CHAPTER OUTLINE
Introduction to the Eicosanoids
Synthesis of Prostaglandins and Thromboxanes: The Cyclic Pathway
High-Yield Terms
Eicosanoids: a family of bioactive lipids derived via the oxidation of 20-carbon omega-3 or omega-6 polyunsaturated fatty acids, such as prostaglandins, thromboxanes, and leukotrienes
Cyclic pathway: describes the pathway, initiated by prostaglandin G/H synthase, PGS (also called prostaglandin endoperoxide synthetase), for the synthesis of arachidonic acid-derived eicosanoids containing a cyclic moiety
Linear pathway: describes the pathway, initiated through the action of lipoxygenases (LOXs), for the synthesis of arachidonic acid-derived eicosanoids with linear structure
Cyclooxygenase (COX): common name for prostaglandin G/H synthase which possesses both cyclooxygenase and peroxidase activities, 2 principal COX enzymes exist in humans, COX1 and COX2
Peptidoleukotrienes: also called the cysteinyl leukotrienes, LTC4, LTD4, LTE4, and LTF4 constitute this group of eicosanoids because of the presence of amino acids
Slow-reacting substance of anaphylaxis (SRS-A): consists of the leukotrienes LTC4, LTD4, and LTE4, secreted by mast cells during anaphylactic reaction, induces slow contraction of smooth muscle resulting in bronchoconstriction
Introduction to the Eicosanoids
The principal eicosanoids consist of the prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX). The PG and TX 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 2 double bonds. There are, however, important series-1 and series-3 prostaglandins and thromboxanes. The predominant leukotrienes are series-4 molecules due to the presence of 4 double bonds. 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 (see Chapter 24) are anti-inflammatory lipids synthesized through lipoxygenase interactions (hence the derivation of the name).
Overall, the various eicosanoids can be divided into 3 distinct groups dependent upon the source of origin. The series-1 and -3 prostanoids (and related leukotrienes) are derived from dietary intake of linoleic acid and α-linolenic acid (ALA), respectively, whereas the series-3 prostanoids (and series-4 leukotrienes and the lipoxins) are derived from arachidonic acid released from membrane phospholipids (Figure 22-1).
FIGURE 22-1: The 3 groups of eicosanoids and their biosynthetic origins. (
, cyclooxygenase pathway;
, lipoxygenase pathway; LT, leukotriene; LX, lipoxin; PG, prostaglandin; PGI, prostacyclin; TX, thromboxane.) The subscript denotes the total number of double bonds in the molecule and the series to which the compound belongs. Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper’s Illustrated Biochemistry, 29th ed. New York, NY: McGraw-Hill; 2012.
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.
Arachidonic Acid Synthesis
The principal eicosanoids of biological significance to humans are a group of molecules derived from the C20 omega-6 polyunsaturated fatty acid (PUFA), that is, 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. Within the cell, arachidonic acid resides predominantly at the C–2 position of membrane phospholipids and is released upon the activation of PLA2 (see Chapter 20).
The immediate dietary precursor of arachidonate is linoleic acid, the essential fatty acid. Linoleic acid is converted to arachidonic acid through a series of 3 reactions (Figure 22-2). The activity of the Δ6-desaturase 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 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.
FIGURE 22-2: Synthesis of DGLA and arachidonic acid from linoleic acid. Reproduced with permission of themedicalbiochemistrypage, LLC.
Synthesis of Prostaglandins and Thromboxanes: The Cyclic Pathway
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–coupled receptor (GPCR) signaling pathways. Two main pathways are involved in the biosynthesis of eicosanoids. The prostaglandins and thromboxanes are synthesized by the cyclic pathway (Figure 22-3), the leukotrienes by the linear pathway (Figure 22-4).
FIGURE 22-3: Conversion of arachidonic acid to prostaglandins and thromboxanes of series 2. (HHT, hydroxyheptadecatrienoate; PG, prostaglandin; PGI, prostacyclin; TX, thromboxane.) (*Both of these starred activities are attributed to the cyclooxgenase enzyme [prostaglandin H synthase]. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.) Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper’s Illustrated Biochemistry, 29th ed. New York, NY: McGraw-Hill; 2012.
FIGURE 22-4: Conversion of arachidonic acid to leukotrienes and lipoxins of series 4 via the lipoxygenase pathway. Some similar conversions occur in series 3 and 5 leukotrienes. (
, peroxidase; 
, leukotriene A4 epoxide hydrolase; 
, glutathione S-transferase; 
, γ-glutamyltranspeptidase; 
, cysteinyl-glycine dipeptidase; HETE, hydroxyeicosatetraenoate; HPETE, hydroperoxyeicosatetraenoate.) Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper’s Illustrated Biochemistry, 29th ed. New York, NY: McGraw-Hill; 2012.
The cyclic pathway is initiated through the action of prostaglandin G/H synthase, PGS (also called prostaglandin endoperoxide synthetase). This enzyme possesses 2 activities, cyclooxygenase (COX) and peroxidase. There are 2 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.
The linear pathway is initiated through the action of LOXs of which there are 3 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 leukocytes, mast cells, lung, spleen, brain, and heart (Table 22-1).
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