Enzymes and Receptors of Prostaglandin Pathways with Arachidonic Acid-derived Versus Eicosapentaenoic Acid-derived Substrates and Products*♦

  title={Enzymes and Receptors of Prostaglandin Pathways with Arachidonic Acid-derived Versus Eicosapentaenoic Acid-derived Substrates and Products*♦},
  author={Masayuki Wada and Cynthia J. DeLong and Yu H. Hong and Caroline Jill Rieke and Inseok Song and Ranjinder S. Sidhu and Chong Yuan and Mark Warnock and Alvin H. Schmaier and Chieko Yokoyama and Emer M. Smyth and Stephen J. Wilson and Garret A. FitzGerald and R. Michael Garavito and Dexin Sui and John W. Regan and William L. Smith},
  journal={Journal of Biological Chemistry},
  pages={22254 - 22266}
Dietary fish oil containing ω3 highly unsaturated fatty acids has cardioprotective and anti-inflammatory effects. Prostaglandins (PGs) and thromboxanes are produced in vivo both from the ω6 fatty acid arachidonic acid (AA) and the ω3 fatty acid eicosapentaenoic acid (EPA). Certain beneficial effects of fish oil may result from altered PG metabolism resulting from increases in the EPA/AA ratios of precursor phospholipids. Here we report in vitro specificities of prostanoid enzymes and receptors… 

Arachidonic Acid-metabolizing Cytochrome P450 Enzymes Are Targets of ω-3 Fatty Acids*

It is found that these ω-3 epoxides are highly active as antiarrhythmic agents, suppressing the Ca2+-induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations.

Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis*

The distinctive binding specificities of PGHS subunits permit different combinations of non-esterified FAs, which can be manipulated dietarily, to regulate AA binding to Eallo and/or Ecat thereby controlling COX activities.

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway[S]

It is proposed that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation.

Cytochrome P 450-dependent metabolism of-6 and-3 long-chain polyunsaturated fatty acids

The currently available data suggest that some of the vasculoand cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA.

Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid*

These studies have, for the first time, definitively characterized novel, highly reactive A/J-ring IsoP compounds that form in abundance from the oxidation of EPA in vivo.

The factor in EDHF: Cytochrome P450 derived lipid mediators and vascular signaling.

Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells.

It is concluded that EPA-FFA drives a COX-2-dependent "PGE (2)-to-PGE(3) switch" in human CRC cells and that PGE (3) acts as a partial agonist at the PGE(2) EP4 receptor.

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

In resident peritoneal macrophages, docosapentaenoic acid (DPA) was responsible for cyclooxygenase inhibition after EPA supplementation, offering fresh insights into how EPA exerts anti-inflammatory effects indirectly through elongation to 22-carbon DPA.



Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1*

Crystal structures of eicosapentaenoic acid and linoleic acid bound in the cyclooxygenase active site of Co3+ protoporphyrin IX-reconstituted ovine PGHS-1 are reported and the effects of active site substitutions on the rates of oxygenation of EPA, LA, and arachidonic acid are compared.

Formation of F-ring Isoprostane-like Compounds (F3-Isoprostanes) in Vivo from Eicosapentaenoic Acid*

These studies provide the first evidence that identify F3-IsoPs as novel oxidation products of EPA that are generated in vivo, and may provide valuable insights into the cardioprotective mechanism of EPA.

Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthases

The divergence in cyclooxygenase characteristics between the trout and mammalian PGHS proteins may reflect accomodations to differences among vertebrates in tissue lipid composition and general redox state.

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands*

Comparisons of reaction rates and catalytic efficiency showed that EETs are one of the best endogenous substrates so far described for rat CYP4A isoforms, suggesting a role for them as endogenous ligands for these orphan nuclear receptors.

Prostaglandin Endoperoxide H Synthase-1

Prostaglandin endoperoxide H synthases (PGHSs) catalyze the committed step in the biosynthesis of prostaglandins and thromboxane, the conversion of arachidonic acid, two molecules of O2, and two

Fatty Acid Substrate Specificities of Human Prostaglandin-endoperoxide H Synthase-1 and −2

Human prostaglandin-endoperoxide H synthase-1 and −2 were expressed by transient transfection of COS-1 cells and substrate specificities suggest that α-linolenate is positioned in the cyclooxygenase active site with a kink in the carbon chain such that hydrogen abstraction occurs from the 5-position in contrast to abstraction of the 8-hydrogen from other substrates.

Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.

Results demonstrate that inhibition of COX-2 expression by n-3 PUFAs is mediated through the modulation of TLR-mediated signaling pathways, and the beneficial or detrimental effects of different types of dietary fatty acids on the risk of the development of many chronic inflammatory diseases may be in part mediated throughThe modulation ofTLRs.

E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation1

It is demonstrated that PGE2 promotes acute inflammation by activating EP3 receptors and suggest thatEP3 receptors may be useful targets for anti-inflammatory therapy.