Eicosanoids are 20-carbon compounds derived from polyunsaturated fatty acids like arachidonic acid that act as local hormones. They include prostaglandins, thromboxanes, and leukotrienes, which play important roles in inflammation and regulating other physiological processes. They are synthesized through the cyclooxygenase and lipoxygenase pathways and have short lifespans, being quickly degraded. Eicosanoids function through G-protein coupled cell surface receptors and though potent, also have diverse tissue-specific actions.

1. Eicosanoids
Structure, functions and metabolism
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. Eicosanoids are 20-carbon compounds
(eicosa means 20 in Greek)
They are made from arachidonic acid
or other polyunsaturated fatty acids
They are synthesized in most cells and
are potent regulators of cellular function

3. Eicosanoids act as local (autocrine or
paracrine) hormones
They can be divided into multiple
subfamilies
The most important are prostaglandins,
thromboxanes and leukotrienes
The other subfamilies are lipoxins,
resolvins, eoxins etc

4. Eicosanoids play an important role in
inflammatory response to infection or
injury
Several other functions are regulated
by eicosanoids
Moreover, the same process can be
stimulated by some and inhibited by
other eicosanoids

5. Hence, they were named prostaglandins
They were first found in seminal fluid and
were believed to be synthesized only in
prostate gland
The first eicosanoids to be discovered
were prostaglandins

6. They were found to affect reproductive
system, cardio-vascular system, central
nervous system, gastro-intestinal tract etc
Prostaglandins were later found to have
wide tissue distribution
They were found to produce profound
physiological and biochemical effects

7. Thromboxanes were initially discovered in
thrombocytes
Leukotrienes were initially discovered in
leukocytes
Some other cells were later found to
synthesize thromboxanes and leukotrienes

8. Prostanoic acid has a five-carbon ring and
two side chains attached to the ring
Prostaglandins (PGs) structurally resemble
prostanoic acid, a 20-carbon fatty acid
Prostaglandins

10. Depending upon the substituents, the prosta-
glandins are divided into PGA, PGB etc
The number of double bonds varies from 1-3
Each type is sub-divided according to the
number of carbon-carbon double bonds in
the side chains

11. For example, PGE1 means that it is a
prostaglandin of type E
The subscript shows that it has one
carbon-carbon double bond
The type of PG is shown by a letter
and the double bonds by a subscript

12. Prostaglandins of type F are PGF1a,
PGF2a and PGF3a
The most important prostaglandins are of
types E and F
Prostaglandins of type E are PGE1, PGE2
and PGE3

15. Thromboxanes are similar in structure to
prostaglandins with the difference that they
have a six-membered oxane ring
Thromboxanes
They are of several types, e.g. TXA1, TXA2
and TXA3 etc, depending upon the number
of double bonds in the side chains

17. Leukotrienes
Leukotrienes are 20-carbon polyenoic
fatty acids having a number of
substituents
Depending upon the substituents, they
are divided into LTA, LTB, LTC, LTD
and LTE

18. The most important leukotrienes are
LTC4, LTD4 and LTE4
Each type is divided into sub-groups
depending upon the number of double
bonds which vary from 3-5

19. In LTC4, glutathione is attached as a
substituent to C6
In LTE4, the substituent is cysteine
The substituent is cysteinylglycine in
LTD4

21. Synthesis of eicosanoids
Eicosanoids are synthesised from 20-
carbon polyunsaturated fatty acids
Cyclo-oxygenase pathway forms prosta-
glandins and thromboxanes from these
fatty acids
Lipo-oxygenase pathway forms leukotri-
enes from these fatty acids

22. Prostaglandins E1 and F1a, thromboxane
A1, and leukotrienes A3, C3 and D3 are
synthesized from 8,11,14-eicosatrienoic
acid (20:3;8,11,14)
8,11,14-Eicosatrienoic acid is synthesized
from linoleic acid

23. Linoleic acid is 18:2; 9, 12
D6- Desaturase creates a double bond
between carbon atoms 6 and 7
The fatty acid 18:2;9,12 is converted into
18:3; 6, 9,12 (g-linolenic acid)

24. Then, chain elongation occurs by addition
of two carbon atoms at the carboxyl end
g-Linolenic acid is converted into 8,11,14-
eicosatrienoic acid
Cyco-oxygenase converts 8,11,14-
eicosatrienoic acid into PGG1

26. PGG1 can be converted into PGE1 as well
as PGF1a
PGE1 is formed from PGG1 by an
isomerase
PGF1a is formed from PGG1 by a
reductase

28. PGG1 can be also be converted into TXA1
and TXB1
TXA1 is formed from PGG1 by thrombo-
xane synthetase
TXB1 is formed from TXA1 by a hydrolase

30. By similar reactions, arachidonic
acid (20:4;5,8,11,14) can form:
Prostaglandins E2 and F2a
Thromboxane A2
Leukotrienes A4, B4, C4, D4 and E4

31. By similar reactions, eicosapentaenoic
acid (20:5;5,8,11,14,17) can form:
Prostaglandins E3 and F3a
Thromboxane A3
Leukotrienes A5, B5 and C5

32. 5,8,11,14,17-Eicosapentaenoic acid, in
turn, is synthesized from a-linolenic acid
a-Linolenic acid (18:3;9,12,15) is
converted into octadecatetraenoic acid
(18:4;6,9,12,15) by D6-desaturase
Two carbon atoms are added at the
carboxyl end to form eicosatetraenoic
acid (20:4;8,11,14,17)

33. Finally, a double bond is introduced
between carbon atoms 5 and 6 by D5-
desaturase to form eicosapentaenoic
acid (20:5;5,8,11,14,17)
Some eicosapentaenoic acid may be
present in diet also

34. Leukotrienes of series 4 are synthesized
from arachidonic acid
Lipo-oxygenase incorporates two oxygen
atoms into arachidonic acid
The product is 5-hydroperoxyeicosatetra-
enoic acid (HPETE)
HPETE is dehydrated to LTA4; LTB4 is
formed from LTA4 by epoxide hydrolase

36. Addition of glutathione to LTA4 converts it
into LTC4
g-Glutamyl transferase removes a gluta-
mate residue from LTC4 to form LTD4
Removal of glycine by cysteinyl-glycine
dipeptidase converts LTD4 into LTE4

38. Eicosanoids are short-lived compounds,
lasting from seconds to minutes
They produce their effects locally, and
are quickly inactivated
Rapid catabolism is essential for
termination of their actions
Catabolism of eicosanoids

39. Prostaglandins are inactivated by 15-
hydroxyprostaglandin dehydrogenase
Thromboxanes of type A are inactivated by
hydration to type B
Leukotrienes are catabolised by w-oxidation
followed by b-oxidation from w-end

40. Eicosanoids act through cell-surface
receptors
The receptors are coupled to G-proteins
Eicosanoids are short-lived but very potent
Functions of eicosanoids

41. Due to their potency, some eicosanoids
are used as drugs
Also, some drugs act by inhibiting the
synthesis or actions of eicosanoids
The effects of eicosanoids vary in different
tissues

42. Prostaglandins inhibit lipolysis in adipose
tissue
They increase the contractility of uterine
muscle, and induce labour
They are bronchodilators and, hence,
may be of use in bronchial asthma
Actions of prostaglandins
Continued …

43. PGs decrease gastric hydrochloric acid
secretion
They cause vasodilatation, and decrease
blood pressure
They increase the permeability of
capillaries
They inhibit aggregation of platelets
Continued …

44. PGs stimulate intestinal peristalsis
They increase the tubular reabsorption of
sodium and water
They are required for formation,
maturation and transport of sperms

45. Throboxanes stimulate aggregation of
platelets
They cause vasoconstriction, and
increase blood pressure
Actions of thromboxanes

46. Leukotrienes increase capillary
permeability
They are chemotactic agents, and attract
leukocytes to the site of inflammation
They are powerful bronchoconstrictors
Actions of leukotrienes

47. Leukotrienes have a role in asthmatic
and allergic reactions
The slow reacting substance of
anaphylaxis (SRS-A) is a mixture of
LTC4, LTD4 and LTE4
SRS-A is responsible for constriction of
bronchioles in bronchial asthma

48. Several drugs produce their effects by
inhibiting the synthesis of eicosanoids
Production of eicosanoids begins with
the release of a polyunsaturated fatty
acid from C2 of membrane phospholipids
Inhibitors of eicosanoid synthesis

49. Phospholipase A2 hydrolyses the fatty
acid from C2 of phospholipids
Corticosteroids are inhibitors of phospho-
lipase A2
They decrease the production of all the
eicosanoids

50. Aspirin decreases the synthesis of PG
and TX by irreversible inhibition of cyclo-
oxygenase
Phenylbutazone and indomethacin
decrease PG and TX synthesis by
reversible inhibition of cyclo-oxygenase

51. Some leukotriene receptor antagonists
are used as drugs to treat allergy and
asthma
Such drugs include montelukast and
zafirlukast