BIOCHEM TRANS 5 - EICOSANOID.pdf

1A BIOCHEMISTRY EICOSANOIDS DR. BRENDO JANDOC M.D. OUTLINE...

1A BIOCHEMISTRY EICOSANOIDS DR. BRENDO JANDOC M.D. OUTLINE  Arabic numerical subscript I. Prostaglandin  PG series (1, 2 or 3) II. Thromboxanes  Determined by the III. Hydroperoxyeicosatetraenoic acid (HPETE) number of unsaturated IV. Leukotrienes bond V. Metabolism of eicosanoids  1 series – between  Arachidonic acid phospholipids carbon 13-14  Arachidonic acid release  2 series – between  Synthesis of Prostaglandins, Thromboxanes, and carbons 13-14 & 5-6 Leukotrienes  3 series – between  Role of Prostaglandin in Platelet Homeostasis carbons 13-14, 5-6  Thromboxane A2 and 17-18  Prostacyclin  Greek letter subscript  Aspirin  Found only in the F series, hydroxyl group at carbon 9  Primarily exists in the α EICOSANOIDS position  Paracrine hormones – substance that act only on cells near the point of hormone synthesis instead of being transported in the blood 3. Function  Derived from arachidonic acid (20- carbon polyunsaturated  At very low concentrations, has a wide range of cellular and fatty acid) tissue functions  not stored, thus, produced only when needed  Smooth muscle contraction (during menstruation and  mediated by G-protein coupled receptors labor)  Functions  Affect blood flow to specific organs  Reproductive function  Wake-sleep cycle  Inflammation (fever and pain)  Platelet aggregation  Formation of blood clots  Inflammatory response  Regulation of blood pressure  Responsiveness to hormones such as epinephrine and  Gastric acid secretion glucagon  PATHWAYS FOR EICOSANOID SYNTHESIS  Cyclooxygenase pathway  Synthesis of prostaglandin and thromboxane  Lipoxygenase pathway  Yields leukotriene, HETE and lipoxin  Cytochrome P450 system  Synthesis of epoxides, HETE and diHETE A. PROSTAGLANDINS 1. Structure B. THROMBOXANES  Fatty acid containing 20 carbon atoms, including internal 5- 1. Structure carbon ring  6-membered ring that includes an oxygen atom  Contain a hydroxyl group at carbon 15  Double bond between carbons 13 and 14 2. Nomenclature  TX 2. Nomenclature  Capital letters – ring substitutions  PG  Subscript – denotes number of unsaturated bond  Additional capital letter which denotes substitution on the ring 3. Function Trans FINALS 5 Abacco, Alderite, Asistin, Balanza, Bayas, Biang 1 of 4  BIOCHEMISTRY EICOSANOIDS  Formation of blood clot  Reduction of blood flow to the site of clot  NSAIDs (Nonsteroidal Anti-inflammatory drugs)  Aspirin  Ibuprofen  Meclofenamate C. HYDROPEROXYEICOSATETRAENOIC ACID 1. Structure  Hydroxyl fatty acid derivative of arachidonic acid  No ring structure  NSAIDs 2. Nomenclature  Inhibit cyclooxygenase  pathway shuttles to  Hydroperoxy substitution (occur at 5, 12, 15) lipoxygenase system  increased leukotrienes  According to the enzyme  May trigger asthma attacks (allergic reaction to NSAID) 3. Function E. METABOLISM OF EICOSANOIDS  No clear biologic activity 1. Arachidonic acid Phospholipids  Can be converted to leukotrienes  Precursor to the major prostaglandins, thromboxanes and leukotrienes nd  Stored as ester of 2 position of the glycerol backbone of cell membrane phospholipid  Released in the presence of phospholipase A2 2. Arachidonic acid Release  Amount of free arachidonic acid released determines the rate of product formation  Cell stimulation by agonist – specific target  Thrombin – platelets and endothelial cells  Bradykinin – renal tubular cell  Hydrolysis of Arachidonate  By phospholipase A2  Phosphatidylinositol  By phospholipase C  Cleaves inositol from phosphatidylinositol  α,β- diacylglycerol rich in arachidonate D. LEUKOTRIENES  Specific diacylglycerol lipase hydrolyze arachidonate 1. Structure from the 2-position  Formed from HPETE by lipoxygenase  Contain 3 conjugated double bonds 2. Nomenclature  LT  Capital letter – modification to the carbon chain of parent compound 3. Function  Chemotaxis, inflammation and allergic response  LTD4 – slow reacting substance of anaphylaxis (SRS-A)  Smooth muscle contraction  1000x more potent than histamine (airway constriction)  Edema (fluid leakage due to increased capillary permeability)  LTB4 - chemoattractant Trans FINALS 5 Abacco, Alderite, Asistin, Balanza, Bayas, Biang 2 of 4  BIOCHEMISTRY EICOSANOIDS  Regulation of arachidonate release  Block access of arachidonic acid to active  Inhibitory protein which is induced by glucocorticoid site hormones  Aspirin toxicity  Anti-inflammatory effects of steroids  Systemic COX-1 inhibition  damage to  Inhibit phospholipase A2 stomach and kidneys, impaired blood clotting 3. Synthesis of Prostaglandins, Thromboxanes and Leukotrienes  Ibuprofen  Linoleic acid  Reversible, noncovalent, and relatively  Ω- 6 fatty acid nonspecific  Essential fatty acid  Block the active site of PGH synthase  Dietary precursor of the prostaglandins  Acetaminophen  Desaturated and elongated to arachidonic acid  Weak anti-inflammatory effects  Immediate precursor of the predominant class of  Poor ability to inhibit COX in the presence of high prostaglandin concentrations of peroxides  PGH2 Synthesis  Dose of 1000 mg 50% inhibition  Oxidative cyclization of free arachidonic acid  Inhibition disproportionately pronounced in  Yield PGH2 by prostaglandin endoperoxide synthase the brain (PGH synthase)  Celecoxib  ER-bound protein  Selective COX-2 inhibitor  Fatty acid cyclooxygenase  Reduce pathologic inflammatory response  Requires 2 oxygen molecule  Peroxidase 3) LIPOXYGENASE SYSTEM  Dependent or reduced glutathione  Lipoxygenase family 1) Isoenzyme of PGH synthase – CYCLOOXYGENASE SYSTEM  Convert arachidonic acid to a linear hydroxyperoxy  Two enzymes acids  COX-1  5-lipoxygenase converts arachidonc acid to 5-HPETE,  Made constitutively in most tissues and eventually to leukotrienes  Required for maintenance of healthy gastric  Not affected by NSAIDs tissue, renal homeostasis, and platelet  LEUKOTRIENES aggregation  Allergic response and inflammation  COX-2  5-lipoxygenase inhibitors, Leukotriene Receptor  Inducible in a limited number of tissues Antagonist  In response to products of activated immune and  Treatment of asthma inflammatory cells  Increase PG synthesis 4. Role of Prostaglandin in platelet homeostasis  Rubor (redness)  PROSTANOIDS = must be of equal concentration  Calor (heat)  Thromboxane A2  Tumor (swelling)  Produced by COX-1 in activated platelets  Dolor (pain)  Promote platelet adhesion and aggregation  Vasoconstriction  Promote thrombus formation  Prostacyclin (PGI2)  Produced by COX-2 in vascular endothelial  Inhibits platelet aggregation  Vasodilation  Impedes thrombogenesis  BLEEDING TENDENCIES  Aspirin  Antithrombogenic effect  Irreversible acetylation 2) Inhibition of prostaglandin synthesis  Inhibits COX-1 (TXA2 synthesis) in platelets  Cortisol  Inhibition not overcome due to lack of nuclei  Inhibit phospholipase A2  Reversed only by platelet renewal  NSAID (Aspirin, Indomethacin, and phenylbutazone)  Inhibits COX-2 (PGI2 synthesis) in endothelial cells  Inhibit COX-1 and COX-2  Overcome acetylation  Prevent formation of prostaglandin  Low-dose aspirin therapy  Aspirin  Lower risk of stroke and heart attack by decreasing  Irreversibly acetylates a specific serine residue thrombi formation Trans FINALS 5 Abacco, Alderite, Asistin, Balanza, Bayas, Biang 3 of 4  BIOCHEMISTRY EICOSANOIDS Trans FINALS 5 Abacco, Alderite, Asistin, Balanza, Bayas, Biang 4 of 4