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Arachidonic acid metabolism pathways and production of 5-oxoeicosatraenoic acids. The structures of the principal ligands are presented.
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Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that have been intimately linked with cellular migration. These metabolites are not only potent chemotaxins but also elicit oxygen radical production as well as induce secretory events in different cells. The most potent native ligand reported is 5-oxo-6,8,11,14-eicosat...
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... provoked by arachidonic acid have generally been attributed to the conversion of this substrate to a variety of metabolites. The enzymatic oxidation of arachidonic acid leads to the formation of a family of lipid mediators known as eicosanoids. These products are produced in a well controlled fashion under the direction of specific enzymes (Fig. 1). Modifications in the levels of the metabolites of arachidonic acid have been intimately linked not only with a variety of cellular functions but also with inflammation and disease. In an attempt to understand this modification, one research approach was to isolate and inhibit the enzymes respon- sible for the formation of specific ...
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... receptors. Furthermore, the lipoxins (Serhan, 1994) were shown to be mediators with potent inhibitory ac- tions via specific ALX receptors ( Fiore et al., 1992). The 5-LO enzymatic pathway was also reported to be pivotal for the transformation of arachidonic acid to another group of biologically active metabolites, namely, the ox- oeicosanoids (Fig. ...
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... the guide- lines advanced by the IUPHAR Nomenclature Commit- tee for Leukotriene ties may be referred to as oxoeicosanoid (OXE) receptors since the native ligand, 5-oxo-ETE, is the most potent agonist in the cloned receptor assays and the oxo group at C-5 is key for activation of this receptor. Several of these ligand structures are presented in Fig. ...
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Eicosanoid signaling controls a wide range of biological processes from blood pressure homeostasis to inflammation and resolution thereof to the perception of pain and to cell survival itself. Disruption of normal eicosanoid signaling is implicated in numerous disease states. Eicosanoid signaling is facilitated by G-protein-coupled, eicosanoid-spec...
Citations
... The 5-Oxo-ETE receptor was named as the OXE receptor by the IUPHAR Nomenclature Committee for Leukotriene and Lipoxin Receptors [37]. The corresponding gene is OXER1, which maps to 2p21 on chromosome 2 [38,39]. ...
b> Background: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-Oxo-ETE) is a metabolite of arachidonic acid shown to promote biological activities in different cell types. Summary: 5-Oxo-ETE is synthesized from the 5-lipoxygenase product 5S-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) in the presence of the nicotinamide adenine dinucleotide phosphate (NADP)<sup>+</sup>-dependent enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under some conditions that promote oxidation of NADPH to NADP<sup>+</sup>, such as the respiratory burst in phagocytic cells, eosinophils, and neutrophils, oxidative stress in monocytes and dendritic cells, and cell death, 5-Oxo-ETE synthesis can be dramatically increased. In addition, 5-Oxo-ETE can also be formed in the absence of 5-lipoxygenase in cells through transcellular biosynthesis by inflammatory cell-derived 5S-HETE. This compound performs its biological activities by the highly selective Gi/o-coupled OXE receptor, which is highly expressed on eosinophils, neutrophils, basophils, and monocytes. As such, 5-Oxo-ETE is a potent chemoattractant for these inflammatory cells, especially for eosinophils. Key Messages: Although the pathophysiological role of 5-Oxo-ETE is not clearly understood, 5-Oxo-ETE may be a significant mediator in allergic diseases, such as allergic asthma, allergic rhinitis, and atopic dermatitis. And targeting the OXE receptor may be a novel therapy for this kind of inflammatory condition. Nowadays, selective OXE receptor antagonists are currently under investigation and could become potential therapeutic agents in allergy.
... G protein coupled oxo-eicosanoid receptor 1 OXER1 (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor) is a GPCR that mediates the biological actions of 5-oxo-eicosatetraenoic acid (5-oxoETE), a product of the metabolism of arachidonic acid by 5-lipoxygenase (5-LOX) and peroxidase [34][35][36]. It is highly expressed in various inflammatory cells, (eosinophils, neutrophils, lymphocytes and monocytes) and tissues (liver, kidney, spleen and lung), as well as in cancer cells and tissues, including prostate and breast [35,37,38]. ...
Accumulating evidence during the last decades revealed that androgens exert membrane-initiated actions leading to the modulation of significant cellular processes, important for cancer cell growth and metastasis (including prostate and breast), that involve signaling via specific kinases. Collectively, many nonclassical, cell surface-initiated androgen actions are mediated by novel membrane androgen receptors (mARs), unrelated to nuclear androgen receptors. Recently, our group identified the G protein coupled oxo-eicosanoid receptor 1 (OXER1) (a receptor of the arachidonic acid metabolite, 5-oxoeicosatetraenoic acid, 5-oxoETE) as a novel mAR involved in the rapid effects of androgens. However, two other membrane proteins, G protein-coupled receptor family C group 6 member A (GPRC6A) and zinc transporter member 9 (ZIP9) have also been portrayed as mARs, related to the extranuclear action of androgens. In the present work, we present a comparative study of in silico pharmacology, gene expression and immunocytochemical data of the three receptors in various prostate and breast cancer cell lines. Furthermore, we analyzed the immunohistochemical expression of these receptors in human tumor and non-tumoral specimens and provide a pattern of expression and intracellular distribution.
... Biological responses to 5-oxo-ETE, a lipid mediator formed by the oxidation of 5S-HETE by 5-hydroxyeicosanoid dehydrogenase, are mediated by the OXE receptor, a Gi coupled GPCR [75] highly expressed in eosinophils. Despite its potential involvement in atopic diseases such as asthma and AR, the lack of mouse and rat orthologues has hampered the understanding of 5-oxo-ETE pathophysiological role. ...
Chronic inflammation and pain is a major global health problem, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most frequently prescribed drugs and common option for the treatment of inflammatory pain. However, they have the potential to cause serious complications, such as gastrointestinal (GI) lesions, bleeding and cardiovascular (CV) problems. NSAIDs exert their anti-inflammatory, analgesic and anti-pyretic actions by inhibiting the cyclooxygenases (COX)-1 and COX-2, key enzymes of the arachidonic acid (AA) cascade. However, not all the AA products or their receptors are pro-inflammatory. Therefore, given the multifaceted interactions of these lipid mediators where a single precursor can trigger multiple events with synergic or opposed function, it is easy to predict that any perturbation of this interplay will cause several unavoidable side effects. Today, we do not have a truly safe NSAID that minimizes GI damage and CV toxicity. One possibility to interfere with this intricate network, while trying to keep its fine balance, is to develop molecules affecting several targets. Different strategies have been proposed for a multitargeted intervention at different levels of the AA cascade, like inhibition of multiple upstream enzymes, such as COX, 5-lipoxygenase, or even soluble epoxide hydrolase and prostaglandin E synthase. Alternative strategies are more focused in the inhibition of targets downstream in the metabolic pathway, such as thromboxane synthase and/or blocking selective receptors. In this review we will briefly summarize the new strategies that have been proposed for a multitargeted pharmacological intervention on this metabolic cascade aimed at developing novel anti-inflammatory therapeutics.
... However, the biological effects of CysLTs do not seem to be mediated only by CysLTR-1 and CysLTR-2. Indeed, these receptors are phylogenetically related to purinergic P2Y class of GPCRs [4] and evidence reported in the literature suggests the existence of additional receptors responding to CysLTs [5], such as GPR17 [6], GPR99 [7], PPARγ [8], P2Y6 [9], and P2Y12 [10]. ...
Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer’s and Parkinson’s diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression.
... OXER1 (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor) is a GPCR that has been deorphanized almost 15 years ago 26,[35][36][37] . It mediates the biological actions of 5-oxoeicosatetraenoic acid (5-oxoETE), a product of the metabolism of arachidonic acid by 5-lipoxygenase (5-LOX) and peroxidase. ...
Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Results of the present work clearly show that androgens can specifically act at the membrane level via the GPCR oxoeicosanoid receptor 1 (OXER1) in prostate cancer cells. In fact, OXER1 expression parallels that of membrane androgen binding in prostate cancer cell lines and tumor specimens, while in silico docking simulation of OXER1 showed that testosterone could bind to OXER1 within the same grove as 5-OxoETE, the natural ligand of OXER1. Interestingly, testosterone antagonizes the effects of 5-oxoETE on specific signaling pathways and rapid effects such as actin cytoskeleton reorganization that ultimately can modulate cell migration and metastasis. These findings verify that membrane-acting androgens exert specific effects through an antagonistic interaction with OXER1. Additionally, this interaction between androgen and OXER1, which is an arachidonic acid metabolite receptor expressed in prostate cancer, provides a novel link between steroid and lipid actions and renders OXER1 as new player in the disease. These findings should be taken into account in the design of novel therapeutic approaches in prostate cancer.
... The actions of 5-oxo-ETE are mediated by the OXE receptor. An extensive review of this area can be found in [62]. Through the combined actions of lipoxygenases the lipoxins are formed [52]. ...
Inflammatory processes and alterations of lipid metabolism play a crucial role in Alzheimer's disease (AD) and other neurodegenerative disorders. Polyunsaturated fatty acids (PUFA) metabolism impaired by cyclooxygenases (COX-1, COX-2), which are responsible for formation of several eicosanoids, and by lipoxygenases (LOXs) that catalyze the addition of oxygen to linolenic, arachidonic (AA), and docosahexaenoic acids (DHA) and other PUFA leading to formation of bioactive lipids, significantly affects the course of neurodegenerative diseases. Among several isoforms, 5-LOX and 12/15-LOX are especially important in neuroinflammation/neurodegeneration. These two LOXs are regulated by substrate concentration and availability, and by phosphorylation/dephosphorylation through protein kinases PKA, PKC and MAP-kinases, including ERK1/ERK2 and p38. The protein/protein interaction also is involved in the mechanism of 5-LOX regulation through FLAP protein and coactosin-like protein. Moreover, non-heme iron and calcium ions are potent regulators of LOXs. The enzyme activity significantly depends on the cell redox state and is differently regulated by various signaling pathways. 5-LOX and 12/15-LOX convert linolenic acid, AA, and DHA into several bioactive compounds e.g. hydroperoxyeicosatetraenoic acids (5-HPETE, 12S-HPETE, 15S-HPETE), which are reduced to corresponding HETE compounds. These enzymes synthesize several bioactive lipids, e.g. leucotrienes, lipoxins, hepoxilins and docosahexaenoids. 15-LOX is responsible for DHA metabolism into neuroprotectin D1 (NPD1) with significant antiapoptotic properties which is down-regulated in AD. In this review, the regulation and impact of 5-LOX and 12/15-LOX in the pathomechanism of AD is discussed. Moreover, we describe the role of several products of LOXs, which may have significant pro- or anti-inflammatory activity in AD, and the cytoprotective effects of LOX inhibitors.
... In other systems such as eosinophils, nucleophils and platelets, a GPCR successively named TG1019, R527 and, more recently, OxeR1 (Brink et al., 2004;Hosoi et al., 2002Hosoi et al., , 2005Jones et al., 2003) appears to be responsible for 5-HpETE action. This receptor has different levels of affinity to different lipidic compounds, and while 5-oxo-ETE is the lipoxygenated product with the highest activating capacity, the binding of a fatty acid such as docosahexanoic acid (DHA,22:6) shows antagonistic actions (Hosoi et al., 2002). ...
Hormone-regulated steroidogenesis and StAR protein induction involve the action of lipoxygenated products. The products of 5-lipoxygenase act on inflammation and immunity by stimulation of a membrane receptor called OxeR1. The presence of OxeR1 in other systems has not been described up to date and little is known about its mechanism of action and other functions. In this context, the aim of this study was the identification and characterization of OxeR1 as a mediator of cAMP-dependent and independent pathways. Overexpression of OxeR1 in MA-10 Leydig cells increased cAMP-dependent progesterone production. Angiotensin II and cAMP stimulation of adrenocortical human H295R cells produced an increase in StAR protein induction and steroidogenesis in cells overexpressing OxeR1 as compared to mock-transfected cells. Additionally, activation of OxeR1 caused a time-dependent increase in ERK1/2 phosphorylation. In summary, membrane receptor OxeR1 is involved in StAR protein induction and activation of steroidogenesis triggered by cAMP or angiotensin II, acting, at least in part, through ERK1/2 activation.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... The endogenous ligands for the LT, lipoxin (LX) and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes shown in Figure 1 (Brink et al., 2003;Brink et al., 2004;Chiang et al., 2006;Bäck et al., 2011). The metabolism of arachidonic acid by 5-lipoxygenase yields the epoxide intermediate LTA4, which serves as precursor for the LT receptor agonists (Figure 1). ...
... Oxoeicosanoids are another family of biologically active arachidonic acid derivatives that have been intimately associated with cellular migration (Powell et al., 1995). 5-Oxo-ETE, formed by the oxidation of 5S-HETE by 5-hydroxyeicosanoid dehydrogenase ( Figure 1) is a potent chemoattractant for human granulocytes and monocytes by means of the OXE receptor (Brink et al., 2004). ...
... The LT, LX and oxoeicosanoid receptor cloning, ligand affinity, expression and functional significance have been reviewed in previous IUPHAR reports (Brink et al., 2003;Brink et al., 2004;Chiang et al., 2006;Bäck et al., 2011) and are summarized in Tables 1-6. The aim of the present review is to give a state of the field on these receptors, with focus on recent important findings. ...
The endogenous ligands for the leukotriene, lipoxin and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes. The leukotriene (LT) receptors are either activated by LTB4 (BLT1 and BLT2 ) or cysteinyl-LTs (CysLT1 and CysLT2 ), whereas oxoeicosanoids exert their action through the OXE receptor. In contrast to these pro-inflammatory mediators, the lipoxin (LX) A4 transduces responses associated with the resolution of inflammation through the receptor FPR2/ALX (ALX/FPR2). The aim of the present review is to give a state of the field on these receptors, with focus on recent important findings. For example, BLT1 receptor signaling in cancer and the dual role of the BLT2 receptor in pro- and anti-inflammation have added more complexity to lipid mediator signaling. Furthermore, a cross-talk between the CysLT and P2Y receptor systems has been described, and also the presence of novel receptors for cysteinyl-LTs, such as GPR17 and GPR99. Finally, lipoxygenase metabolites derived from omega-3 essential polyunsaturated referred to as resolvins activate the receptors GPR32 and ChemR23. In conclusion, the receptors for the lipoxygenase products make up a sophisticated and tightly controlled system of endogenous pro- and anti-inflammatory signaling in physiology and pathology.
... Reduction of its length to 5 carbons (9) resulted in a small decrease in potency, whereas further shortening to a butyl group (8) had a much more dramatic effect, reducing the potency by over 10-fold. In contrast, increasing the length of the side chain to seven (11), eight (12), or 11 (13) carbons appeared to result in slightly increased potency. These compounds were synthesized from the common precursor 1H-indole-2-carboxylic acid as shown in Scheme 1, and the detailed synthesis was reported previously. ...
... Prior to biological assay, the purity of all final compounds was determined to be >95% by NMR and HPLC. HPLC conditions: Waters Synthesis of 8,9,10,11,12,13. These compounds were synthesized from 1H-Indole-2-carboxylic acid (1) as described previously. ...
... The organic layer was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na 2 SO 4. The solvents were evaporated under reduced pressure, and the crude was purified by silica gel chromatography using 50% EtOAc/Hex as eluent to afford 15 (37.4 mg, 52%). HRMS (ESI) m/z calcd for [C 24 H 33 NO 3 13 Synthesis of 5-(2-Hexyl-1H-indol-1-yl)-3,3-dimethyl-5-oxopentanoic Acid (17). To a solution of "6, n = 3" (12 mg, 0.06 mmol) in DMSO (0.2 mL) was added KOH (13 mg, 0.24 mmol) at rt. ...
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that is a potent granulocyte chemoattractant, which induces the infiltration of eosinophils into human skin when injected intradermally. It could therefore be an important proinflammatory mediator in eosinophilic diseases such as asthma and allergic rhinitis and the OXE receptor, which mediates its actions, is therefore an attractive drug target. Using a structure-based approach in which substituents mimicking the essential polar (C1-C5) and hydrophobic (C15-C20) regions of 5-oxo-ETE were incorporated on an indole scaffold, we identified two potent selective OXE antagonists with IC50 values of about 30 nM. Neither compound displayed agonist activity and both inhibited 5-oxo-ETE-induced chemotaxis and actin polymerization and were relatively resistant to metabolism by rat liver homogenates. The active enantiomers of these racemic antagonists were even more potent, with IC50 values of <10 nM. These selective OXE antagonists could potentially be useful therapeutic agents in allergic diseases such as asthma.
... Oxoeicosanoid receptors (OXE, nomenclature agreed by NC-IUPHAR on Oxoeicosanoid Receptors; [1056]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. ...
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.
G protein-coupled receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.
It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.
