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Essential fatty acids &

Eicosanoids
Dr. Sandeep Agrawal MD DNB
Assistant Professor
Dept. of Biochemistry
AIIMS, Raebareli
drsandeepagrawal25@gmail.com
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Unsaturated Fatty acids

*Essential Fatty acids

 Essential Fatty acids
 Palmitoleic and oleic acids are not essential in the diet because the tissues
can introduce a double bond at the Δ9 position of a saturated fatty acid.

 Linoleic and α-linolenic acids are the only fatty acids known to be essential
for the complete nutrition of many species of animals, including humans,
and are termed the nutritionally essential fatty acids.

 In most mammals, arachidonic acid can be formed from linoleic acid.

Double bonds can be introduced at the Δ4, Δ5, Δ6, and Δ9 positions in most
animals, but never beyond the Δ9 position.

 In contrast, plants are able to synthesize the nutritionally essential fatty

acids by introducing double bonds at the Δ12 and Δ15 positions.

 Arachidonic acid is not one of the essential fatty acids. However it does
become essential if there is a deficiency in linoleic acid or if there is an
inability to convert linoleic acid to arachidonic acid which is required by
most mammals.
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∆9 desaturase system

 Monounsaturated fatty acids can be

obtained by introduction of double
bond in the corresponding saturated
fatty acids.

 A membrane bound desaturase

system in the ER of liver and some
other organs can do so.

 The bond is most commonly

introduced at position ∆9 of palmitic
or stearic acid producing palmitoleic
or oleic acid respectively.

 The system for desaturation requires

molecular oxygen, NADH and
Cytochrome B5.
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Synthesis of PUFA

AA, arachidonic acid;

E, elongase;
EFA, essential fatty acids;
EPA, eicosapentaenoic acid;
GLA, γ-linolenic acid;
DS, desaturase
⊝, Inhibition
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Essential fatty acids (EFA) deficiency

 Linoleic, α-linolenic, and arachidonic acids are found in high concentrations in
vegetable oils and in small amounts in animal carcasses. Essential fatty acids are
required for prostaglandin, thromboxane, leukotriene, and lipoxin formation.

 They are found in the structural lipids of the cell, often in the position 2 of
phospholipids, and are concerned with the structural integrity of the
mitochondrial membrane. Arachidonic acid is present in membranes and
accounts for 5% to 15% of the fatty acids in phospholipids.

 Docosahexaenoic acid (DHA; ω3, 22:6), which is synthesized to a limited extent

from α-linolenic acid or obtained directly from fish oils, is present in high
concentrations in retina, cerebral cortex, testis, and sperm. DHA is particularly
needed for development of the brain and retina and is supplied via the placenta
and milk. Patients with retinitis pigmentosa are reported to have low blood levels
of DHA.
 In essential fatty acid deficiency, nonessential polyenoic acids of the ω9 family,
particularly Δ5,8,11-eicosatrienoic acid (ω9 20:3), replace the essential fatty acids in
phospholipids, other complex lipids, and membranes. The triene:tetraene ratio in
plasma lipids can be used to diagnose the extent of essential fatty acid deficiency.
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Eicosanoids
 Eicosanoids are physiologically and pharmacologically active substances
derived from arachidonic acid (ω6, 20:4, ∆5,8,11,14 eicosatetraenoic acid).

 Eicosanoids are classified into two main groups:

1. Prostanoids
2. Leukotrienes and Lipoxins

 Prostanoids are subclassified into:

1. Prostaglandins (PGs)
2. Prostacyclin (PGIs)
3. Thromboxanes (TXs)

 Prostaglandins are so named because they were initially discovered in the

secretion of prostate gland. However, now it is known that they are produced
by nearly all the cells and tissues in the body.
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Prostanoids

 Prostaglandins (PGs) are derivatives of prostanoic acid- a 20 carbon fatty acid

containing 5-carbon ring (encompassing carbons 8 to 12) and two side chains.
One chain of 7-carbons lies below the plane of ring and another chain of 8-
carbons lies above the plane of ring.

 Thus, all PGs are C-20 compounds containing a cyclopentane ring.

 Prostaglandin I (prostacyclin), contains an additional five membered oxygen

containing ring.

 The thromboxanes are similar but have heterocyclic oxane ring- a six member
ring interrupted by O atom.

 Series 1, 2 and 3 PGs are derived from linoleic, arachidonic and linolenic acid
respectively.

 Only PGD2, PGE2, PGF2 and PGI2 are synthesised in our body from
arachidonic acid.
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Prostanoids

 In the approved nomenclature, each prostaglandin is named using the prefix 'PG' followed
by a letter A to K depending on the nature and position of the substituents on the ring.
 PGA to PGE and PGJ have a keto group in various positions on the ring, and are further
distinguished by the presence or absence of double bonds or hydroxyl groups in various
positions in the ring.
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Series of prostaglandins

Linoleic acid-----

Arachidonic acid-----

Linolenic acid-----

 A numerical subscript (1 to 3) is used to denote the total number of double bonds in the
alkyl substituents, and a Greek subscript (α or β) is used with prostaglandins of the PGF
series to describe the stereochemistry of the hydroxyl group on carbon 9.
 The number of double bonds depends on the nature of the fatty acid precursor.
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Characteristics of prostaglandins

 Act as local hormones through G-protein-linked receptors and show autocrine

or paracrine effects.

 Are not stored in the body.

 Have a very short life span and are inactivated within few seconds or minutes.

 Production increases or decreases in response to diverse stimuli or drugs.

 Are very potent in action. Even in minute concentration (ng/ml), biological

effects are observed.
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Biosynthesis of Eicosanoids

 There are three groups of eicosanoids that are synthesized from C20
eicosaenoic acids derived from the essential fatty acids linoleate and -
linolenate, or directly from dietary arachidonate and eicosapentaenoate.

 Arachidonate, which may be obtained from the diet, but is usually derived from
the position 2 of phospholipids in the plasma membrane by the action of
phospholipase A2.

 Phospholipase A2 is stimulated by histamine, bradykinin, epinephrine and

cytokines, angiotensin II, thrombin etc.

 Once arachidonic acid is released from the membrane, it is acted upon by two
enzyme systems- cyclooxygenase and lipoxygenase.

 Arachidonic acid is the substrate for both the enzymes (cyclooxygenase and
lipoxygenase) and both the enzymes compete for it.
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Cyclo-oxygenase pathway: Synthesis of PGs & TXs

 Cyclooxygenase is called prostaglandin H-synthase. It occurs in two forms

called PGHS-I and PGHS-II or cyclooxygenase (COX-I and COX-II).

 PGHS has two activities- cyclooxygenase and peroxidase.

 In the first step arachidonic acid is cyclized by COX and then two molecules of
O2 are incorporated to produce an unstable intermediate PGG2.

 PGG2 is reduced by peroxidase using reduced glutathione to PGH2.

 PGH2 is a substrate for the synthesis of prostaglandins, prostacyclins and

thromboxanes.

 PGH2 is converted to PGE2, PGF2 and PGD2; prostacyclin PGI2 and

thromboxane TX2 in a tissue specific manner.

 COX is a suicidal enzyme which is self destroyed during catalysis.

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Cyclo-oxygenase pathway: Synthesis of PGs & TXs

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Biological actions of prostaglandins

 Prostaglandins have overlapping and opposing actions on many tissues. Hence

it is difficult to demarcate their actions clearly.

 PGD2 is the major prostaglandin synthesized in the mast cells and PGI2 in
vascular endothelium. PGF2 PGE2 are synthesised in many tissues.

 Effect on CVS:
 PGE2 decreases blood pressure by causing vasodilation but PGF2 increase
BP by causing vasoconstriction.
 PGI2 produced in vascular endothelium causes vasodilation and inhibits
platelet aggregation caused by thromboxanes.
 In vascular endothelial injury, due to lack or decrease of PGI2, this
protective action is removed and platelet aggregation occurs to promote
thrombosis.

 Effect on respiratory system:

 PGE2 causes bronchial muscle dilatation but PGF2 causes bronchial
muscle constriction.
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Biological actions of prostaglandins

 Effects on gastric secretion:
 Most PGs inhibit gastric juice secretion including HCl but enhance mucin
secretion. Due to their inhibitory effects on HCl secretion, they are used in
peptic ulcer disease.

 Effects on kidney:
 PGs cause vasodilation leading to increased blood flow and increased
urinary output.
 Increase Na+, K+ and Cl- absorption from renal tubules.

 Effects on reproduction:
 PGF2 enhances uterine contractions and, are used in-
 Medical termination of pregnancy as abortifacient
 Induction of labour to hasten the delivery.
 Arresting haemorrhage during delivery

 Effects on inflammation:
 PGE2 and PGD2 promote inflammation, sensitivity to pain and cause
vasodilation leading to oedema.
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Biological actions of prostacyclins

 Prostacyclins (PGI2) contain additional ring in their structure formed by
linkage of C9 and C6 through an oxygen atom.

 PGI2 is synthesised in vascular endothelium.

 PGI2 causes vasodilation and inhibits platelet aggregation and hence prevents
thrombus formation.

 Their actions are antagonistic to the effects of thromboxanes and are beneficial.
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Thromboxanes
 Throboxanes TX2 are synthesised in platelets and TXA2 is the most common
thromboxane produced.

 TXA2 is a substrate for TXB2 which is formed by reduction of bond between C9

and C11 by reductase enzyme.

 TXA2 promotes thrombus formation by causing platelet aggregation and

vasoconstriction .

 Its effects are opposed by prostacyclin PGI2.

 Thromboxanes help in preventing bleeding.

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Mechanism of action of prostanoids

 PGs and TXs act by binding to GPCRs, leading to alteration of levels of second
messengers like cAMP and Ca++ levels.

 PGD, PGE and PGF series produce their effect through cAMP.

 PGF2 and TXA2 mediate their effects through alteration of intracellular

calcium levels.
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Catabolism of prostanoids
 Eicosanoids have very short half life varying from few seconds to minutes.

 They are catabolised first by oxidation of hydroxyl group (C-15) and reduction
of double bond (C-13) and then oxidizing them like β and ω oxidations.

 Initial modifications in TXA2 involve the cleavage of bond between C9 and C11.
Then they are metabolized in the same way.
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Lipoxygenase pathway- Leukotrienes & Lipoxins

 Arachidonic acid is also a precursor for LTs and LXs through lipoxygenase
enzyme.

 Lipoxygenase introduces hydro-peroxy group (-OOH) at different positions in

arachidonic acid usually at C-5, C-12 and C-15 to produce different LTs and
LXs.

 Different tissues produce different lipoxygenase activities, e.g.,

 5-lipoxygenase activity is present in neutrophils.
 12-lipoxygenase activity is present in platelets.
 15-lipoxygenase activity is present in eosinophils.
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Leukotrienes (LTs) synthesis

 5-lipoxygenase activity leads to LTA4 synthesis while lipoxins (LXs) are
synthesized by 5 and 15 lipoxygenase activities.

 LTA4 is the first LT synthesized by 5-lipoxygenase. It serves as a precursor for

LTB4, LTC4, LTD4 and LTE4.

 LTC4 is formed by conjugation of LTA4 with glutathione.

 From LTC4 then, glutamate and glycine are removed to give LTD4 and LTE4.
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1, peroxidase;
2, leukotriene A4 epoxide
hydrolase;
3, glutathione S-transferase;
4, γ-glutamyltranspeptidase;
5, cysteinyl-glycine
dipeptidase;
HETE,
hydroxyeicosatetraenoate;
HPETE,
hydroperoxyeicosatetraenoat
e
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Leukotrienes (LTs) actions

 LTs are involved in inflammation and immediate hypersensitivity reactions.
They lead to following changes:
 Increase in vascular permeability
 Increased bronchoconstrictions leading to asthma

 LTs cause:
 Attraction, activation and migration of leukocytes to the site of injury
 Increase in cell activation
 Increase in production of IFN-γ, IL-1 and IL-2

 SRS-A (Slow reacting substances of anaphylaxis) is a mixture of LTC4, LTD4

and LTE4. It is hundred times more potent than histamine in causing
vasoconstriction.
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Lipoxins (LXs)
 Lipoxins are reduced tetraenes derived from arachidonic acid.

 Their synthesis involves 5 and 15 lipoxygenase activities.

 LTA4 also serves as a precursor of LXA4.

 Lipoxins act as vasoactive substances and are also involved in chemotaxis.

 They stimulate superoxide ion generation on leukocytes in order to kill micro-

organisms.

 They also have immunoregulatory function

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Low dose aspirin in coronary artery disease

 Low dose aspirin (75mg/day) significantly reduces the incidence of heart attack
as it selectively inhibits platelet aggregation and thrombus formation by
platelets.

 Aspirin inhibits COX. Once inhibited, the COX is not re-synthesized in platelets
which have no nucleus and have a short half life of 10 days.

 Vascular endothelium is not significantly affected by low dose. Moreover they

can resynthesize COX and prostaglandins.
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Fish oils prevent thrombus formation

 Damaged endothelial wall is devoid of prostacyclin synthase. So PGI2 is not
produced.

 Thrombus formation is enhanced in such vessel wall due to the unopposed

thrombogenic action of thromboxanes without the antagonistic and protective
effect of PGI2. Also endothelial damage stimulate clotting.

 Fish oils are rich in eicosapentaenoic acid which gives rise to series to series 3
eicosanoid like TX3 and PGI3.

 PGI3 is a potent inhibitor of platelet aggregation that PGI2, but TX3 is a weak
platelet aggregator than TX2. Overall the balance of PGI3 and TX3 is anti-
thrombogenic which is beneficial.
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Prostaglandins as H2-blockers in gastric ulcers

 PGE1 and PGE2 are involved in gastric acid secretion through H2 receptors on
gastric mucosa.

 Analogues of PGE1 and PGE2 inhibit gastric acid secretion by blocking H2

receptors.

 H2 blockers (Mesoprostol) help in gastric and duodenal ulcer healing.

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