Eicosanoid Biochemistry

RayMosteller


EicosanoidBiochemistry/QuestionsAndAnswers

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BiochemistryLearningModules

Biochemistry Practice Quizzes

Prostaglandins, Thromboxanes and Leukotrienes (metabolic chart)


Recommended Reading

1. Textbook of Biochemistry with Clinical Correlations, 6th edition (2006), T.Devlin, Ed., pp. 730-738.

2. Eicosanoid on Wikipedia:

3. The Medical Biochemistry Page, Dr. Michael W. King, Indiana University School of Medicine:

4. Eicosanoids and inflammation

5. Synthesis of Eicosanoids, Rensselaer Polytechnic Institute

6. Eicosanoid Synthesis Pathways


Learning Objectives

  1. Discuss the general physiological activities of eicosanoids.
  2. Recognize the names of the fatty acid precursors of eicosanoids.
  3. Describe the origin of fatty acids used to synthesize eicosanoids.
  4. Recognize the names of the major pathways of eicosanoid synthesis (cyclooxygenase, lipoxygenase, cytochrome P450).
  5. Describe the mode of action of eicosanoids.
  6. List the general types (classes) of eicosanoids.
  7. Name the class of eicosanoids which contain amino acid residues and describe their importance.
  8. Discuss the eventual metabolic fate of eicosanoids.

What? Where? How? Why?


Definition of Eicosanoids

arachidonic_acid.gif

Definition - Small organic molecules made from polyunsaturated (polyenoic), membrane-derived C20 fatty acids (e.g. arachidonic acid shown on the left and below) which have potent physiological and pharmacological activities.

Note that the bent shape results from the presence of 4 cis double bonds (see below).

The chemical name of Arachidonic acid (omega-6, n-6) is 5,8,11,14-Eicosatetraenoic acid (ETE)BRThe term 'eicosa' means 20 (carbons)

arachidonic_acid.png


Eicosanoids - The BIG Picture

eicosanoids_bigpix_small.gif


Eiscosanoids - Major Pathways

eicosanoids_major_pathways.gif


Eicosanoids - Major Classes

eicosanoids_major_classes.gif


Eicosanoids - Overview of Metabolism


Eicosanoids - Physiological Activities

Activity

Tissue

Pain and fever

hypothalamus

Swelling and inflammation

joints, skin, eyes

Smooth muscle contraction

intestine, uterus

Smooth muscle relaxation

blood vessels

Platelet aggregation

blood clotting

Allergy, immediate hypersensitivity

skin, lungs, macrophages

White blood cell functions

neutrophils, eosinophils

Secretion

stomach

Cell growth

endothelial cells, liver

Chemotaxis

white blood cells

Ion transport

blood cells, kidney


Eicosanoids - Clinical Importance


Eicosanoids - Some (Potential) Clinical Applications


Eicosanoids - Prostaglandin H2(PGH2) Synthase Complex

http://ftp.dna.affrc.go.jp/pub/pdb/images/GIF/1PTH/

Hydroperoxidase: contains a heme group used in the peroxidation reaction.

hydroperoxidase.jpg

Cyclooxygenase (COX): contains Aspirin (salicylic acid) covalently bound to the Ser530 residue.

cox_aspirin.jpg


Eicosanoids - Prostaglandin Synthesis from PUFAs


Eicosanoids - Prostaglandin Structure and Nomenclature


Eicosanoids - Thromboxane Synthesis from Prostaglandin H2

http://en.wikipedia.org/wiki/Thromboxane - images from here

Thromboxane A2 (active form)

Thromboxane B2 (inactive)

Thromboxane_A2.png

Thromboxane_B2.png


Lipoxygenase Pathways - in progress

http://en.wikipedia.org/wiki/Lipoxygenase


Leukotrienes - in progress

http://en.wikipedia.org/wiki/Leukotriene


Lipoxins - in progress

http://en.wikipedia.org/wiki/Lipoxin


Eicosanoids - 20-HETE (omega OH)

16, 17, 18, 19 HETE have similar properties


Major Renal Eicosanoids

Epoxyeicosatrienoic acids (EETs) - http://en.wikipedia.org/wiki/Epoxyeicosatrienoic_acid

EETs are also important in the cardiovascular system and act in the corpus cavernosum to maintain penile erection.

eicosanoids_major_renal.gif


Eicosanoids - Overview of Metabolism


Inhibitors of Eicosanoid Synthesis - supplemental because this will be covered in Pharmacology

Inhibitors may block release of fatty acids from the plasma membrane or the subsequent conversion to various eicosanoids.

Steroids - Anti-inflammatory steroids inhibit Phospholipase A2 and thus block the release of fatty acid precursors (e.g. arachidonic acid) from membrane phospholipids. Examples include: hydrocortisone, prednisone and betamethasone.

NSAIDs - Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX). Some inhibit the constitutive COX1, the inducible COX2 or both enzymes. Examples include: indomethacin, phenylbutazone.

Analgesics - Analgesics are used to relieve or reduce pain, fever and inflammation. Aspirin (acetylsalicylic acid), the most commonly used analgesic, inhibits both COX1 and COX2 by covalently modifying the active site (Serine residue) of the enzyme. Aspirin is also used to block blood clotting.

COX2 inhibitors - Inhibitors specific for the inducible COX2 have been developed to avoid the "side effects" of blocking the constitutive COX1 (e.g. inhibition of blood clotting).


Eicosanoids - Nobel Prizes

eicosanoids_nobel_prizes.gif


Eicosanoids - Summary

eicosanoids_summary.gif


Eicosanoids - Keyword List

You should recognize each of these terms and understand their relationship to eicosanoid metabolism.


Docosahexenoic acid (fish oil) - C22:6 cis-4,7,10,13,16,19 (omega-3)


Eicosanoids: Peanut Hypersensitivity - http://en.wikipedia.org/wiki/Peanut_allergy


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