Eicosanoids is the class of lipids derived from arachidonic acid. Eicosanoids play an important role in the growth and development, cellular signalling, drug response, platelet action and maintenance of body homeostasis.

1. EICOSANOIDS
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2. Introduction to Eicosanoids
• Eicosanoids are the derivatives of the 20 carbon polyunsaturated fatty
acids (PUFA).
• Eicosanoids can act as the paracrine or autocrine hormones.
• Involved in physiological process such as platelet aggregation, pain
induction, role in reproduction and maintenance of haemodynamics of
blood.
2

3. Types of Eicosanoids
• Eicosanoids can be of following types
• Prostaglandins (PG)
• Thromboxanes (TX)
• Leukotrienes (LT)
• Infact, the discovery of the eicosanoids was based upon the
identification of prostaglandins in the human semen.
• Origin: PG = Prostate gland, TX = Platelets, LT = Leucocytes.
3

4. Structure of Eicosanoids
4
Parent
molecules
Ref:
Chapter
8,
Eicosanoids,
Hormones,
2015

5. Nomenclature of Eicosanoids
• Prostaglandins are labelled as either E or F depending upon their
solubility in ether or fats respectively. Also, there exist PGD and PGI2
(prostacyclin).
• The numeric value (n) subscripted after the PGxn (x=E, F, D, I) defines
the number of the double bonds in side chain of the molecule such as
PGE2, PGE3, PGF2α.
• Leukotrienes are named as the LT with the third letter following A, B,
C and D based on their structure. Similar to the PG, the LT are
subscripted in by the number of double bonds in the chain.
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6. 6

7. Phospholipases
• Phospholipases are the class of enzyme
which act upon the phospholipid
molecules.
• Phospholipases can be of following
types, A1, A2, C and D. Each having a
specific cleavage site in the phospholipid
molecule.
• Phospholipase act on the extracellular as
well as intracellular membranes such as
that of the nuclear envelope and
endoplasmic reticulum.
• The activity of phospholipase is
regulated by the calcium ions and
phosphorylation of specific serine
residues. 7
C1
C2
C3
R1=Fatty acid molecule generally saturated
R2= Fatty acid molecule generally unsaturated
R3= Base group such as choline, ethanolamine etc.
Ref:
Chapter
8,
Eicosanoids,
Hormones,
2015

8. Cyclooxygenases (COX) & Lipoxygenases (LOX)
• Cyclooxygenases or COX or
Prostaglandin H synthetase is the
class of the dioxygenases that
catalyse the insertion of the oxygen
(O=O) to the substrate leading to
the formation of epoxides.
• The COX enzymes can be of two
isoforms COX 1 and COX 2.
• The binding of one monomer of the
homodimer with ligand
cooperatively activates the catalytic
activity of the other.
8
• Lipoxygenase or LOX are
monoxygeanses that catalyse the
peroxidation of the arachidonic
acid or linoleic acid.
• LOX can be 5-lipoxygenases, 12-
lipoxygenases based upon the
position of carbon they act upon.
• This enzyme is inhibited by its
product.
The activity of both the oxygenase is regulated by the calcium ion and
phosphorylation of specific serine residues.

9. Cyclooxygenase
Reaction
Peroxidase
Reaction
LT= Leukotrienes, PG= Prostaglandins, TX=
Thromboxanes, COX= Cyclooxygenase, 5-HpETE= 5-
Hydroperoxy-6,8,9,14-eicosatetranoate
Biosynthesis of Eicosanoids
9
Cytochrome P450
Ref:
Cyclooxygenase
Isozymes:
The
Biology
of
Prostaglandin
Synthesis
and
Inhibition;
Daniel
L.
Simmons

10. Transport of Eicosanoids
• To act in a paracrine manner, the
eicosanoids synthesised in the cell has
to be transported outside the
membrane.
• Influx of prostanoids: Prostaglandin
transporter (PGT)
• Efflux of prostanoids: Multidrug
resistance protein 4 (MRP4)
• For leukotrienes, multidrug resistance
protein are used for the flux across
the cell.
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Intracellular
Extracellular
(A) PGT Structure
Intracellular
Extracellular
(B) MRP4 Structure
Ref: (A) Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver, Ting-Ting Li,
World J Clin Cases 2019 (B) Multidrug resistance in cancer: role of ATP–dependent transporter, M. Gottesman, Medicine Nature
Reviews Cancer, 2002

11. Receptor of Eicosanoids – Prostanoids
• Prostanoids act upon the cell by acting as a ligand for the G-coupled
protein cell receptors.
• They can classified in three categories based on the result of the
downstream cell signalling.
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Ref: Chapter 8, Eicosanoids, Hormones, 2015

12. Receptor of Eicosanoids – Leukotrienes
• Leukotrienes act upon by binding to cysteine leukotriene receptor
(CysLT 1 or CysLT 2) and leukotriene B4 receptor (BLT 1 or BLT 2).
12
BLT 1
c-AMP, Ca+2
BLT 2
c-AMP, Ca+2
LTB4 CysLT 2
Ca+2
LTC4 CysLT 1
Ca+2
LTD4

13. 13
Overview of Functions of Prostaglandins and Thromboxane
Ref:
Prostaglandins
analysis
service,
Creative
Proteomics

14. 14
Role of Prostaglandins in Pain reception
Ref:
Chapter
8,
Eicosanoids,
Hormones,
2015

15. 15
PGI2
Platelets
IP Receptor
cAMP
Adenyl cyclase
Inhibition of
platelet spreading
Vasodilation
AMP

16. Role of Prostaglandins in Reproduction
• As known PG play a vital role in female reproductive cycle.
• PGE2 is responsible for the suppression of chemokine signalling
(caused by ovulation) causing the ECM disassembly and sperm
penetration, which leads to occurrence of the fertilization.
• PGF2α is involved in the parturition by the termination of the
progesterone production.
• Moreover, certain signals from the PGE2 receptor EP are also
responsible for the myometrial contraction at the time of parturition.
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17. 17
Ptgs2 gene for
COX-2
Ptger2 gene for
PGE EP
receptor
Ref:
Roles
of
prostaglandin
receptors
in
female
reproduction,
Yukihiko
Sugimoto,
J.
Biochem.
2015

18. Action of Prostaglandins PGE2 and PGF2α
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Role of PGE2 at the time of fertilization Role of PGF2α at the time of luteolysis and parturition
Ref: Roles of prostaglandin receptors in female reproduction, Yukihiko Sugimoto, J. Biochem. 2015

19. Function of Thromboxane
• Ligand based downstream
signalling leads to the synthesis of
the thromboxane in the platelets.
• Thromboxanes are responsible to
induce the platelet aggregation by
increasing the cAMP concentration
in the cell.
• Thromboxane are also acts on the
smooth muscle through myosin light
chain kinases and cause
vasoconstriction.
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Upon binding with the ligand
such as fibrinogen, platelet
activates
Synthesis of Thromboxane A2
Binding of the TXA2 with the TP
receptor (a GPCR) on platelets
Platelet shape change
and spreading
Calcium ion concentration
increases

20. Functions of Leukotrienes
• Leukotrienes can have affect on physiology of lungs, kidney, cardio-
vasculature system and can also lead to the inflammatory diseases.
• Cysteine leukotrienes are found to constrict the pulmonary airway leading
to the asthma in patients. The use of Zafirlukast, Montelukast and 5-
lipoxygenase Zileuton has been approved against this issue.
• Cysteine leukotrienes have also been reported to cause vasoconstriction of
pulmonary arterioles. Though, it has to be studied extensively.
• The higher expression of the 5-lipoxygenase and LTA4 synthase has found
to affect the glomerular filtration rate and renal blood flow.
• The LTB4 act as a potent chemotactic agent for the infiltration of leukocytes
in GI tissue or skin.
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21. Non Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin
• Acetyl salicylate molecule that
irreversibly acetylates the serine
residues at active site.
• Acts efficiently on the COX 1
homodimer as compared to COX 2.
• Hence, it irreversibly inhibits the
activity of the COX 1.
• Ibuprofen
• Acts immediately by binding as the
antagonist to COX 1.
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Ref:
Chapter
21,
Lehninger
Principles
of
Biochemistry,
David
L.
Nelson

22. Specific NSAIDs
• Celecoxib and Rofecoxib are
the specific drugs that inhibit
the activity of the COX 2.
• These drugs have
comparatively low interference
in the gastro-intestinal
production of the PG, as it is
required to secrete the gastric
mucin.
• Though, only celecoxib is
mostly used for the arthritis.
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Ref: Eicosanoids in
Inflammation: Biosynthesis,
Pharmacology, and
Therapeutic Frontiers,
Subhash P. Khanapure, Current
Topics in Medicinal Chemistry,
2007

23. LOX Inhibitors & LT Receptor Antagonists
• 5-lipoxygenase Zileuton and ABT 761 are the potent inhibitors of the
5-lipoxygenase enzyme. They are effective in asthmatic treatment and
reduction in pulmonary inflammation.
• Zafirlukast; Accolate are the orally consumed indole derivates that
act the antagonist to the cysteine leukotriene receptor.
• Pro-drug (Biil284) for BLT receptor effectively inhibits the neutrophil
expression suggesting its potent role in the treatment of the
Rheumatoid arthritis.
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24. References
• Chapter 8, Eicosanoids, Hormones, 2015 DOI: 10.1016/B978-0-12-369444-7.00008-5.
• Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition; Daniel L. Simmons, Regina M. Botting, and
Timothy Hla, The American Society for Pharmacology and Experimental Therapeutics 40304/1169404, Pharmacol Rev 56:387–437,
2004.
• Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers, Subhash P. Khanapure, David S. Garvey,
David R. Janero and L. Gordon Letts, Current Topics in Medicinal Chemistry, 2007, 7, 311-340.
• Lehninger Principles of Biochemistry, David L. Nelson, Michael M. Cox.
• Leukotrienes: Biosynthesis, Transport, Inactivation, and Analysis, Dietrich Keppler, Rev. Physiol. Biochem. Pharmacol., Vol. 121,
1992.
• Multidrug resistance in cancer: role of ATP–dependent transporters, M. Gottesman, T. Fojo, S. Bates, Medicine Nature Reviews
Cancer, 2002.
• Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver, Ting-Ting Li, Jia-Xing
An, Jing-Yu Xu, Bi-Guang Tuo, World J Clin Cases, Dec 6, 2019; 7(23): 3915-3933.
• Prostaglandins analysis service, Creative Proteomics.
• Roles of prostaglandin receptors in female reproduction, Yukihiko Sugimoto, Tomoaki Inazumi and Soken Tsuchiya, J. Biochem.
2015; 157(2):73–80 DOI :10.1093/jb/mvu081
• The Eicosanoids: A Historical Overview, R. Roy Baker, Clin Biochem, Vol. 23, pp. 455-458, 1990. 24

25. Thank You
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