Eicosanoids

= Eicosanoids = Meagan Long and Francesca Longobardo

Overview
toc Eicosanoids get their namesthe two compounds they are derived from: eicosatetraenoic acid (an omega-3 fatty acid) and arachidonic acid (an omega-6 fatty acid). They are a family of lipids characterized by being oxygenated 20-carbon fatty acids (Gk. eikos means 20). The numbering system in the precursor molecule, arachidonic acid, dictates the numbering of the atoms in the eicosanoid molecule(1). Beginning with the -CO2H carbon as C1 and continuing until the CH3 carbon-20 is reached. The first eicosanoid to be discovered was prostaglandin, discovered in 1936 by Ulf von Euler(2). They are biologically active signaling molecules that primarily act on specific G protein-coupled receptors(3).

In the human body, eicosanoids are considered local hormones. The compounds are synthesized biologically from arachidonic acid, after it has been released from phospholipids in the cell membrane, through two main enzymes each located at the nuclear membrane into the three major groups of eicosanoids(4). Prostaglandins(PG), thromboxanes(TX), and leukotrienes(LT) comprise the group eicosanoids but the prostaglandins and thromboxanes are commonly called "prostanoids" because of the similarity in their biosynthetic pathways(1). The two enzymatic pathways used to form the three major groups are the cyclo-oxygenase pathway (COX) and the lipoxygenase pathway (LOX).



Prostanoids
Prostaglandins, prostacyclins, and thromboxanes comprise the family prostanoids. Prostaglandins were first isolated from semen and named after the prostate gland, which they were thought to come from until the 1960’s. Although prostaglandins are in nanomolar quantities in tissues their affect on the body are immense. Prostaglandins can also be described as derivatives of C20 saturated fatty acid. One key feature is a five membered ring containing carbons 8 to 12. (5) The major thromboxanes are thromboxane A2 and thromboxane B2(7). While prostaglandins (PG) have a cyclopentane ring with two long side chains, thromboxanes have a six-membered oxygen containing ring with two long side chains.(1)

**Biosynthesis**
Prostanoids are synthesized in response to hormonal stimuli. This pathway is named the cyclo-oxygenase pathway (COX pathway). The synthesis is summed up into three stages. The first stage is the release of arachidonic acid from precursor glycerophospholipids. The second is oxygenation of free arachi donic acid by prostaglandin endoperoxide G/H (PGG/H) synthase (cyclo-oxygenase). The third includes metabolism of PGH2 to a specific biologically active endproduct PGE2, PGF2a, PGD2, PGI2 (prostacyclin), or thromboxane  A2 (TxA2) (6). The biochemical mechanism involves eight steps. The mechanism leading to many of the prostanoids is shown in figure 2. The first step in synthesis is the release of the fatty acid substrate by phospholipase A2 (this is consistent for each eicosanoid). Next, the free acids are acted upon by cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2). Both COX-1 and COX-2 perform the same reaction (1). PGH2 is an intermediate from which all prostanoids are synthesized via different reactions. PGH2 is then converted to PGE2 via prostaglandin E synthases. (5)



**In the Body**
One of the main functions of prostaglandins and thromboxanes is the inflammatory and immune response they affect in the body. The prostanoids can have a pro- or anti-inflammatory affect. Prostanoids thromboxane and prostacyclin affect the cardiovascular system. There are also some effects on the lungs from prostanoids by having anti-asthmatic qualities. Prostanoids have also been know to affect kidney function, aspects of reproduction, overexpression in certain cancers, and also affects protein metabolism (5). In the kidney prostanoids (PGE2) play a role in water reabsorption (6). Thromboxanes play a major role in blood clotting. Thromboxane A-synthase aids in the production of prostaglandin H2 to thromboxane (7).

Leukotrienes
Leukotriene comes from the words leukocyte and triene. The compounds were first found in leukocytes or white blood cells. Triene refers tothe presence of three conjugated double bonds in the molecule (8).Leukotrienes are acyclic eicosanoids containing four C-C double bondsin total, though three are conjugated (1). Like prostanoids, they are potent eicosanoid lipid mediators, participating in many homeostatic and inflammatory mechanisms within the body (9).



Biosynthesis
As with the other eicosanoid leukotrienes are oxidized in vivo from arachidonic acid. 5-Lipoxygenase is the enzyme that converts arachidonic acid into the leukotrienes. The enzyme requires the cofactor calcium and is ATP-dependent and converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acids (HPETEs) by catalyzing the insertion of an oxygen moiety in the arachidonic acid backbone at C5. 5-HPETE spontaneously converts itself to 5-HETE and is then rearranged in the rate-limiting step to form the unstable LTA4 using LTA synthase. LTA4 is then converted into LTB4 or LTC4. LTC4 is further converted into LTD4 or LTE4 after being actively transported out of the cells (10).



In the Body
Leukotrienes are involved in the mediation of various inflammatory disorders. They play a role in inflammation by causing constriction of bronchioles, causing asthma attacks and are found in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis (11). In this way, they cause the symptoms of hay fever and asthma by mediating immediate hypersensitivity. Leukotriene B4 is a potent chemoattractant for leukocytes. C4, D4, and E4 all increase vascular permeability and constrict smooth muscle (9). They do this through the previously mentioned G protein-coupled receptors (10). Therefore there is a group of compounds called leukotriene modifiers that are pharmaceutically used to prevent the production or action of leukotrienes. Asthma drugs such as Zyflo and Singulair inhibit binding of leukotrienes to their appropriate receptors in airway smooth muscle (11). FLAP or 5-lipoxygenase activating protein can be inhibited and therefore block the formation of HPETEs from arachidonic acid. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to counteract the affects of leukotrienes as well. They inhibit the synthesis of 5-HPETE, inhibiting the pathway leading to leukotrienes (3).