Docosanoid

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In biochemistry, docosanoids are signaling molecules made by the metabolism of twenty-two-carbon fatty acids (EFAs), especially the omega-3 fatty acid, docosahexaenoic acid (DHA) (i.e. 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid) by lipoxygenase, cyclooxygenase, and cytochrome P450 enzymes. Other docosanoids are metabolites of n-3 docosapentaenoic acid (DPA) (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid, or clupanodonic acid), n-6 DPA (i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid, or osbond acid), and docosatetraenoic acid (i.e. 7Z,10Z,13Z,16Z-docosatetraenoic acid, DTA, or adrenic acid). Prominent docosanoid metabolites of DPA and n-3 DHA are members of the specialized pro-resolving mediators class of polyunsaturated fatty acid metabolites that possess potent anti-inflammation, tissue healing, and other activities.

Contents

Prominent docosanoids

Specialized proresolving mediator docosanoids

Potently bioactive agents of the specialized proresolving mediator class include:

These DHA metabolites possess anti-inflammation and tissue-protection activities in animal models of inflammatory diseases; they are proposed to inhibit innate immune responses and thereby to protect from and to resolve a wide range of inflammatory responses in animals and humans. These metabolites are also proposed to contribute to the anti-inflammatory and other beneficial effects of dietary omega-3 fatty acids by being metabolized to them. [1] [2] [3] [4]

Neurofuran docosanoids

DHA can be converted non-enzymatically by free radical-mediated peroxidation to 8 different neurofuran regioisomers termed neuroprostanes and neurofuranes including 4-, 7-, 10-, 11-, 13-, 14-, 17-, and 20-series neurofurans/neuroporstanes for a total of 128 different racemic compounds. The most studied DHA-derived of these products are members of the 4-series, neurofuran 4-Fαneuroprostane and 4(RS)-ST-Δ6-8-neurofurane. These metabolites have been used mainly as biomarkers of oxidative stress that are formed in nerve tissues of the central nervous system. [5] [6]

Hydroxy-docosanoids

Cells metabolize DHA to 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HpDHA) and then rapidly reduce this hydroperoxide to 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HDHA) and similarly metabolize DHA to 13S-hydroperoxy-4Z,7Z,10Z,14Z,16Z,19Z-docosahexaenoic acid (13-HpDHA) and then to 13S-hydroxy-4Z,7Z,10Z,14Z,16Z,19Z-docosahexaenoic acid (13-HDHA). 17-HDHA exhibits potent in vitro as well as in vivo (animal model) anti-inflammatory activity while 17-HpDHA and to a lesser extent 17-HDHA inhibit the growth of cultured human breast cancer cells. [7] [8] Other SPM docosanoids, e.g. RvD1 and RvD2, have anti-growth effects against cancer cells in animal models. [9]

Oxo-docosanoids

Cells can metabolize DHA to products that possess an oxo (i.e. ketone) residue. These products include 13-oxo-DHA (termed EFOXD6) and 17-oxo-DHA (termed 18-EFOXD6). Both oxo metabolites possess anti-inflammatory activity as assesses in in vitro systems (see Specialized proresolving mediators § Oxo-DHA and oxo-DPA metabolites). [10]

DTA-derived docosanoids

Cyclooxygenase and cytochrome P450 oxidase act upon docosatetraenoic acid to produce dihomoprostaglandins, [11] dihomo-epoxyeicosatrienoic acids, [12] and dihomo-EETs. [13]

Related Research Articles

Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health, but cannot synthesize them.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil. The consumption of DHA contributes to numerous physiological benefits, including cognition. As the primary structural component of nerve cells in the brain, the function of DHA is to support neuronal conduction and to allow optimal function of neuronal membrane proteins.

<span class="mw-page-title-main">Resolvin</span> Class of chemical compounds

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).

<span class="mw-page-title-main">Docosatetraenoic acid</span> Chemical compound

Docosatetraenoic acid designates any straight chain 22:4 fatty acid.

Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, all-cis-4,7,10,13,16-docosapentaenoic acid and all-cis-7,10,13,16,19-docosapentaenoic acid. They are also commonly termed n-6 DPA and n-3 DPA, respectively; these designations describe the position of the double bond being 6 or 3 carbons closest to the (omega) carbon at the methyl end of the molecule and is based on the biologically important difference that n-6 and n-3 PUFA are separate PUFA classes, i.e. the omega-6 fatty acids and omega-3 fatty acids, respectively. Mammals, including humans, can not interconvert these two classes and therefore must obtain dietary essential PUFA fatty acids from both classes in order to maintain normal health.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">Formyl peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">GPR32</span> Human biochemical receptor

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

In cell biology, efferocytosis is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'.

<span class="mw-page-title-main">Maresin</span> Chemical compound

Maresin 1 (MaR1 or 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are 12-lipoxygenase-derived metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), that possess potent anti-inflammatory, pro-resolving, protective, and pro-healing properties similar to a variety of other members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid (PUFA) metabolites. SPM are dihydroxy, trihydroxy, and epoxy-hydroxy metabolites of long chain PUFA made by certain dioxygenase enzymes viz., cyclooxygenases and lipoxygenases. In addition to the maresins, this class of mediators includes: the 15-lipoxygenase (i.e. ALOX15 and/or possibly ALOX15B)-derived lipoxin A4 and B4 metabolites of the omega 6 fatty acid, arachidonic acid; the cyclooxygenase 2-derived resolvin E series metabolites of the omega 3 fatty acid, eicosapentaenoic acid; certain 15-lipoxygenase-derived resolvin D series metabolites of DHA; certain other 15-lipoxygenase-derived protectin D1 and related metabolites of DHA; and the more recently defined and therefore less fully studied 15-lipoxygenase-derived resolvin Dn-3DPA metabolites of the omega-3 fatty acid n-3 docosapentaenoic acid (n-3 DPA or clupanodonic acid), the cyclooxygenase 2-derived resolvin T metabolites of this clupanodonic acid, and the 15-lipoxygenase-derived products of the N-acetylated fatty acid amide of the DHA metabolite, docosahexaenoyl ethanolamide.

Protectin D1 also known as neuroprotectin D1 and abbreviated most commonly as PD1 or NPD1 is a member of the class of specialized proresolving mediators. Like other members of this class of polyunsaturated fatty acid metabolites, it possesses strong anti-inflammatory, anti-apoptotic and neuroprotective activity. PD1 is an aliphatic acyclic alkene 22 carbons in length with two hydroxyl groups at the 10 and 17 carbon positions and one carboxylic acid group at the one carbon position.

<span class="mw-page-title-main">13-Hydroxyoctadecadienoic acid</span> Chemical compound

13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE). The production of 13(S)-HODE is often accompanied by the production of its stereoisomer, 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE). The adjacent figure gives the structure for the (S) stereoisomer of 13-HODE. Two other naturally occurring 13-HODEs that may accompany the production of 13(S)-HODE are its cis-trans (i.e., 9E,11E) isomers viz., 13(S)-hydroxy-9E,11E-octadecadienoic acid (13(S)-EE-HODE) and 13(R)-hydroxy-9E,11E-octadecadienoic acid (13(R)-EE-HODE). Studies credit 13(S)-HODE with a range of clinically relevant bioactivities; recent studies have assigned activities to 13(R)-HODE that differ from those of 13(S)-HODE; and other studies have proposed that one or more of these HODEs mediate physiological and pathological responses, are markers of various human diseases, and/or contribute to the progression of certain diseases in humans. Since, however, many studies on the identification, quantification, and actions of 13(S)-HODE in cells and tissues have employed methods that did not distinguish between these isomers, 13-HODE is used here when the actual isomer studied is unclear.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

Dihydroxy-E,Z,E-PUFA are metabolites of polyunsaturated fatty acids (PUFA) that possess two hydroxyl residues and three in series conjugated double bonds having the E,Z,E cis-trans configuration. These recently classified metabolites are distinguished from the many other dihydroxy-PUFA with three conjugated double bonds that do not have this critical E,Z,E configuration: they inhibit the function of platelets and therefore may be involved in controlling and prove useful for inhibiting human diseases which involve the pathological activation of these blood-borne elements.

References

  1. ↑ Calder PC (2015). "Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 469–84. doi:10.1016/j.bbalip.2014.08.010. PMID   25149823.
  2. ↑ Serhan CN, Chiang N, Dalli J, Levy BD (2015). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology. 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMC   4315926 . PMID   25359497.
  3. ↑ Barden AE, Mas E, Mori TA (2016). "n-3 Fatty acid supplementation and proresolving mediators of inflammation". Current Opinion in Lipidology. 27 (1): 26–32. doi:10.1097/MOL.0000000000000262. PMID   26655290. S2CID   45820130.
  4. ↑ Balas L, Durand T (2016). "Dihydroxylated E,E,Z-docosatrienes. An overview of their synthesis and biological significance". Progress in Lipid Research. 61: 1–18. doi:10.1016/j.plipres.2015.10.002. PMID   26545300.
  5. ↑ Arneson KO, Roberts LJ (2007). "Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and neurofurans". Lipidomics and Bioactive Lipids: Specialized Analytical Methods and Lipids in Disease. Methods in Enzymology. Vol. 433. pp. 127–43. doi:10.1016/S0076-6879(07)33007-3. ISBN   9780123739667. PMID   17954232.
  6. ↑ Leung KS, Galano JM, Durand T, Lee JC (2015). "Current development in non-enzymatic lipid peroxidation products, isoprostanoids and isofuranoids, in novel biological samples". Free Radical Research. 49 (7): 816–26. doi:10.3109/10715762.2014.960867. PMID   25184341. S2CID   34479417.
  7. ↑ Chiu CY, Gomolka B, Dierkes C, Huang NR, Schroeder M, Purschke M, Manstein D, Dangi B, Weylandt KH (2012). "Omega-6 docosapentaenoic acid-derived resolvins and 17-hydroxydocosahexaenoic acid modulate macrophage function and alleviate experimental colitis". Inflammation Research. 61 (9): 967–76. doi:10.1007/s00011-012-0489-8. PMID   22618200. S2CID   18265905.
  8. ↑ O'Flaherty JT, Hu Y, Wooten RE, Horita DA, Samuel MP, Thomas MJ, Sun H, Edwards IJ (2012). "15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival". PLOS ONE. 7 (9): e45480. Bibcode:2012PLoSO...745480O. doi: 10.1371/journal.pone.0045480 . PMC   3447860 . PMID   23029040.
  9. ↑ Serhan CN, Chiang N, Dalli J (2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology. 27 (3): 200–15. doi:10.1016/j.smim.2015.03.004. PMC   4515371 . PMID   25857211.
  10. ↑ Weylandt KH (2015). "Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell". European Journal of Pharmacology. 785: 108–115. doi:10.1016/j.ejphar.2015.11.002. PMID   26546723.
  11. ↑ Campbell WB, Falck JR, Okita JR, Johnson AR, Callahan KS (1985). "Synthesis of dihomoprostaglandins from adrenic acid (7,10,13,16-docosatetraenoic acid) by human endothelial cells". Biochim. Biophys. Acta. 837 (1): 67–76. doi:10.1016/0005-2760(85)90086-4. PMID   3931686.
  12. ↑ Kopf PG, Zhang DX, Gauthier KM, Nithipatikom K, Yi XY, Falck JR, Campbell WB (2010). "Adrenic acid metabolites as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors". Hypertension. 55 (2): 547–54. doi:10.1161/HYPERTENSIONAHA.109.144147. PMC   2819927 . PMID   20038752.
  13. ↑ Yi XY, Gauthier KM, Cui L, Nithipatikom K, Falck JR, Campbell WB (May 2007). "Metabolism of adrenic acid to vasodilatory 1α,1β-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries". Am J Physiol Heart Circ Physiol. 292 (5): H2265–74. doi: 10.1152/ajpheart.00947.2006 . PMID   17209008. S2CID   86090552.
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