene (R261Q [3957 G>A]) has been associated with essential hypertension and elevation in the urinary excretion of 12(S)-HETE in humans and may be a contributing factor for to essential hypertension (see also 12-HETE#Blood pressure). [9] [25]
Patients with Alzheimer's disease or other forms of dementia have significantly higher levels of 12(S)-HETE (and 15(S)-HETE) in cerebrospinal fluid compared to aged-matched normal individuals. Complementary studies in rodent models bearing human mutated genes for Amyloid precursor protein and/or tau protein (see tau protein#Clinical significance) that produce Alzheimer's dementia-like syndromes implicate 12(S)-HETE, 15(S)-HETE, and a 12/15-lipoxygenase type enzyme in the development and progression of the Alzhiemer's disease-like symptoms and findings in these animals. [23] In a single study, ALOX12 mRNA was found elevated in the brain tissue of Alzheimer disease patients compared to control patients. [13] These results suggest that ALOX12 (or ALOX15) may contribute to the development of Alzheimer's disease in humans.
Studies in prostate cancer find that human prostate cancer cell lines in culture overexpress ALOX12, overproduce 12(S)-HETE, and respond to 12(S)-HETE by increasing their rate of proliferation, increasing their cell surface expression of integrins, increasing their survival and delaying their apoptosis, and increasing their production of vascular endothelial growth factor and MMP9 (i.e. Matrix metallopeptidase 9); selective (but not entirely) specific ALOX12 inhibitors reduced the proliferation and survival of these cells (see also 12-HETE#prostate cancer). These finding suggest that ALOX12 and its 12(S)-HETE product may contribute to the growth and spread of prostate cancer in humans. [19] Recently, hypermethylation of the ALOX12 gene in prostate cancer tissue was associated with clinical predictors for a high rate of recurrent disease. [26] Some studies have found that 12(S)-HETE also promotes the growth and/or related pro-malignant behaviors of various other types of cultured cancer cell lines (see 12-HETE#Other cancers). [19] ALOX12 has been shown to interact with Keratin 5 and LMNA as screened in a yeast two-hybrid interaction library from human epidermoid carcinoma A431 cells; these proteins are candidates for regulating 12-LOX, particularly in tumor cells. [27]
Although first identified in human platelets, the role of ALOX12 and its major metabolites, 12(S)-HpETE and 12(S)-HETE in platelet function remains controversial and unclear; it is possible that the ALOX12-12(S)-HETE metabolic pathway has dual functions in promoting or inhibiting platelet responses depending on the stimulating agent and response studied but that inhibiting ALOX12 may ultimately prove useful in inhibiting platelet-related blood clotting. [19]
The ALOX12 gene has susceptibility alleles (rs6502997, [28] rs312462, [29] rs6502998, [30] and rs434473 [31] ) for the parasitic disease, human congenital toxoplasmosis. [13] [32] Fetus bearer of these alleles thus suffer an increased susceptibility to this disease.
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the Neo-Latin word arachis (peanut), but peanut oil does not contain any arachidonic acid.
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.
Lipoxygenases are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells.
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.
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.
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
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.
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).
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.
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.
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), 5S,15S-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.
12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was first detected and structurally defined by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.
20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, Hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.
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.
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.
