Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Feltenmark, Stina; Gautam, Narinder; Brunnström, Åsa; Griffiths, William J.; Backman, Linda; Edenius, Charlotte; Lindbom, Lennart; Björkholm, Magnus; Claesson, Hans‐Erik

doi:10.1073/pnas.0710127105

Cited by 149 publications

(150 citation statements)

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“…This is the first study to report that identified serum eoxin C 4 metabolite levels are higher in patients with AERD than in patients with ATA and increased significantly during the Lys-ASA BPT in patients with AERD. Eoxins have been reported to enhance vascular permeability, a hallmark of inflammation, and suggested to be almost as potent as cysLTs [36]. Increased eoxin levels have been shown to be associated with increased bronchial hyperresponsiveness in childhood asthmatics [32].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

Ban

Cho

Kim

et al. 2016

Clin Experimental Allergy

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SummaryBackground To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). Objective To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. Methods An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/QToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. Results A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE 4 and LTE 4 /PGF 2 a ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE 4 and LTE 4 /PGF 2 a ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE 4 levels were significantly correlated with the fall in FEV 1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). Conclusions and Clinical Relevance Serum metabolite level of LTE 4 and LTE 4 /PGF 2 a ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/QToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.

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Section: Discussionmentioning

confidence: 99%

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

Ban

Cho

Kim

et al. 2016

Clin Experimental Allergy

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“…Mammalian 15-LOX-1, for example, can further convert 15S-HPETE to a structural analogue of LTA 4 , named 14,15-LTA 4 based on the position of the epoxide group between C-14 and C-15 (3,4). This 14,15-epoxide was recently given the name of eoxin A 4 on account of its production by eosinophils and its further transformation, analogous to LTA 4 , to a series of biologically active peptidyl derivatives, 14,15-LTC 4 , -LTD 4 , and -LTE 4 (eoxins C 4 , D 4 , and E 4 ) (5).…”

Section: Lipoxygenases (Lox)mentioning

confidence: 99%

“…S8 and Table S2). Thus, product 4 is 5,15-dihydroxyeicosa-6E,8E,11E,13E-tetraenoic acid (5,, and product 5 is the corresponding ␦-lactone.…”

Section: Contribution Of the Fe(iii) Enzyme To The Anaerobic Reactionmentioning

confidence: 99%

“…S8 and Table S2). Thus, product 4 is 5,15-dihydroxyeicosa-6E,8E,11E,13E-tetraenoic acid (5,, and product 5 is the corresponding ␦-lactone.Products 4 and 5 Are Each a Mixture of Diastereomers-Although each appeared as a single peak on RP-HPLC and SP-HPLC, each could be further resolved using a chiral HPLC column into a 50:50 mixture of two peaks with identical UV spectra (supplemental Fig. S9).…”

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confidence: 99%

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Formation of a Cyclopropyl Epoxide via a Leukotriene A Synthase-related Pathway in an Anaerobic Reaction of Soybean Lipoxygenase-1 with 15S-Hydroperoxyeicosatetraenoic Acid

Zheng

Brash

2010

Journal of Biological Chemistry

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The further conversion of an arachidonic acid hydroperoxide to a leukotriene A (LTA) type epoxide by specific lipoxygenase (LOX) enzymes constitutes a key step in inflammatory mediator biosynthesis. Whereas mammalian 5-LOX transforms its primary product (5S-hydroperoxyeicosatetraenoic acid; 5S-HPETE) almost exclusively to LTA 4 , the model enzyme, soybean LOX-1, normally produces no detectable leukotrienes and instead further oxygenates its primary product 15S-HPETE to 5,15-and 8,15-dihydroperoxides. Mammalian 15-LOX-1 displays both types of activity. We reasoned that availability of molecular oxygen within the LOX active site favors oxygenation, whereas lack of O 2 promotes LTA epoxide synthesis. To test this, we reacted 15S-HPETE with soybean LOX-1 under anaerobic conditions and identified the products by high pressure liquid chromatography, UV, mass spectrometry, and NMR. Among the products, we identified a pair of 8,15-dihydroxy diastereomers with all-transconjugated trienes that incorporated 18 O from H 2 18 O at C-8, indicative of the formation of 14,15-LTA 4 . A pair of 5,15-dihydroxy diastereomers containing two trans,trans-conjugated dienes (6E,8E,11E,13E) and that incorporated 18 O from H 2 18 O at C-5 was deduced to arise from hydrolysis of a novel epoxide containing a cyclopropyl ring, 14,15-epoxy-[9,10,11-cyclopropyl]-eicosa-5Z,7E,13E-trienoic acid. Also identified was the ␦-lactone of the 5,15-diol, a derivative that exhibited no 18 O incorporation due to its formation by intramolecular reaction of the carboxyl anion with the proposed epoxide intermediate. Our results support a model in which access to molecular oxygen within the active site directs the outcome from competing pathways in the secondary reactions of lipoxygenases. Lipoxygenases (LOX)2 are named for their oxygenase activity with polyunsaturated fatty acids, yet they also catalyze other types of reaction. One of the most important in a biological context is leukocyte 5-LOX-catalyzed further conversion of the hydroperoxide product 5S-HPETE to leukotriene A 4 (LTA 4 ) (1). LTA 4 , an unstable epoxide, will then be subject to metabolism of downstream enzymes in the pathway to more stable and biologically active LTs, including the dihydroxy LTB 4 and the peptidyl LTC 4 , LTD 4 , and LTE 4 (2). Parallels of the LTA synthase activity of 5-LOX also exist in some other LOX enzymes. Mammalian 15-LOX-1, for example, can further convert 15S-HPETE to a structural analogue of LTA 4 , named 14,15-LTA 4 based on the position of the epoxide group between C-14 and C-15 (3,4). This 14,15-epoxide was recently given the name of eoxin A 4 on account of its production by eosinophils and its further transformation, analogous to LTA 4 , to a series of biologically active peptidyl derivatives, 14,15-LTC 4 , -LTD 4 , and -LTE 4 (eoxins C 4 , D 4 , and E 4 ) (5).Despite the general parallels between leukocyte 5-LOX and mammalian 15-LOX-1 within the physiological context, the two enzymes exhibit notable differences in their reactions toward 5S-HPETE and 15S-HPETE...

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“…Since then, additional pro-inflammatory products have been discovered (Feltenmark et al, 2008). On the other hand, anti-inflammatory and/or pro-resolving lipids generated by mammalian isoforms have also been identified, including lipoxins (Serhan et al, 1984;Maderna & Gordon, 2009), resolvins (Serhan et al, 2004), protectins (Ariel et al, 2005;Schwab et al, 2007) and maresins (Serhan et al, 2009).…”

mentioning

confidence: 99%

Lipoxygenase-Quercetin Interaction: A Kinetic Study Through Biochemical and Spectroscopy Approaches

Chedea¹,

Vicaş²,

Socaciu³

et al. 2012

Biochemical Testing

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Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Cited by 149 publications

References 35 publications

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin‐exacerbated respiratory disease

Formation of a Cyclopropyl Epoxide via a Leukotriene A Synthase-related Pathway in an Anaerobic Reaction of Soybean Lipoxygenase-1 with 15S-Hydroperoxyeicosatetraenoic Acid

Lipoxygenase-Quercetin Interaction: A Kinetic Study Through Biochemical and Spectroscopy Approaches

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