54232-59-6Relevant articles and documents
Dehydrogenase reductase 9 (SDR9C4) and related homologs recognize a broad spectrum of lipid mediator oxylipins as substrates
Belyaeva, Olga V.,Boeglin, William E.,Brash, Alan R.,Goggans, Kelli R.,Karki, Suman,Kedishvili, Natalia Y.,Popov, Kirill M.,Wendell, Stacy G.,Wirth, Samuel E.
, (2022/01/31)
Bioactive oxylipins play multiple roles during inflammation and in the immune response, with termination of their actions partly dependent on the activity of yet-to-be characterized dehydrogenases. Here, we report that human microsomal dehydrogenase reductase 9 (DHRS9, also known as SDR9C4 of the short-chain dehydrogenase/reductase (SDR) superfamily) exhibits a robust oxidative activity toward oxylipins with hydroxyl groups located at carbons C9 and C13 of octadecanoids, C12 and C15 carbons of eicosanoids, and C14 carbon of docosanoids. DHRS9/SDR9C4 is also active toward lipid inflammatory mediator dihydroxylated Leukotriene B4 and pro-resolving mediators such as tri-hydroxylated Resolvin D1 and Lipoxin A4, although notably, with lack of activity on the 15-hydroxyl of prostaglandins. We also found that the SDR enzymes phylogenetically related to DHRS9, i.e., human SDR9C8 (or retinol dehydrogenase 16), the rat SDR9C family member known as retinol dehydrogenase 7, and the mouse ortholog of human DHRS9 display similar activity toward oxylipin substrates. Mice deficient in DHRS9 protein are viable, fertile, and display no apparent phenotype under normal conditions. However, the oxidative activity of microsomal membranes from the skin, lung, and trachea of Dhrs9?/? mice toward 1 μM Leukotriene B4 is 1.7- to 6-fold lower than that of microsomes from wild-type littermates. In addition, the oxidative activity toward 1 μM Resolvin D1 is reduced by about 2.5-fold with DHRS9-null microsomes from the skin and trachea. These results strongly suggest that DHRS9 might play an important role in the metabolism of a wide range of bioactive oxylipins in vivo.
Catalytic production of oxo-fatty acids by lipoxygenases is mediated by the radical-radical dismutation between fatty acid alkoxyl radicals and fatty acid peroxyl radicals in fatty acid assembly
Takigawa, Yuta,Koshiishi, Ichiro
, p. 258 - 264 (2020/11/26)
Oxo-octadecadienoic acids (OxoODEs) act as peroxisome proliferator-activated receptor (PPAR) agonists biologically, and are known to be produced in the lipoxygenase/linoleate system. OxoODEs seem to originate from the linoleate alkoxyl radicals that are generated from (E/Z)-hydroperoxy octadecadienoic acids ((E/Z)HpODEs) by a pseudoperoxidase reaction that is catalyzed by ferrous lipoxygenase. However, the mechanism underlying the conversion of alkoxyl radical into OxoODE remains obscure. In the present study, we confirmed that OxoODEs are produced in the lipoxygenase/linoleate system in an oxygen-dependent manner. Interestingly, we revealed a correlation between the (E/Z)-OxoODEs content and the (E/E)-HpODEs content in the system. (E/E)-HpODEs could have been derived from (E/E)-linoleate peroxyl radicals, which are generated by the reaction between a free linoleate allyl radical and an oxygen molecule. Notably, the ferrous lipoxygenase-linoleate allyl radical (LOx(Fe2+)-L·) complex, which is an intermediate in the lipoxygenase/linoleate system, tends to dissociate into LOx(Fe2+) and a linoleate allyl radical. Subsequently, LOx(Fe2+) converts (E/Z)-HpODEs to an (E/Z)-linoleate alkoxyl radical through one-electron reduction. Taken together, we propose that (E/Z)-OxoODEs and (E/E)-HpODEs are produced through radical-radical dismutation between (E/Z)-linoleate alkoxyl radical and (E/E)-linoleate peroxyl radical. Furthermore, the production of (E/Z)OxoODEs and (E/E)-HpODEs was remarkably inhibited by a hydrophobic radical scavenger, 2,2,6,6-tetra-methylpiperidine 1-oxyl (TEMPO). On the contrary, water-miscible radical scavengers, 4-hydroxyl-2,2,6,6-tetramethylpiperidine 1-oxyl (OH-TEMPO) and 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (CmΔP) only modestly or sparingly inhibited the production of (E/Z)-OxoODEs and (E/E)-HpODEs. These facts indicate that the radical-radical dismutation between linoleate alkoxyl radical and linoleate peroxyl radical proceeds in the interior of micelles.
Oxidation of C18 Hydroxy-Polyunsaturated Fatty Acids to Epoxide or Ketone by Catalase-Related Hemoproteins Activated with Iodosylbenzene
Teder, Tarvi,Boeglin, William E.,Brash, Alan R.
, p. 587 - 597 (2017/06/30)
Small catalase-related hemoproteins with a facility to react with fatty acid hydroperoxides were examined for their potential mono-oxygenase activity when activated using iodosylbenzene. The proteins tested were a Fusarium graminearum 41?kD catalase hemoprotein (Fg-cat, gene FGSG_02217), a Pseudomonas fluorescens Pfl01 catalase (37.5?kD, accession number WP_011333788.1), and a Mycobacterium avium ssp. paratuberculosis 33?kD catalase (gene MAP-2744c). 13-Hydroxy-octadecenoic acids (which are normally unreactive) were selected as substrates because these enzymes react specifically with the corresponding 13S-hydroperoxides (Pakhomova et al. 18:2559–2568, 5; Teder et al. 1862:706–715, 14). In the presence of iodosylbenzene Fg-cat converted 13S-hydroxy-fatty acids to two products: the 15,16-double bond of 13S-hydroxy α-linolenic acid was oxidized stereospecifically to the 15S,16R-cis-epoxide or the 13-hydroxyl was oxidized to the 13-ketone. Products were identified by UV, HPLC, LC–MS, NMR and by comparison with authentic standards prepared for this study. The Pfl01-cat displayed similar activity. MAP-2744c oxidized 13S-hydroxy-linoleic acid to the 13-ketone, and epoxidized the double bonds to form the 9,10-epoxy-13-hydroxy, 11,12-epoxy-13-hydroxy, and 9,10-epoxy-13-keto derivatives; equivalent transformations occurred with 9S-hydroxy-linoleic acid as substrate. In parallel incubations in the presence of iodosylbenzene, human catalase displayed no activity towards 13S-hydroxy-linoleic acid, as expected from the highly restricted access to its active site. The results indicated that with suitable transformation to Compound I, monooxygenase activity can be demonstrated by these catalase-related hemoproteins with tyrosine as the proximal heme ligand.
Macamides compound and synthetic method and application thereof
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Paragraph 0070; 0071; 0072; 0084; 0088, (2017/12/09)
The invention relates to the field of drugs, in particular to a macamides compound and a synthetic method and application thereof. The synthetic method of macamides comprises the steps that linoleic acid and an oxidizing agent are subjected to catalytic oxidation through pyridine derivatives to obtain a macaenes mixture; the macaenes mixture and benzylamine or benzylamine derivatives are subjected to amidation and then separated through preparative chromatography, wherein the oxidizing agent is one of 2,2,6,6-tempol-nitrogen-oxide, pyridinium tribromide, 2-Iodoxybenzoic acid; the benzylamine derivatives are 3-trimethoprim or 3,4-dimethoxybenzamine. Linoleic acid is adopted as a starting reactant to be synthesized, and compared with the prior art that mecamide is extracted from plant maca, the needed raw material is low in cost and easy to obtain; in addition, in the synthesis preparation process, operation is easy, few by-products are produced, the needed reagents and solvents are small in toxicity and easy to obtain, and the novel path is provided for preparing a large number of macamides monomeric compounds.
Physcomitrella patens has lipoxygenases for both eicosanoid and octadecanoid pathways
Anterola, Aldwin,G?bel, Cornelia,Hornung, Ellen,Sellhorn, George,Feussner, Ivo,Grimes, Howard
experimental part, p. 40 - 52 (2009/07/11)
Mosses have substantial amounts of long chain C20 polyunsaturated fatty acids, such as arachidonic and eicosapentaenoic acid, in addition to the shorter chain C18 α-linolenic and linoleic acids, which are typical substrates of lipoxygenases in flowering p
Characterization and quantification of free and esterified 9- and 13-hydroxyoctadecadienoic acids (HODE) in barley, germinating barley, and finished malt
Hobke, Holger,Garbe, Leif-Alexander,Tressl, Roland
, p. 1556 - 1562 (2007/10/03)
The analysis of (R)-9- and (S)-9-hydroxy-10E,12Z-octadecadienoic acid as well as (R)-13- and (S)-13-hydroxy-9Z,11E-octadecadienoic acid (HODE) as free acids, esterified in triacylglycerols (storage lipids), and esterified in polar lipids (phospholipids, glycolipids, etc.) in barley, germinating barley, and finished malt was performed using [13-18O1]-(S)-13-HODE isotope dilution assays with GC-MS and straight- and chiral-phase HPLC. 9- and 13-HODE occur approximately racemically in barley, indicating an autoxidation. The enantiomeric excesses increase to 78% S for free 9-HODE and to 58% S for free 13-HODE in germinating barley as a result of lipoxygenase-2 (LOX-2) catalysis, but free HODEs are at low concentration. More than 90% of HODEs in barley and malt are esterified. In the storage lipids of green malt 53 mg/kg 9-HODE and 147 mg/kg 13-HODE were detected. This ratio of 30:70 reflects the regioselectivity of the LOX-2 enzyme in malt. In the polar lipids 45 mg/kg 9-HODE and 44 mg/kg 13-HODE were characterized. The latter indicate a hitherto unknown 9-lipoxygenase activity with polar lipids as substrates. During kilning the contents of most HODEs decreased significantly due to chemical and enzymatic degradation, whereas polar-esterified (R)-13-HODE increased (43%) in the finished malt.
Regio- and stereoselective oxidation of linoleic acid bound to serum albumin: Identification by ESI-mass spectrometry and NMR of the oxidation products
Dufour, Claire,Loonis, Michele
, p. 60 - 68 (2007/10/03)
An efficient RP-HPLC method was developed for the detection of the oxidation products derived from the AAPH-initiated peroxidation of linoleic acid bound to human serum albumin. Diode array UV-detection allowed the quantification at 234 nm of four regioisomeric hydroperoxyoctadecadienoic acids (HPODE) and four hydroxyoctadecadienoic acids (HODE) while at 280 nm four oxooctadecadienoic acid isomers (KODE) were detected. Full identification of the different underivatized HODE, HPODE and KODE isomers was achieved by negative ESI-mass spectrometry outlining common fragmentation pathways for 9- and 13-regioisomers. Chemical synthesis of 9-(E,Z)-, 9-(E,E)-, 13-(Z,E)- and 13-(E,E)-KODE helped to their structural characterization by 1H NMR. Lipid peroxidation in the presence of albumin proved to be regioselective with a larger accumulation of 13-HPODE and 9-KODE isomers. Thermodynamically more stable E,E-stereoisomers were also favored by albumin for both HPODE and KODE.
9-Oxooctadeca-10,12-dienoic acids as Acetyl-CoA carboxylase inhibitors from red pepper (Capsicum annuum L.)
Watanebe, Jun,Kawabata, Jun,Kasai, Takanori
, p. 489 - 493 (2007/10/03)
A methanol extract of red pepper showed potent acetylCoA carboxylase inhibitory activity. The active principles were isolated and identified as (E, E)- and (E, Z)-9-oxooctadeca-10,12-dienoic acids by instrumental analyses. The IC50 values of the compounds were 1.4 x 10-6 and 1.5 x 10-6 M, respectively, their activity being nearly sixty-times higher than that of the common fatty acids themselves. A comparative study of the structure-activity relationship among their related compounds showed that the inhibitory activity was influenced neither by the position and species of the oxygen functional group in the middle of the alkyl chain nor by the configurations of the double bonds. However, it was found that the presence of double bonds between the terminal carboxyl and the mid-chain oxygen functional group lowered the inhibitory activity which could be recovered by hydrogenation of the double bonds.
High-Performance Liquid Chromatographic Analysis of the Products of Linoleic Acid Oxidation Catalyzed by Pea (Pisum sativum) Seed Lipoxygenases
Wu, Zecai,Robinson, David S.,Domoney, Claire,Casey, Rod
, p. 337 - 342 (2007/10/02)
An HPLC method is discussed for the analysis of the products formed by the pea (Pisum sativum) lipoxygenase catalyzed oxidation of linoleic acid.The results demonstrate the feasibility of analyzing all of the hydroperoxides, hydroxides, and keto fatty acids in a single chromatographic step and show that it will be possible to analyze the product profile from the lipoxygenase activity contained in a portion of a seed, which will permit the remainder of the seed to be grown on for subsequent generations.The chemical structures of the products have been identified by HPLC analysis and GC-MS. Keywords: Lipoxygenase; hydroperoxides; chromatography
Preparative Separation and 1H NMR Identification of Products of Linoleic Acid Autooxidation
Chudinova, V. V.,Chudinov, M. V.,Eremin, S. V.,Alekseev, S. M.
, p. 470 - 477 (2007/10/03)
Bulk phase oxidation of linoleic acid in a diffuse system in the dark at 2-5 deg C was found to produce three types of oxygenated derivatives.An effective method of HPLC on the nitrile phase was developed for the analysis and preparative isolation of products, which made it possible to prepare individual structural isomers of each type.After preliminary identification by chemical, chromatographic, and UV methods, the isolated compounds were identified as 9- and 13-isomers of hydroperoxy-, hydroxy-, and ketooctadecadienoic acids with Z-E-conjugated double bond systems.The formation of minor E-E-regioisomers of linoleic acid hydroperoxides was also observed.The assignment of signals in the 1H NMR spectra of the compounds isolated, including homonuclear proton-decoupled spectra, validated the proposed structures.It is suggested that the preferable formation of Z-E-isomers of oxygenated products during linoleic acid autooxidation under low temperature is connected with impossibility of overcoming the energy barrier of primary peroxyradical isomerization.Key words: polyunsaturated fatty acids, peroxidation, isolation and identification of products, high-performance liquid chromatography (HPLC), 1H NMR spectroscopy
