Eicosanoids PDF

MEDICAL BIOCHEMISTRY II Eicosanoids Objectives: Know what an Eicosanoid is and what they do Know how lipids are removed from membranes Be able to explain the difference between bioactive lipids formed from omega 3 and 6 FA METABOLISM OF EICOSANOIDS Know how Eicosanoids form (precursors) Know the str...

MEDICAL BIOCHEMISTRY II Eicosanoids Objectives: Know what an Eicosanoid is and what they do Know how lipids are removed from membranes Be able to explain the difference between bioactive lipids formed from omega 3 and 6 FA METABOLISM OF EICOSANOIDS Know how Eicosanoids form (precursors) Know the structure of Eicosanoids Know the different categories of Eicosanoids Know the function of Eicosanoids Know the importance of cyclooxygenase Know how Eicosanoids are inhibited and inactivated Know what membrane lipids synthesize endocannabinoids ESSENTIAL FA CANNOT BE SYNTHESIZED IN MAMMALIAN HEPATOCYTES Mammalian enzymes can readily introduce double bonds at the Δ9 position but no additional bonds can be introduced between C-10 and the methyl terminal end Mammalian hepatocytes cannot synthesize 18:2(Δ9,12, linoleate) or 18:3(Δ9, 12, 15, αlinolenate) Plants can synthesize both: the desaturases that introduce double bonds at the Δ12 and the Δ15 positions are located in the smooth ER and in chloroplasts ω3 fatty acids & ω6 fatty acids must be present in diet or the diet must contain other fatty acids that can be converted to these fatty acids for eicosanoid synthesis Linoleic acid can be converted by elongation and desaturation to arachidonic acid used for the synthesis of prostaglandins and other eicosanoids Elongation and desaturation of αlinolenic acid produces eicosapentaenoic acid (EPA), precursor of a different class of eicosanoids The essential fatty acid linoleic acid is required in the diet for at least three reasons: it serves as a precursor of arachidonic acid it covalently binds another fatty acid attached to cerebrosides in the skin, forming an unusual lipid (acyglucosylceramide) Glucosylceramide is major glycosphingolipid of the epidermis it is the precursor of C22:6ω3, an important neuronal fatty acid. The other essential fatty acid, αlinolenic acid also forms eicosanoids OMEGA 6 VS. OMEGA 3 Omega 6 Omega 3 Incorporate into membranes Incorporate into membranes Form AA Form precursors to resolvins and protectins (anti-inflammatory) Proinflammatory D series from DHA E series for EPA DHA important for normal brain development EICOSANOIDS OVERVIEW Local hormones, impact cells nearby and include: Prostaglandins (PG, identified in prostate gland) Thromboxanes (TX, identified in platelets) Leukotrienes (LT, identified in leukocytes) Lipoxins (LX, synthesized through lipoxygenase interactions) Important inflammation modulating eicosanoid derivatives PROSTANOIDS Prostaglandins and thromboxanes Nomenclature includes a subscript number that refers to the number of carbon-carbon double bonds Biologically active lipids are usually series 2 There are important series 1 as well CLINICALLY RELEVANT EICOSANOIDS PGE2 – known as dinoprostone – principal mediator of inflammation – both pro and anti inflammatory TXA2 – stimulates activation of platelets and platelet aggregation LTB4 – involved in inflammation and may promote insulin resistance LXA4 – anti-inflammatory mediator (aspirin can trigger production of) LXB4 – presence signals resolution of inflammation ROLE OF PHOSOPHOLIPASES located in cell membranes or lysosomes and degrade glycerolphosphlipids Phospholipase A1 – removes fatty acyl group on C1 of phospholipids Phospholipase A2 removes fatty acid on C2. C2 is usually an unsaturated FA in cell membrane phospholipids and frequently arachidonic acid Phospholipase C cleaves the bond between C3 and glycerol Phospholipase D cleaves Bond between phosphate and head group E series RESOLVINS: MAJOR IMMUNE MODULATING LIPID FROM OMEGA 3 FA From EPA RvE1 increase following aspirin or consuming EPA Reduce inflammation Block transendothelial migration Reduce immune cell function (specifically dendritic cells) Resolve inflammatory responses D series From DHA D1 formed in the presence of aspirin and DHA Block T cell and PMN migration Promote T cell apoptosis Decrease pro-inflammatory cytokine secretion Reduce airway inflammation EICOSANOID SYNTHESIS All cells except RBCs can synthesize Eicosanoids are potent: a little goes a long way Eicosanoids work locally: autocrine or paracrine Receptors are G proteins Two main pathways for synthesis 1. Cyclic pathway: prostaglandins 2. Linear pathway: leukotrienes GETTING AA OUT OF THE MEMBRANE FUNCTION OF PGD2 Produced by MAST cells MAST cells are important producers of histamine during an inflammatory response PGD2 promotes: Immune cell recruitment Bronchoconstriction Vasodilation FUNCTION OF PGE2: DINOPROSTONE Main effects Cervical “ripening” Uterine contraction Abortifacient Other effects Vasodilation Bronchoconstriction Protect stomach lining Increase body temp Promote inflammation FUNCTION OF PGF2A: DINOPROST Uterine contraction Bronchoconstriction Abortifacient INACTIVATION OF PROSTAGLANDINS & THROMBOXANES Prostaglandins and thromboxanes are rapidly inactivated from seconds to minutes By oxidation of the 15hydroxy group, critical for their activity, to a ketone b- and w- oxidation of the non-ring portions occur, producing dicarboxylic acids that are excreted in the urine Double bond at carbon13 is reduced TXA2 is rapidly metabolized to TXB2 by cleavage of the oxygen bridge LEUKOTRIENE SYNTHESIS: LINEAR PATHWAY Initiated by arachidonate lipoxygenases (LOXs) 1. 5-LOX (arachidonate 5-lipoxygenase) 2. 12-LOX (arachidonate 12-lipoxygenase) 3. 15-LOX (arachidonate 15-lipoxygenase) Leukotriene are made by: white blood cells, mast cells, lung, spleen, brain and heart 12-LOX and 15-LOX are involved in the synthesis of lipoxins LIPOXYGENASE PATHWAY: SYNTHESIS OF THE LEUKOTRIENES, HETE, AND LIPOXINS Arachidonic acid also acts as a substrate for the lipoxygenase pathway Lipoxygenase catalyzes incorporation of an oxygen molecule onto a carbon of one of several double bonds of arachidonic acid, forming a hydroperoxy (-OOH) group Double bond isomerizes to a position one carbon removed from the hydroperoxy group and is transformed from cis to trans Unstable hydroperoxy group is converted to hydroxy group LT FUNCTION LTB4 increases: Vascular permeability T-cell proliferation Leukocyte aggretation INF-g (interferon), IL-1, IL-2 LTC4, LTD4 increase: Brochoconstriction Vascular permeability INF-g (interferon) Fig. 11* ASPIRIN Inhibits action of COX-1 and COX-2 via acetylation COX-1 is constitutively expressed COX-2 is inducible following inflammation in immune cells In endothelial and epithelial cells acetylation of COX-2 alters the enzyme to form 15R hydroxyeicosatetraenoic acid (15R-HETE) Series 2 prostaglandins and thromboxanes are pro-inflammatory (PGE2 and TXA2 especially) Series 4 leukotrienes (LTB4 especially) EICOSANOIDS AND INFLAMMATION NSAIDS (non-steroidal anti-inflammatory drugs target cyclooxygenase activity (both COX-1 and COX-2) NSAIDS include aspirin, ibuprofen, indomethacin, naproxen and phenylbutazone CORTICOSTEROIDAL DRUGS Target PLA2 Prevents AA release from membrane PATHWAYS FOR AA CYTOCHROME P450 PATHWAY: SYNTHESIS AND ACTIONS OF EPOXIDES, HETES, AND DIHETES A mechanism for the oxygenation of AA involves the cytochrome P450 pathway The activity of the monooxygenases in this microsomal system yields epoxides, certain forms of HETEs and diol forms (diHETEs) Fig. 35.13 The biologic activities of these compounds include actions in ocular, vascular, endocrine, and renal systems This eicosanoid-receptor binding either activates the adenylate cyclase-cAMP-protein kinase A system (PGE, PGD, and PGI series) or causes an increase in the level of calcium in the cytosol of target cells (PGF2a, TXA2, the endoperoxides, and the leukotrienes) MECHANISM OF ACTION OF THE EICOSANOIDS The eicosanoid may bind to a regulatory subunit of the GTP-binding proteins (G proteins) within the plasma membrane of the target cell If the eicosanoid binds to the stimulatory subunit, the effect of the stimulus is amplified Conversely, if the eicosanoid binds to the inhibitory subunit, the cellular response to the stimulus is reduced ISOPROSTANE SYNTHESIS Isoprostanes are derived from arachidonic acid by lipid peroxidation, initiated by free radicals Arachidonic acid, while still a component of a phospholipid, undergoes free radical damage, and then phsopholipase A2 removes the altered eicosanoid from the phospholipid and releases it into circulation Useful biologic marker for patients undergoing oxidative stress ENDOCANNABINOID SYNTHESIS Endocannabinoids are endogenous ligands for the cannabinoid receptor, with effects primarily in the nervous system Anandamide is synthesized in neurons from phosphatidylethanolamine Intracellular calcium elevation is key for endocannabinoid synthesis Calcium levels increase due to depolarization-induced influx following neurotransmission on post-synaptic neuron ENDOCANNABINOID SYNTHESIS Calcium influx activated the transacylase (TAE) Phospholypase D cleaves NAPE to yield anandamide Once anandamide is released, it acts as a retrograde messenger, binding to receptors on the presynaptic membrane that alter ion fluxes such that neurotransmitter release from the presynaptic neuron can be increased and results in an analgesic effect