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Home , Prostaglandin E, Prostaglandin H2, Thromboxane A2

Prostaglandin H2

Introduction...... 1 Chemical structure...... 2 Biosynthesis of H2 (PGH2) ...... 3 Synthesis products of PGH2...... 5 in inflammation reactions...... 6 Mechanism of action of ...... 7 Mechanism of action of (=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 (PGE) and Prostaglandin F (PGF) according to their solvent characteristics.

Five years later this research group was able to name a hypothetical (20- 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 ) 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 ) 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: 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 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 include two active sites: the (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 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 from C-13 of the arachidonic acid. Thus an arachidonic radical, localised at C11 and 9, is formed. This is where molecular 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 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, and , 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 are released during inflammation reactions and play a major role as chemical messengers in the body. Certainly, everyone has already felt how a normal stimulus can be felt as pain at inflamed spots. In topical research a team from the Max-Planck institute took a closer look at molecular mechanisms concerning the role of prostaglandins in inflammation reactions and found out the following:

Not only prostaglandins are produced by cells in immediate surroundings of the inflammation area, but also in the spinal cord the prostaglandin concentration increases noticeable. Particularly the subtype E2 (PGE2) is responsible for the fact that arriving pain signals are strengthened in the spinal cord with a signal cascade dependent on PGE2 again and then passed on to the brain: Nociceptive afferents (nerve fibres that convey information from a sensory that responds to potentially damaging stimuli to the spinal cord and brain) express prostaglandin receptors which couple to G- proteins. Thus the adenylate cyclase is activated which leads to formation of cAMP and also to the activation of proteinkinase A. This phosphorylates a tetrodotoxin resistant Na+- canal which provides a part of the inward flow of sodium ions through the nociceptor membrane. The threshold of this influx is lowered by the PGE2, i.e. the voltage sensibility is increased, facilitating the release of action potentials.

A hyperpolarization (immediately following the action potential ordinarily) limits the maximum unloading rate in the nociceptive nervous fiber and makes it less excitable. This afterthyperpolarization is provided partly by a Ca2 +-activated slow K +-outward current. Prostaglandins inhibit the K +-current and allow higher unloading rates in nociceptors. As a result, salvo-like discharges, followed by temporal summation of the exciting postsynaptic potentials lead directly to a stronger excitement of the connected nociceptive neurons in the posterior horn of the spinal cord and can contribute to a central sensitization.

Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Aspirin and Paracetamol (=Acetaminophen) inhibit the synthesis of prostaglandin H2

Mechanism of action of Aspirin Aspirin is part of the group of „Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)“ having pain killing and anti-inflammatory effects. All NSAIDs inhibit the active regions of the COX enzymes, only aspirin does this by covalently modifying and thus irreversibly inhibiting COX. It acetylizes Ser530 in the active site of COX.

After entrance of aspirin into the reactive channel of the COX, aspirin forms a hydrogen bond with Tyr385, positioning it in a way that allows it to acetylize Ser530. Futhermore, Tyr385 forms another hydrogen bond with Tyr348 which optimizes positioning of aspirin and supports further polarisation of its carbonyl-group. Thus, aspirin is strongly activated and ready to acetylize Ser530:

The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, 2004, Morgan Kaufman Publ Inc, pg 282, 23.Juni 2010

Consequences of the acetylation

At COX-1, after acetylation neither PGH2 is synthezised nor is arachadonic acid transformed in any other way. This is, because steric hindrance due to the acetylation of Serin prohibits productive binding of arachidonic acid in the active site and thus its transformation.

The active site of COX-2 is slightly larger in comparison to COX-1 which reduces the positioning of aspirin for acetylation.

After acetylation of COX-2 PGH2 cannot be produced either. However, since the active site of COX-2 is larger than that of COX-1 arachidonic acid can still bind in the active site and hydrogen can be removed. Cyclisation and formation of endoperoxide does not occur, whatsoever and 15-R- hydroxyeicosotetraenoic acid (15-R-HETE) is formed instead of PGH2. This is explained by taking into account that normally the OH-group of the non-acetylated Ser530 playes an essential role together with Val349 when it comes to positioning the substrate before O2 attacks.

Acetylation of COX is basically irreversible as there is no water present for hydrolysis in the extreme hydrophobic surroundings of Ser530 in the active site.

Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Mechanism of action of Paracetamol (=Acetaminophen)

In the case of paracetamol, several mechanisms of action are discussed. Primary effects probably also occur through inhibition of the prostaglandin synthesis.

Basis: As described above, a Tyrosyl radical is needed for the transformation of arachidanic acid into

PGG2 (and thus finally into PGH2) at COX.

Paracetamol (Acetaminophen): mechanisms of action by BRIAN J . ANDERSON PhD FANZCA FJFICM Department of Anaesthesiology, University of Auckland, Auckland, New Zealand; Pediatric Anesthesia 2008

Paracetamol acts as a competitive inhibitor of the POX (in contrast to NSAIDs which inhibit COX (e.g. Aspirin). It is a reducing cosubstrate which partially reduces the ferryl protoporphyrin IX radical cation (Fe4+ = OPP*+) leading to an decreased availability of (Fe4+ = OPP*+) for the transformation of Tyr385 to Tyr385*. Thus, less COX is activated and less arachidonic acid is transformed to PGG2.

Why does Paracetamol compared to Aspirin not/hardly have an anti-thrombotic / anti- inflammatory effect?

Paracetamol inhibits competitively which is why the inhibition can be counteracted by an high excess of substrate like PGG2. (This is because an increased production of PGG2 leads to an increased availability of Fe4+ = OPP*+. This guarantees the formation of Tyr385* despite the presence of Paracetamol.)

Paracetamol strongly acts in places that do not show an increasing amount of PGG2 formation (e.g. during in the brain endothelial cells) because not much arachidonic acid gets here.

In contrast, Paracetamol does not show effects in that have been activated by thrombin. Activated platelets synthesize a lot of Phospholipase A2 and PGG2 which can thus counteract Paracetamol.

Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein Sources: Introduction and chemical structure: http://deposit.d-nb.de/cgi-bin/dokserv idn=968795218&dok_var=d1&dok_ext=pdf&filename=968795218.pdf http://de.wikibooks.org/wiki/Datei:Prostaglandin_H2.svg http://www.chemie.uni-hamburg.de/bibliothek/2006/DissertationWinkler.pdf http://de.wikipedia.org/wiki/Prostaglandin_H2 http://www.3dchem.com/moremolecules.asp?ID=303&othername=Prostaglandin%20H2 http://de.wikipedia.org/w/index.php?title=Datei:Prostaglandin_H2.png&filetimestamp=20070929160545 http://www.chemgapedia.de/vsengine/vlu/vsc/de/ch/12/thr/vlu_thr/aspirin.vlu/Page/vsc/de/ch/12/thr/wirkstoffe/aspi rin/a4_4_cox_mechanismus/cox_mechanismus.vscml.html http://userpage.chemie.fu-berlin.de/~steven/publications/dissertation/Einleitung.pdf

Synthesis products of PGH2: http://de.academic.ru/dic.nsf/dewiki/1135097 http://www.vetpharm.uzh.ch/wir/00000055/1111__F.htm http://medikamente.onmeda.de/Wirkstoffgruppe/Prostaglandine.html http://www.apoverlag.at/oeaz/zeitung/3aktuell/2008/13/haupt/haupt13_2008_arzneimittel.html

Allgemeine und spezielle Pharmakologie und Toxikolgie, Wolfgang Forth, Ulrich Förstermann, S. 351 ff

Allgemeine Pathologie, Dombrowski, Grundmann, Rössner, S. 153 f

Die Akute Entzündung, Gerd Egger, S. 41

Prostaglandins in inflammation reactions: Steffen Gay,Stefan Laufer,Kay Brune: Rheumatische Erkrankungen und Entzündung: von den molekularen Grundlagen zur medikamentösen Therapie, Thieme, Stuttgart, 2002 http://www.alles-ueber.com/2010/02/07/ueber-schmerzmittel/ (viewed 20.April 2010) http://de.wikipedia.org/wiki/Entz%C3%BCndung#Molekulare_Mechanismen (viewed 5.Juni 2010) www.mpih-frankfurt.mpg.de/ www.mpg.de/bilderBerichteDokumente/dokumentation/pressemitteilungen/

Mechanism of action of Aspirin and Paracetamol 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 http://www.chemgapedia.de/vsengine/vlu/vsc/de/ch/12/thr/vlu_thr/aspirin_5_coxhemmung.vlu/Page/vsc/de/ch/12/t hr/wirkstoffe/aspirin/a4_52_cox_aspirin/cox_aspirin.vscml.html http://de.academic.ru/pictures/dewiki/65/AspirinWirkung.png http://cti.itc.virginia.edu/~cmg/Demo/pdb/cycox/cycox.html

The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, 2004,Morgan Kaufman Publ Inc, pg 282 http://www.chemistry.uwaterloo.ca/undergrad/courses/web_courses/chem434/CourseMaterials/slides/Eicosanoids.ppt

Review article: Paracetamol (Acetaminophen): mechanisms of action BRIAN J . ANDERSON PhD FANZCA FJFICM, Department of Anaesthesiology, University of Auckland, Auckland, New Zealand Pediatric Anesthesia 2008

Acetylation of Human Prostaglandin Endoperoxide Synthase-2 (Cyclooxygenase-2) by Aspirin"(Received for publication, February 24, 1994) Marc Lecomte, Odette Laneuville, Chuan JiS, David L. DeWitt, and William L. Smiths From the Department of , Michigan State University, East Lansing, Michigan 48824 and the Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232

Prostaglandin H2 – Damocles 2010 presentation and text by Tina Gadau, Patricia Gerdes, Chantal Jagow, Carmen Klein