Prostaglandin H2 Introduction..................................................................................................................1 Chemical structure.........................................................................................................2 Biosynthesis of prostaglandin H2 (PGH2) ..........................................................................3 Synthesis products of PGH2............................................................................................5 Prostaglandins in inflammation reactions...........................................................................6 Mechanism of action of Aspirin.........................................................................................7 Mechanism of action of Paracetamol (=Acetaminophen)......................................................8 Introduction The term prostaglandin was initially mentioned by Ulf von Euler in the 1935s when he considered the prostate gland to be the main place of synthesis of the lipid-like substance. Only later did this turn out to be wrong together with the idea of there being only one prostaglandin as prostaglandins are a group of oxygenated polyene fatty acids. Sune Bergström and Bengt Samuelsson first isolated two prostaglandins in cristalline form in 1962 and named them Prostaglandin E (PGE) and Prostaglandin F (PGF) according to their solvent characteristics. Five years later this research group was able to name a hypothetical eicosanoid (20-carbon acid) as a basic structure. In 1964 Van Dorp and Sune Bergström succeeded in synthesizing prostaglandins from fatty acids. As measurement methods were gradually getting better, over 14 different prostaglandins could be made out by Hamberg and Bengt until 1974. Prostaglandins are subdivided into three main groups. Series-1 prostaglandins (from gamma- linolenic acid) have many positive effects. For example, they decrease blood coagulation and have anti-inflammatory effects. Series-2 prostaglandins (from arachidonic acid) counteract series–1 prostaglandins, causing or increasing inflammations and blood coagulation and intensifying pain- perception. In the body, they induce the adequate measures to react to wounds or other injuries. Series – 3 prostaglandins (from eicosapentaenoic acid) reduce synthesis of series – 2 prostaglandins and are therefore often described as anti-inflammatory. Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Chemical structure Name: Prostaglandin H2 Empirical formula : C20H32O5 Family: Eicosanoids IUPAC: (Z)-7-((1R,4S,5R,6R)-6-((S,E)-3-hydroxyoct-1-enyl)-2,3- dioxabicyclo[2.2.1]heptan-5-yl)hept-5-enoic acid CAS-number: 42935-17-1 molar mass: 352,46 g/mol Prostaglandins are a group of cyclic, oxygenated, unsaturated polyene fatty acids. They can be deduced from a basic structure, the 20-carbon fatty acid. In 1980 Corey proposed calling all derivates of fatty acids with 20 C- atoms eicosanoids. All prostaglandins have a cyclopentane ring substituted with two diphatic side chains of which one has a carboxyl ending. It is distinguished between an a-chain (containing the carboxyl) and a ω -chain. The nomenclature of the prostaglandins is based on the structure of the cyclopentane ring, the number of double bounds in the side chains and the steric orientation of the substituents on the cyclopentane ring. The letter following „PG“ describes the structure of the cyclopentane ring. All naturally occuring prostaglandins have the α-configuration on C-9. Thromboxanes (TX) are closely related structures that can analogously be deduced from a hypothetical „thrombane acid“. Nomenclature of thromboxane corresponds to that of prostaglandins. Many prostaglandins are derived from the under physiological conditions unstable, endoperoxide containing Prostaglandin H2. Apart from the endoperoxide, PGH2 contains two double bonds, an hydoxy-group, a carboxylic acid and five chiral centers. Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Biosynthesis of prostaglandin H2 (PGH2 ) from arachidonic acid is carried out by prostaglandin-H-synthases (PGHS) There are two major forms of PGHS, the isoenzymes PGHS-1 and PGHS-2. Their structures are a little different and they have different regions of action but they catalyse the same reactions. COX-1 produces normal physiological prostaglandins while COX–2 is induced during inflammatory reactions. The PGHS enzymes include two active sites: the cyclooxygenase (COX) – region, where aracidonic acid is transformed to PGG2 as well as the peroxidase (POX) – region, where PGG2 is transformed to PGH2. The hydrophobic substrate (arachidonic acid) reaches the active site of the COX by passing through its hydrophobic channel. The cyclooxygenase of PGHS-1 is referred to as COX-1, whereas COX-2 is the cyclooxygenase of PGHS-2. COX-2's active site is slightly larger than COX-1's. COX takes place inside the enzyme while POX is situated at a heme- containing active site on the outside of PGHS. Reactions of COX during the transformation of arachidoncic acid to PGG2: Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition DANIEL L. SIMMONS, REGINA M. BOTTING, AND TIMOTHY HLA; PHARMACOLOGICAL REVIEWS Vol. 56, No. 3; Pharmacol Rev 56:387–437, 2004 Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Phospholipase A2 releases arachidonic acid released from the cell membrane. Arachidonic acid then binds to the active site in the COX. It is oriented in a way that allows tyrosine (tyr 385), which becomes a tyrosyl radical once the enzyme is activated, to abstract hydrogen from C-13 of the arachidonic acid. Thus an arachidonic radical, localised at C11 and 9, is formed. This is where molecular oxygen attacks to form an endoperoxide. The radical at C15 is then attacked by another molecule of oxygen. Transfer of hydrogen from Tyr385 yields PGG2, while the tyrosyl radical is regenerated. At the peroxidase (POX) site PGG2 is reduced to PGH2. POX is essential for COX as a ferryl protoporphyrin IX radical cation (Fe4+ = OPP*+) is formed from the reducing agent Fe3+ . This is needed for the transformation of Tyr385 to its radical form Tyr 385*. http://www.chemistry.uwaterloo.ca/undergrad/courses/web_courses/chem434/CourseMaterials/slides/Eicosanoids.ppt , 24. Juni 2010 The endoperoxides PGG2 and PGH2 are very unstable under physiological conditions. Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Synthesis products of PGH 2 There are a lot of important prostaglandins which are synthesized from PGH2. They can be found in the whole organism but their effects and reactions can be different depending on the tissue they are in. Therefore they are also used in medical treatment. Thromboxane A2 is basically synthesized in thrombocytes with the aid of TXA-Synthase. However TXA2 is quite unstable and hydrolyzes with a half-life of about 30 seconds to the biologically inactive but stable TXB2 which probably acts for extraction. If a vascular wall gets injured, thrombocytes will adhere to it and become activated. In this progress TXA2 will be discharged. It effects vasoconstrictive in the cardiovascular musculature and the blood circulatory/circulation decreases. In addition, it arranges an irreversible aggregation of the thrombocytes so that the blood vessel is closed by interlinked thrombocytes. Afterwards the blood clotting occurs. Prostacycline (PGI2) is the antagonist of TXA2. It is generated in the endothelial tissue by the PGI-Synthase. In the cardiovascular musculature prostacyclin operates vasilatory. Furthermore, it inhibits the aggregation of the thrombocytes and as a result the blood clotting. So it lowers e.g. the blood pressure. Based on this fact it is used in medicine to prevent acute blood vessel closing. Prostaglandin D2 appears especially in the brain and in the spinal marrow and is synthesized in nerve cells and mast cells. It causes the production of cAMP. Assumedly, it plays an important role in allergic reactions because it evokes bronchia constriction and distinctive inflammations. That is the reason why inhibitors of PGD2-receptors operate anti-allergic. Asthma patients have a PGD2-concentration in their bronchial secretion which is ten times higher than normal. Additionally, PGD2 lowers the body temperature and stimulates the sleep (in contrast to PGE2). The main area of Prostaglandin F2-alpha is the uterus. COX-2 is induced perinatal to the placenta. Consequently, PGF2-alpha will be synthesized. It causes contraction of the uteri musculature. For this reason it is used for abortion and the medical induction of labor. The active pharmaceutical ingredients Latanosprost, Bimatoprost and Travoprost, that are derived from PGF2-alpha, are used for the medical treatment of glaucoma. They expand the drain canals for the aqueous fluid in the sclera of the eyes. Also the contractivity of muscles of other organs can be influenced by PGF2-alpha. 15-Hydroxyprostaglandindehydrogenase inactivates prostaglandines. The decomposition happens predominantly in the lungs, the liver and the kidneys. For medical treatment prostaglandines are usually injected or applied as e.g. an inhalant, eye drops or gel. Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Prostaglandins in inflammation reactions Prostaglandins