Arachidonic Acid Release from Membrane Phospholipids

Arachidonic acid released from membrane phospholipids or other sources is metabolized by the LO pathway to the smooth muscle contractile and vasoactive leukotrienes (LT), LTC4, and LTD4, as well as to the potent chemoattractant LTB4. These molecules are intimately involved in inflammation, asthma, and allergy, as well as in other multiple physiological and pathological processes. For example, cirsiliol (3, 4, 5-trihydroxy-6,7-dimethoxyflavone) proved to be a potent inhibitor of 5-LO (IC50, 0.1 pM) derived from basophilic leukemia cells and peritoneal polymorphonuclear leukocytes. 

Arachidonic Acid Release from Membrane Phospholipids... 

Fig. 35.1. Overview of eicosanoid metabolism. Eicosanoids are produced from fatly acids released from membrane phospholipids. In humans, arachidonic acid is the major precursor of the eicosanoids, which include the prostaglandins, leukotrienes, and thromboxanes. The circled minus sign = inhibits cyt = cytochrome.

Leukotriene biosynthesis depends upon the availability of arachidonic acid (8) as the free carboxylic acid as the 5-LOX substrate, which typically requires the action of cytosolic phospholipase to release arachidonic acid (8) from membrane phospholipids [27]. The name leukotriene was conceived to capture two unique attributes of these molecules. The first relates to those white blood cells derived from the bone marrow that have the capacity to synthesize this class of eicosanoids, for example, the polymorph nuclear leukocyte. The last part of the name refers to the unique chemical structure, a conjugated triene retained within these eicosanoids [29,30]. The first step for the leukotriene biosynthesis is the insertion of molecular oxygen at position 5 of arachidonic add (8) to produce 5-HPETE (17) that can be converted to leukotriene (18) by the second catalytic activity... 

Another vasoactive substance produced by the endothelium is thromboxane A2 (TxA2). Normally, small amounts of TxA2 are released continuously however, increased synthesis appears to be associated with some cardiac diseases. Synthesized from arachidonic acid, a plasma membrane phospholipid, TxA2 is a potent vasoconstrictor. Furthermore, this substance stimulates platelet aggregation, suggesting that it plays a role in thrombotic events such as myocardial infarction (heart attack). Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen block formation of TxA2 and reduce formation of blood clots. 

Figure 6.17. Leukotriene formation in neutrophils. Arachidonic acid, which is released from membrane phospholipids by the action of either phospholipase A2 or diacylglycerol lipase (see Fig. 6.13), is oxygenated by 5-lipoxygenase to yield 5 hydroperoxy-6,8,11,14 eicosa-tetraenoic acid (5-HPETE). This is then converted into 5 hydroxy-6,8,11,14 eicosatetra-enoic acid (5-HETE) and leukotriene (LT) A4. LTA4 may then be enzymically converted into LTC4 and LTB4. LTB4 is the major product in activated neutrophils.

Prostaglandins are a subgroup of a larger family of compounds known collectively as eicosanoids, which are synthesized from arachidonic acid (arachidonate) this is a 20-carbon omega-6 unsaturated fatty acid (C20 4). The source of the arachidonic acid for PG synthesis is the cell membrane. Most membrane phospholipids have an unsaturated fatty acid as arachidonate at carbon 2 on the glycerol backbone to help maintain membrane fluidity. The arachidonic acid released from the membrane by the... 

Calcitriol modulates the maturation of chondrocytes via a cell surface receptor linked to phospholipase and protein kinase C in response to calcitriol, there are rapid changes in arachidonic acid release from, and reincorporation into, membrane phospholipids, and increased synthesis of prostaglandins Ei and E2 (Boyan et al., 1999). 24-Hydroxycalcidiol also modulates the maturation of chondrocytes, acting via cell surface receptors linked to phospholipase D, causing inactivation of both protein kinase C and MAP kinases, thus... 

Prostaglandins, thromboxanes, and leukotrienes are synthesized from 20-carbon polyunsaturated fatty acids (e.g., arachidonic acid) that are released from membrane phospholipids by phospholipase A2, which is inhibited by glucocorticoids and other steroidal anti-inflammatory agents. 

FIGURE 33-3. Metabolism of arachidonic acid after its release from membrane phospholipids. ASA, aspirin HPETE, hydroperoxyeicosatetraenoic acid NSAlDs, nonsteroidal antiinflammatory drugs PC, prostaglandin. Broken arrow indicates inhibitory effects. 

Production of eicosanoids begins after arachidonic acid is released from membrane phospholipid molecules by the enzyme phospholipase A2. The eicosanoids, which include the prostaglandins, thromboxanes, and leukotrienes (Figure 11 A), are extremely difficult to study because they are active for short periods (often measured in seconds or minutes). In addition, they are produced only in small amounts. 

The arachidonic acid present in membrane phospholipids is released from the lipid bilayer as a consequence of the activation of membrane-bound phospholipase A2 or C (see Fig. 33.31 and Fig. 35.2). This activation occurs when a variety of stimuli (agonists), such as histamine and the cytokines, interact with a specific plasma membrane receptor on the target cell surface. Phospholipase A2 is specific for the sn-2 position of phosphoacylglycerols, the site of attachment of arachidonic acid to the glycerol moiety. Phospholipase C hydrolyzes phosphorylated inositol... 

Prostacyclin. Prostacyclin inhibits platelet aggregation and the release reaction. This involves binding to a specific membrane receptor, and a subsequent increase in cyclic AMP. In this respect prostacychn is 10 times more potent than PGD2 and 30 times more potent than PCEj. An increase in platelet cyclic AMP has been reported to inhibit arachidonic acid release from phospholipids, to inhibit cyclooxygenase and to have a direct inhibitory action on the contractile mechanism of the release reaction (Granstrom et al. 1982). 

With respect to vasodilation, niacin-elicited vasodilation requires the activation of GPR109A in skin Langerhans cells [34,35], which then triggers the release of arachidonic acid from membrane phospholipids and its subsequent metabolism to PGD2. The production of PGD2 then activates DPI receptors in dermal blood vessels to cause vasodilation [36]. 

Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, is a product of membrane lipid breakdown at the onset of cerebral ischemia, seizures and other forms of brain trauma. Because polyunsaturated fatty acids are the predominant FFA pool components that accumulate under these conditions, this further supports the notion that fatty acids released from the C2 position of membrane phospholipids are major contributors to the FFA pool, implicating PLA2 activation as the critical step in FFA release [1,2] (Fig. 33-6). 

The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid. It is elongated and desaturated to arachidonic acid, the immediate precursor of the predominant class of prostaglandins (those with two double bonds) in humans (Figure 17.22). [Note Arachidonic acid is released from membrane-bound phospholipids by phospholipase Ap in response to a variety of signals (Figure 17.23).]... 

Enzyme that releases arachidonic acid from membrane phospholipid... 

Antiinflammatory steroids inhibit the release of arachidonic acid from membrane phospholipids by inhibiting a phospholipase A2. If arachidonate is not released, it is not converted to either leukotrienes or prostaglandins. Aspirin, a synthetic antiinflammatory agent, inhibits cyclooxygenase but not lipooxygenase. 

Phospholipase A2, not C, is involved in the release of arachidonic acid from membrane phospholipids. 

Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins and related compounds (see Figure 39.3). Arachidonic acid is present as a component of the phospholipids of cell membranes, primarily phosphatidyl inositol and other complex lipids.1 Free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2 and other acyl hydrolases, via a process controlled by hormones and other stimuli (see Figure 39.3). There are two major pathways in the synthesis of the eicosanoids from arachidonic acid (see Figure 39.3). 

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