Eicosanoid Synthesis and Metabolism: Prostaglandins, Thromboxanes, Leukotrienes, Lipoxins


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Introduction to the Eicosanoids

The eicosanoids consist of the prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and lipoxins (LX). The PGs and TXs are collectively identified as prostanoids. The nomenclature of the prostanoids includes a subscript number which refers to the number of carbon-carbon double bonds that exist in the molecule. The majority of the biologically active prostaglandins and thromboxanes are referred to as series 2 molecules due to the presence of two double bonds. The predominant leukotrienes are series 4 molecules due to the presence of four double bonds. There are, however, important series 1 prostaglandins and thromboxanes as described below.

 

 

 

 

 

 

 

 

 

 

Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. The lipoxins are anti-inflammatory eicosanoids synthesized through lipoxygenase interactions (hence the derivation of the name). Lipoxins are potent anti-inflammatory eicosanoid derivatives and their synthesis can be increased in response to ingestion of aspirin (see the Lipid-Derived Inflammatory Modulators page for more details on lipoxin functions). An additional class of anti-inflammatory lipid compounds, whose syntheses can also be triggered by aspirin, are the resolvins (Rv) and the protectins (PD) and these are also discussed in the Lipid-Derived Inflammatory Modulators page.

Structures of Representative Clinically Relevant Eicosanoids

Structure of PGE2

PGE2

Structure of TXA2

TXA2

Structure of LTB4

LTB4

Structure of LXA4

LXA4

Structure of LXB4

LXB4

The eicosanoids produce a wide range of biological effects on inflammatory responses (predominantly those of the joints, skin and eyes), on the intensity and duration of pain and fever, and on reproductive function (including the induction of labor). They also play important roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis.

The principal eicosanoids of biological significance to humans are a group of molecules derived from the C20 fatty acid, arachidonic acid. Additional biologically significant eicosanoids are derived from dihomo-γ-linolenic acid (DGLA) which is produced in the reaction pathway leading to arachidonic acid from linoleic acid (see Figure below). Minor eicosanoids are derived from eicosapentaenoic acid which is itself derived from α-linolenic acid or obtained in the diet. The major source of arachidonic acid is through its release from cellular stores. Within the cell, it resides predominantly at the C–2 position of membrane phospholipids and is released from there upon the activation of PLA2 (see Lipid Synthesis page for details).

The immediate dietary precursor of arachidonate is linoleic acid. Linoleic acid is converted to arachidonic acid through the steps outlined in the figure below. The activity of the Δ6-desaturase (D6D) is slow and can be further compromised due to nutritional deficiencies as well as during inflammatory conditions. Therefore, maximal capacity for synthesis of arachidonic acid occurs with ingested γ-linolenic acid (GLA) the product of the Δ6-desaturase. GLA is converted to dihomo-γ-linolenic acid (DGLA) and then to arachidonic acid. Like the Δ6-desaturase, the activity of the Δ5-desaturase (D5D) is limiting in arachidonic acid synthesis and its activity is also influenced by diet and environmental factors. Due to the limited activity of the Δ5-desaturase most of the DGLA formed from GLA is inserted into membrane phospholipids at the same C-2 position as for arachidonic acid.

The major dietary sources of GLA are borage oil, evening primrose seed oil, hemp seed oil, and black currant seed oil. Diets containing sources of GLA have been shown have distinct cardiovascular benefit similar to diets rich in omega-3 polyunsaturated fatty acids such as is found in cold water fishes (see above).

Reactions of arachidonic acid synthesis

Arachidonic acid synthesis


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Metabolism of the Eicosanoids

All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways.

Two main pathways are involved in the biosynthesis of eicosanoids. The prostaglandins and thromboxanes are synthesized by the cyclic pathway, the leukotrienes by the linear pathway.

The cyclic pathway is initiated through the action of prostaglandin G/H synthase, PGS (also called prostaglandin endoperoxide synthetase). This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase. There are two forms of the COX activity in humans. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells. COX-2 (PGS-2) is inducible and is expressed in macrophages and monocytes in response to inflammation. The primary triggers for COX-2 induction in monocytes and macrophages are platelet-activating factor, PAF and interleukin-1, IL-1. Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic acid to PGG2 and then to PGH2.


Synthesis of the prostaglandins

Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from cellular membrane phospholipids. As shown, the bradykinin receptor (specifically BDKR2) is coupled to both Gi/0 and Gq G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC. Both PKC phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated, hydrolyze arachidonic acid from PIP2. Arachidonic acid is converted to PGH2 via the action of the bi-functional enzymes COX-1 and COX-2 (also called prostaglandin G/H synthase, PGS or prostaglandin endoperoxide synthetase). The prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin. PGE2 is synthesized from PGH2 via the action of one of several PGE synthases, where PGE synthase-1 (PGES1) appears to be the key enzyme. Two forms of PGD2 synthases have been identified (hematopoietic and lipocalin prostaglandin D synthases, hPGDS and lPGDS) that convert PGD2 from PGH2. Prostacyclin (PGI2) is synthesized from PGH2 via the action of prostacyclin synthase (PGIS). Prostaglandin F synthase (PGFS) converts PGH2 to PGF or PGD2 to 9α,11β-PGF2α,β. The principal thromboxanes (TXA2 and TXB2) are derived PGH2 via the action if thromboxane synthase. The three most physiologically significant cyclic eicosanoids are enclosed in the red boxes. Green arrows denote positive effects. The subscript 2 in each molecule refers to the number of carbon-carbon double bonds present. LPI: lysophosphoinositol. Place mouse over structure names to see the structure.


The linear pathway is initiated through the action of lipoxygenases (LOXs) of which there are three forms, 5-LOX, 12-LOX and 15-LOX. It is 5-LOX that gives rise to the leukotrienes. The leukotrienes are synthesized by several different cell types including white blood cells (leukocytes, hence the derivation of the name of the compounds), mast cells, lung, spleen, brain and heart.

Synthesis of the leukotrienes

Synthesis of the clinically relevant leukotrienes from arachidonic acid. The leukotrienes are identified as LT. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from cellular membrane phospholipids. As shown, the bradykinin receptor (specifically BDKR2) is coupled to both Gi/0 and Gq G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC. Both PKC phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated, hydrolyze arachidonic acid from PIP2. The enzyme, 5-lipoxygenase (5-LOX) in association with the protein, 5-LOX activating protein (FLAP), catalyzes the conversion of arachidonic acid, first to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE), and then to LTA4. LTA4 is unstable and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. LTB4 is enclosed in a red box to denote its critical significance as one of the most potent inflammation-medicating lipids. In mast cells and eosinophils, which harbor LTC4 synthase, LTA4 is converted to LTC4. The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids. The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA). SRSA was originally identified as an activity released from sensitized lung after immunologic challenge. Green arrows denote positive effectes. LPI: lysophosphoinositol. The subscript 4 in each molecule refers to the number of carbon-carbon double bonds present. Place mouse over structure names to see the structure.


The lipoxins are synthesized through the concerted actions of 15-LOX (acting on arachidonic acid in epithelial cells, such as in the airway) followed by 5-LOX in leukocytes or through the actions of 5-LOX in leukocytes followed by 12-LOX action in platelets. Details of the functions of the lipoxins can be found in the Lipid-Derived Inflammatory Modulators page.

Synthesis of the lipoxins

Synthesis of the lipoxins from arachidonic acid via transcellular interactions. Three pathways exist for the synthesis of the lipoxins. The "classic" pathway involves 5-LOX activity in leukocytes followed by 12-LOX action in platelets. The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX action in leukocytes is the second major lipoxin synthesis pathway. The action of aspirin on COX-2 (see the Lipid-Derived Inflammatory Modulators page for more details) in epithelial, or endothelial cells as wells as in monocytes results in the eventual production of the 15 epi-lipoxins (also referred to as aspirin triggered lipoxins, ATLs).

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Eicosanoids and Inflammatory Responses

Each of the eicosanoids function via interactions with cell-surface receptors that are members of the G-protein coupled receptor (GPCR) family. There are at least 9 characterized prostaglandin receptors. Receptors that bind the prostaglandin D family of lipids are called the PGD receptors and those that bind E family prostaglandins are called the PGE receptors. The PGD receptors are coupled to the production of cAMP and activation of PKA. The PGE receptors couple to the activation of PLCγ and as a consequence the production of DAG and IP3 from membrane phospholipids. The receptor for prostacyclin (PGI2) is called the PC receptor and it couples to production of cAMP. There are 2 receptors that bind LTB4 called BLT1 and BLT2. The peptidoleukotrienes (cysteinyl leukotrienes) bind to receptors called CysLT1 and CysLT2. The thromboxane receptor is coupled to the activation of PLCγ.

As indicated in the Table below, the major actions of the series-2 prostaglandins and thromboxanes (predominantly PGE2 and TXA2) are pro-inflammatory as are the series-4 leukotrienes (predominantly LTB4). Thus, it makes sense that drugs that reduce the production of these compounds would be beneficial at reducing inflammation and the associated vascular pathologies. A widely used class of drugs, the non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, and phenylbutazone all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2. Aspirin is unique among the class of NSAIDs in that its actions on relief from pain (analgesia) and as an anti-inflammatory as well as a heart protective drug are not solely due to its ability to inhibit COX activity (see the Lipid-Derived Inflammatory Modulators page for details).

Research over the past 10–15 years has demonstrated the physiological benefits (i.e. anti-inflammatory) of alternative pathways of polyunsaturated fatty acid metabolism. Much of this topic is covered in the Lipid-Derived Inflammatory Modulators page. As described above for the synthesis of arachidonate, much of the DGLA derived from ingested linoleic acid or GLA is diverted into membrane phospholipids due to the inefficiency of the Δ5-desaturase catalyzing the conversion of DGLA to arachidonic acid. Incorporation of DGLA into membrane phospholipids competes with the incorporation of arachidonate so that diets enriched in GLA result in an alteration in the ratio of membrane arachidonate to DGLA. Release of membrane DGLA occurs through the action of PLA2 just as for release of arachidonate. Once DGLA is released it will compete with arachidonate for COXs and LOXs. The products of COX action on DGLA are series-1 prostaglandins (PGE1) and thromboxanes (TXA1). These eicosanoids are structurally similar to the series-2 eicosanoids except, of course, they have a single double bond. Although structurally similar, the series-1 eicosanoids have distinctly different biological actions. PGE1 and TXA1 are anti-inflammatory, they induce vasodilation, and they inhibit platelet aggregation. When DGLA is a substrate for 15-LOX the product is 15-hydroxyeicosatrienoic acid (15-HETrE). 15-HETrE is a potent inhibitor of 5-LOX which is the enzyme responsible for the conversion of arachidonic acid to LTB4. LTB4 is a potent inflammatory molecule through its action on neutrophils, thus, DGLA serves to inhibit inflammation via the linear eicosanoid pathway as well.

Due to the vasodilating action of PGE1 it is used pharmaceutically as alprostadil for the treatment of erectile dysfunction (ED). The ED applications of PGE1 are sold as MUSE® and Caverject®. MUSE is a urethral suppository and Caverject is an injectable version. Alprostadil is also used clinically to treat newborn infants with ductal-dependent congenital heart disease. The administration of alprostadil in these infants maintains a patent ductus arteriosus until surgery can carried out to correct the underlying heart defect. Ductus arteriosus is a normal structure of the fetal heart that allows blood to bypass circulation to the lungs since the fetus does not use his/her lungs in utero. The ductus arteriosus shunts blood flow from the left pulmonary artery to the aorta. Shortly after birth the ductus closes due to the high levels of oxygen the newborn is exposed to at birth. However, in newborns with certain congenital heart defects, maintaining a patent ductus arteriosus is clinically significant.

Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity [e.g. Celebrex® (celecoxib), Prexige® (lumiracoxib) and the recently removed Vioxx® (rofecoxib) and Bextra® (valdecoxib)]. Unlike the effects of aspirin on the action and synthesis activities of COX-2, this latter class of drug does not induce the synthesis of anti-inflammatory lipids. In fact the cardiac benefits of low-dose aspirin are negated when taken along with COX-2 specific inhibitors such as Celebrex.

Another class of anti-inflammatory drug, the corticosteroidal drugs, act to inhibit PLA2, thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosanoids.


Eicosanoid Major site(s) of synthesis Major biological activities
LXA4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs reduce PMN and eosinophil infiltration to sites of inflammation, stimulate nonphlogistic (non-inflammatory-inducing) monocyte recruitment, stimulate macrophage phagocytosis of apoptotic PMNs, block IL-8 (chemokine) expression, block TNF-α release and actions, stimulate TGF-β action
LXB4 platelets, endothelial cells, mucosal epithelial cells and other leukocytes via inteactions with PMNs same as for LXA4
PGD2 mast cells, eosinophils, brain induces inflammatory responses principally by recruiting eosinophils and basophils; induces bronchoconstriction; involved in androgenetic alopecia, inhibitors of PGD2 being studied to treat male pattern baldness
PGE1   induces vasodilation and inhibits platelet aggregation
PGE2 kidney, spleen, heart increases vasodilation and cAMP production, enhancement of the effects of bradykinin and histamine, induction of uterine contractions and of platelet aggregation, maintaining the open passageway of the fetal ductus arteriosus; decreases T-cell proliferation and lymphocyte migration and secretion of IL-1α and IL-2
PGF kidney, spleen, heart increases vasoconstriction, bronchoconstriction and smooth muscle contraction
PGH2   precursor to thromboxanes A2 and B2, induction of platelet aggregation and vasoconstriction
PGI2 heart, vascular endothelial cells inhibits platelet and leukocyte aggregation, decreases T-cell proliferation and lymphocyte migration and secretion of IL-1α and IL-2; induces vasodilation and production of cAMP
TXA1   induces vasodilation and inhibits platelet aggregation
TXA2 platelets induces platelet aggregation, vasoconstriction, lymphocyte proliferation and bronchoconstriction
TXB2 platelets induces vasoconstriction
LTB4 monocytes, basophils, neutrophils, eosinophils, mast cells, epithelial cells powerful inducer of leukocyte chemotaxis and aggregation, vascular permeability, T-cell proliferation and secretion of INF-γ, IL-1 and IL-2
LTC4 monocytes and alveolar macrophages, basophils, eosinophils, mast cells, epithelial cells component of SRS-A, microvascular vasoconstrictor, vascular permeability and bronchoconstriction and secretion of INF-γ, recruitment of leukocytes to sites of inflammation, enhance mucus secretions in gut and airway
LTD4 monocytes and alveolar macrophages, eosinophils, mast cells, epithelial cells same as LTC4
LTE4 mast cells and basophils same as LTC4
**SRS-A = slow-reactive substance of anaphylaxis

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Michael W King, PhD | © 1996–2014 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: November 13, 2014