17(<i>R</i>),18(<i>S</i>)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues

Falck, John R.; Wallukat, Gerd; Narender, P.; Goli, Mohan; Arnold, Cosima; Konkel, Anne; Rothe, Michael; Fischer, Robert; Müller, Dominik N.; Schunck, Wolf Hagen

doi:10.1021/jm200132q

Cited by 63 publications

(65 citation statements)

References 55 publications

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“…Increasing evidence obtained in mammalian systems suggests the existence of GPCRs (G protein-coupled receptors) that specifically interact with selected sets of epoxy and hydroxy metabolites derived from n−6 and n−3 PUFAs [52,66,67]. Supporting the hypothesis that 17,18-EEQ may interact with similar targets in mammals and C. elegans, we found that a metabolically robust synthetic analogue, developed to mimic the effect of 17,18-EEQ on cardiomyocyte contractility [20], was also effective in modulating the locomotive activity of C. elegans. Further genetic analysis of the components mediating the 17,18-EEQ effects in C. elegans may facilitate the search for the thus far unknown receptors of CYPeicosanoids.…”

Section: Discussionsupporting

confidence: 75%

“…In mammals, CYP-eicosanoids act in an autocrine or paracrine manner and serve as second messengers of diverse hormones regulating the contractility of vascular smooth muscle cells and cardiomyoctes [20,60,61]. In C. elegans, 17,18-EEQ mediates the O2-ON response by increasing the activity of body muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…The compound used as 17,18-EEQ agonist was synthesized as described previously [20]. To prevent autooxidation, all stock solutions were prepared in an oxygen evacuated nitrogen chamber.…”

Section: Chemicalsmentioning

confidence: 99%

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CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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SHORT TITLE:CYP-13A12 of C. elegans is a PUFA-epoxygenase 4 SYNOPSISA specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. Here we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal monooxygenase system that metabolised EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. Main products included 17,18-EEQ (epoxyeicosatetraenoic acid) from EPA and 14,15-EET (epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA-deficient, ∆ -12 and ∆ -6 fatty acid desaturase mutants (fat-2 and fat-3, respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolisable AAanalogue. Already short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. Based on these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with C20-PUFA mutants but to a lesser extent also with wild-type worms. KEYWORDS:Eicosanoids; Polyunsaturated fatty acids; Caenorhabditis elegans; Cytochrome P450; Reoxygenation; 17,18-EEQ ABBREVIATIONS USED: AA, arachidonic acid; CID, collision-induced dissociation; COD, carbon monoxide difference; CPR, NADPH-CYP reductase; CYP, cytochrome P450; DiHETE, dihydroxyeicosatetraenoic acid; DTT, dithiothreitol; EGL, egg laying defect; EGLN, EGL nine; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ETYA, eicosatetraynoic acid; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HEET, hydroxyepoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HIF, hypoxia inducible factor; LC, liquid chromatography; MC, pharyngeal marginal cell; MS, mass spectrometry; NGM, nematode growth medium; PUFA, polyunsaturated fatty acid; RP, reversed-phase 5 INTRODUCTIONOxygen deprivation upon restriction of blood supply followed by reperfusion and concomitant reoxygenation causes tissue injury and is involved in the initiation of various human pathologies including ischemic stroke, myocardial infarction, and ac...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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“…Both quantity and purity of prepared eicosanoid stock solutions were confi rmed by LC/MS/MS measurements (data not shown). The compound used as 17,18-EEQ agonist was synthesized as described previously ( 21 ). To prevent autoxidation, all stock solutions, except for neurohormones, were prepared in an oxygen evacuated nitrogen chamber.…”

Section: Chemicalsmentioning

confidence: 99%

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

Zhou

Falck

Rothe

et al. 2015

Journal of Lipid Research

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“…[10] We have reported iridium-catalyzed synthesis of dialkylated ureas from ureas and alcohols. [11][12] The dialkylated ureas are important classess of biologically active compounds.However, the reaction required long reaction time (12 h). [13] Therefore, herein we wish to demonstrate that microwave irradiation significantly accelerated the process of the reaction.…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Efficient Synthesis of Dialkylated Ureas from Ureas

Li¹,

Ma²

2015

Proceedings of the 2015 International Conference on Education, Management, Information and Medicine

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Abstract. Microwave irradiation provided an effective tool for rapid, clean, and high-yielding transformations of organic reactions. Despite these advances, the N-alkylation of amines with alcohols under microwave irradiation remains less unexplored. We demonstrated a general and efficient method for the synthesis of dialkylated ureas from ureas under microwave irradiation is described. Reactios of ureas with a series of alcohols, such as benzyl alcohol, benzylic alcohols bearing a electron-donating group or a electron-withdrawing group, afforded the desired dialkylated ureas with good yields at a short time. Experimental results exhibited obvious advantages of microwave irradiation.

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17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure–Activity Relationships and Stable Analogues

Cited by 63 publications

References 55 publications

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

Microwave-Assisted Efficient Synthesis of Dialkylated Ureas from Ureas

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