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5(S),15(S)-DiHETE

目录号 : GC41127

A dihydroxy fatty acid synthesized by 15-LO from 5(S)-HETE

5(S),15(S)-DiHETE Chemical Structure

Cas No.:82200-87-1

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25μg
¥1,352.00
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50μg
¥2,570.00
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100μg
¥4,865.00
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产品描述

5(S),15(S)-DiHETE is synthesized by 15-LO from 5(S)-HETE. It potentiates the degranulation of human PMNL in response to PAF, but not fMLP, calcium ionophore A23187, or LTB4. 5(S),15(S)-DiHETE is chemotactic for eosinophils with an ED50 value of 0.3 µM.

Chemical Properties

Cas No. 82200-87-1 SDF
Canonical SMILES CCCCC[C@H](O)/C=C/C=C\C/C=C\C=C\[C@@H](O)CCCC(O)=O
分子式 C20H32O4 分子量 336.5
溶解度 DMF: >50 mg/ml (per Rao Maddipati),DMSO: >50 mg/ml (per Rao Maddipati),Ethanol: >50 mg/ml (per Rao Maddipati),PBS pH 7.2: >1 mg/ml (from 13(S)-HODE) 储存条件 Store at -20°C, protect from light
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1 mM 2.9718 mL 14.8588 mL 29.7177 mL
5 mM 0.5944 mL 2.9718 mL 5.9435 mL
10 mM 0.2972 mL 1.4859 mL 2.9718 mL
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Research Update

5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors

J Exp Med 1996 Apr 1;183(4):1633-43.PMID:8666921DOI:10.1084/jem.183.4.1633.

5-Lipoxygenase activation of human blood polymorphonuclear cells (PMN) from asthmatic patients (asthmatics) was studied to investigate whether differences may exist with healthy subjects (controls). The respective cell capacities to produce lipoxins (LXs), leukotrienes, and 5(S), 15(S)-dihydroxyeicosatetraenoic acid [5(S),15(S)-DiHETE] were compared under in vitro stimulation by ionophore A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid [15(S)-diHETE]. Eicosanoids were analyzed by elution with an isocratic reverse-phase high performance liquid chromatography system, and their profiles, detected by simultaneous monitoring at 302, 280, and 246 nm, were evaluated on the basis of chromatographic behavior: UV spectral characteristics and coelution with synthetic standards. In the presence of exogenous 15(S)-HETE, human PMN were able to produce LXs and 5(S),15(S)-DiHETE, PMN from asthmatics were able to produce 5(S), 5(S),15(S)-DiHETE, and LXs from endogenous sources, whereas in the same experimental conditions, no detectable amounts of these compounds were released by PMN from controls. The levels of 5(S),15(S)-DiHETE, and LXs biosynthesized from endogenous arachidonic acid were highly correlated. Two different LX patterns were observed involving two possible metabolic pathways: (a) via the intermediate 5,6-epoxytetraene alone for LXs generation from exogenous 15(S)-HETE; and (b) via 5,6- and/or 14,15-epoxytetraenes leading to the formation of an enzyme-bound delocalized carbocation for LXs generation from endogenous arachidonate, respectively. The enhanced 5-lipoxygenase activation of blood PMN from asthmatics and the metabolism of exogenous 15(S)-HETE may reflect a priming induced by various mediators released from environmental cells, and could be considered as a model of transcellular signalization between PMN and endothelial cells.

Deciphering the Molecular Details of the Lipoxin Formation Mechanism in the 5( S),15( S)-DiHpETE Biosynthetic Pathway Catalyzed by Reticulocyte 15-Lipoxygenase-1

J Phys Chem B 2020 Dec 17;124(50):11406-11418.PMID:33274949DOI:10.1021/acs.jpcb.0c09147.

Chronic inflammation is now widely recognized to play important roles in many commonly occurring diseases, including COVID-19. The resolution response to this chronic inflammation is an active process governed by specialized pro-resolving mediators (SPMs) like the lipid mediators known as lipoxins. The biosynthesis of lipoxins is catalyzed by several lipoxygenases (LOXs) from arachidonic acid. However, the molecular details of the mechanisms involved are not well known yet. In this paper, we have combined molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations to analyze how reticulocyte 15-LOX-1 catalyzes the production of lipoxins from 5(S),15(S)-diHpETE. Our results indicate that the dehydration mechanism from 5(S),15(S)-diHpETE, via the formation of an epoxide, presents huge energy barriers even though it was one of the two a priori synthetic proposals. This result is compatible with the fact that no epoxide has been directly detected as an intermediate in the catalytic formation of lipoxins from 5(S),15(S)-diHpETE. Conversely, the oxygenation of 5(S),15(S)-diHpETE at C14 is feasible because there is an open channel connecting the protein surface with this carbon atom, and the energy barrier for oxygen addition through this channel is small. The analysis of the following steps of this mechanism, leading to the corresponding hydroperoxide at the 15-LOX-1 active site, indicates that the oxygenation mechanism will lead to the formation of lipoxinB4 after the final action of a reductase. In contrast, our calculations are in agreement with experiments that lipoxinA4 cannot derive from 5(S),15(S)-diHpETE by either of the two proposed mechanisms and that 5(S),15(S)-DiHETE is not an intermediate of lipoxin biosynthesis catalyzed by 15-LOX-1.

Transformations of 5-HETE by activated keratinocyte 15-lipoxygenase and the activation mechanism

Lipids 1990 Oct;25(10):618-23.PMID:2127820DOI:10.1007/BF02536012.

There is convincing evidence that normal cultured human keratinocytes possess a 15-lipoxygenase activity which, however, does not appear to manifest itself without cell membrane damage. When "activated", this enzyme transforms arachidonic acid into 15-hydroxyeicosatetraenoic acid (15-HETE), and linoleic acid into 13-hydroxyoctadecadienoic acid, presumably by peroxidase action on their respective hydroperoxy intermediates. Normal but not membrane-damaged keratinocytes metabolize exogenous 5-HETE, principally by esterifying the eicosanoid intact, primarily in the triacylglycerol fraction. In the present study, membrane-damaged keratinocytes were found to transform 5-HETE to 5,15-diHETE and also to a lipoxin-like group of tetraenes. Similar, if not identical, tetraenes were produced by action of the keratinocyte enzyme on 5(S),15(S)-DiHETE, which points to the role of the latter as an intermediate between 5-HETE and the tetraenes. A direction for further study of the mechanism of the "activation" step is presented.

On the biosynthesis of specialized pro-resolving mediators in human neutrophils and the influence of cell integrity

Biochim Biophys Acta Mol Cell Biol Lipids 2022 Mar;1867(3):159093.PMID:34942381DOI:10.1016/j.bbalip.2021.159093.

Neutrophils are key players in inflammation initiation and resolution. Little attention has been paid to the detailed biosynthesis of specialized pro-resolving mediators (SPM) in these cells. We investigated SPM formation in human polymorphonuclear leukocytes (PMNL), in broken PMNL preparations and recombinant human 5-lipoxygenase (5-LO) supplemented with the SPM precursor lipids 15-Hydroxyeicosatetraenoic acid (15-HETE), 18-Hydroxyeicosapentaenoic acid (18-HEPE) or 17-Hydroxydocosahexaenoic acid (17-HDHA). In addition, the influence of 5-LO activating protein (FLAP) inhibition on SPM formation in PMNL was assessed. Intact human PMNL preferred ARA over DHA for lipid mediator formation. In contrast, in incubations supplemented with the SPM precursor lipids DHA-derived 17-HDHA was preferred over 15-HETE and 18-HEPE. SPM formation in the cells was dominated by 5(S),15(S)-DiHETE (800 pmol/20 mio cells) and Resolvin D5 (2300 pmol/20 mio cells). Formation of lipoxins (<10 pmol/20 mio cells), E-series (<70 pmol/20 mio cells) and other D-series resolvins (<20 pmol/20 mio cells) was low and only detected after addition of the precursor lipids. Upon destruction of cell integrity, formation of lipoxins and 5(S),15(S)-DiHETE increased while formation of 17-HDHA- and 18-HEPE-derived SPMs was attenuated. Recombinant 5-LO did not accept the precursors for SPM formation and FLAP inhibition prevented the formation of the 5-LO-dependent SPMs. Together with the data on FLAP inhibition our results point to unknown factors that control SPM formation in human neutrophils and also render lipoxin and 5(S),15(S)-DiHETE formation independent of membrane association and FLAP when cellular integrity is destroyed.

Generation of eicosanoids from 15(S)-hydroxyeicosatetraenoic acid in blood monocytes from steroid-dependent asthmatic patients

Biochem Pharmacol 1998 Aug 15;56(4):535-41.PMID:9763231DOI:10.1016/s0006-2952(98)00086-0.

The aim of this study was to investigate eicosanoid metabolism by human peripheral blood monocytes (PBM) from steroid-dependent asthmatic patients as compared to control subjects and untreated asthmatic patients. Eicosanoid biosynthesis by PBM isolated from venous blood using Percoll gradient centrifugation was evaluated following stimulation of 5 x 10(6) cells with calcium ionophore A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), and analyzed by reverse phase high performance liquid chromatography (RP-HPLC). Without 15(S)-HETE, PBM synthesized leukotriene B4 (LTB4) only (40 +/- 12 ng and 59 +/- 11 ng for untreated and steroid-dependent asthmatics, respectively). In the presence of 15(S)-HETE, PBM produced six-fold smaller amounts of leukotriene B4 (P < 0.0001). They also released 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-DiHETE) in similar amounts for all the populations, whereas low amounts of lipoxins (LXs) were produced by PBM from asthmatics only (2.7 +/- 0.7 ng and 4.6 +/- 2.8 ng for untreated and steroid-dependent asthmatics, respectively). Moreover, PBM were also able to release an unknown compound containing conjugated triene chromophore. Cells from steroid-dependent asthmatic patients synthesized this unknown metabolite in higher amounts than controls and untreated asthmatics (133 +/- 18 ng vs 52 +/- 19 ng and 68 +/- 15 ng, respectively, P < 0.02). This work shows for the first time that human PBM are able to metabolize 15(S)-HETE and lead to lipoxins and to an unknown metabolite, with the amounts of the latter being enhanced by long-term corticosteroid treatment.