Eicosanoid Synthesis - Molecular Biochemistry II Eicosanoid...

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Eicosanoid Synthesis Copyright © 1999-2008 by Joyce J. Diwan. All rights reserved. Molecular Biochemistry II
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Prostaglandins and related compounds are collectively known as eicosanoids . Most are produced from arachidonic acid , a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid). The eicosanoids are considered " local hormones ." w They have specific effects on target cells close to their site of formation. w They are rapidly degraded, so they are not transported to distal sites within the body. But in addition to participating in intercellular signaling , there is evidence for involvement of eicosanoids in intracellular signal cascades .
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w Examples of eicosanoids : prostaglandins prostacyclins thromboxanes leukotrienes epoxyeicosatrienoic acids. w They have roles in: inflammation fever regulation of blood pressure blood clotting immune system modulation control of reproductive processes & tissue growth regulation of sleep/wake cycle.
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Arachidonic acid COOH PGE2 (prostaglandin E2) is an example of a prostaglandin, produced from arachidonic acid . COOH O HO OH PGE 2
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PGE2 (prostaglandin E2). Prostaglandins all have a cyclopentane ring . w A letter code is based on ring modifications (e.g., hydroxyl or keto groups). w A subscript refers to the number of double bonds in the two side-chains. Thromboxanes are similar but have instead a 6-member ring . COOH O HO OH PGE 2
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Prostaglandin receptors: w Prostaglandins & related compounds are transported out of the cells that synthesize them. w Most affect other cells by interacting with plasma membrane G-protein coupled receptors . Depending on the cell type, the activated G- protein may stimulate or inhibit formation of cAMP , or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release. w Another prostaglandin receptor, designated PPAR γ , is related to a family of nuclear receptors with transcription factor activity.
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w Prostaglandin receptors are specified by the same letter code. E.g., receptors for E-class prostaglandins are EP . Thromboxane receptors are designated TP . w Multiple receptors for a prostaglandin are specified by subscripts (E.g., EP1, EP2, EP3, etc.). Different receptors for a particular prostaglandin may activate different signal cascades. Effects of a particular prostaglandin may vary in different tissues, depending on which receptors are expressed. E.g., in different cells PGE2 may activate either stimulatory or inhibitory or G-proteins, leading to either increase or decrease in cAMP formation.
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Arachidonate is released from phospholipids by hydrolysis catalyzed by Phospholipase A2 . This enzyme hydrolyzes the ester linkage between a fatty acid and the OH at C2 of the glycerol backbone, releasing the fatty acid & a lysophospholipid as products. Phosphatidyl inositol C H O CH 2 O H 2 C O C R 1 O C R 2 O P O O O- H H OH OH H H OH OH H OH H Site of cleavage by Phospholipase A 2 Site of cleavage by Phospholipase C The fatty acid arachidonate is often esterified to OH on C2 of glycerophospho- lipids, especially phosphatidyl inositol.
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  • Spring '08
  • ALLISON
  • Biochemistry, Arachidonic acid, Prostaglandin, Phospholipase A2, Arachidonate

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