Download Eicosanoid Synthesis

Eicosanoids
Deficiency symptoms in the absence of
essential fatty acids from the diet:
Nonlipid diet plus vitamins A and D
Rat –––––––––––––––––––––––––––––––– Reduced growth rate
and
reproductive
deficiency
• Deficiency syndrome was cured by the addition of
linoleic, a-linolenic, and arachidonic acids to the diet.
• Essential fatty acids are found in structural lipids of the
cell and are concerned with structural integrity of
mitochondrial membrane.
• Arachidonic acid is present in membranes and accounts
for 5-15% of the fatty acids in phospholipids.
SOME MAJOR POLYUNSATURATED FATTY
ACIDS
Name
Linoleic
Structure
18:2(9,12)
Type
ω-6
Significance
Essential FA
Linolenic
18:3(9,12,15)
ω-3
Essential FA
Arachidonic
20:4(5,8,11,14) ω-6
Prostaglandin
precursor
METABOLISM OF LINOLEIC VERSUS LINOLENIC INTO
POLYUNSATURATED FATTY ACIDS (PUFAS):
Linoleic (18:2) (ω-6)
arachidonic (AA) (20:4) (ω-6)
Linolenic (18:3)(ω-3)
eicosapentanoic acid (EPA) (20:5) (ω-3)
and
docosahexanoic acid (DHA) (22:6) (ω-3)
Dietary linoleic acid is the precursor. It is elongated and further
desaturated to 20-carbon, 3, 4, or 5 double bond FAs
Omega-3 fatty acids
• EPA & DHA are precursors for different
eicosanoids than arachidonic acid
• Fish oils have high content of ω-3 FA
METABOLISM OF UNSATURATED FATTY ACIDS AND
EICOSANOIDS
• Humans have limited ability in desaturating fatty acids.
• Dietary intake of certain polyunsaturated fatty acids
derived from a plant source is necessary.
• These essential fatty acids give rise to eicosanoic (C20)
fatty
acids,
from
which
are
derived
families
of
compounds known as eicosanoids.
• Eicosanoids
include
prostaglandins,
thromboxanes, leukotrienes, and lipoxins.
prostacyclins,
Eicosanoids
• The eicosanoids are considered "local hormones.“
• Eicosanoids have strong hormone-like actions in the
tissues where they are produced
 They have specific effects on target cells close to
their site of formation.
They are rapidly degraded, so they are not
transported to distal sites within the body.
• Eicosanoids are not stored and are very unstable
Biological actions of eicosanoids
• Biologic actions of eicosanoids are diverse in
various organs:
– vasodilation, constriction, platelet
aggregation, contraction of smooth muscle,
chemotaxis of leukocytes, release of
lysosomal enzymes
Biological actions of eicosanoids ……. 2
 Also, they have roles in:
regulation of blood pressure, blood clotting and
immune system modulation
Excess production symptoms:
pain, inflammation, fever, nausea, vomiting
• Arachidonic acid, 20:4 (5, 8, 11, 14), is the precursor of many
eicosanoids
• Arachidonic acid is normally part of membrane phospholipids
(especially phosphatidylinositol).
• Arachidonic acid is released by a specialized phospholipase A2
The fatty acid
arachidonic acid
is often esterified
to OH on C2 of
glycerophospholipids, especially
phosphatidyl
inositol.
Site of cleavage by
Phospholipase A2
O
R2
C
O
O
H2C
O
C
C
H
O
CH2O
P
R1
H
OH
O
Site of cleavage by OH
Phospholipase C
H
OH
OH
H
OH
OH
H
H
Phosphatidyl inositol
Arachidonic acid is released from phospholipids by
hydrolysis catalyzed by Phospholipase A2.
This enzyme hydrolyzes the ester linkage between a fatty
acid and the OH at C2 of the glycerol backbone, releasing
the fatty acid & a lysophospholipid as products.
O
Phosphatidyl
inositol signal
cascades may
lead to release
of arachidonic
acid.
O
R1
C
H2C
O
O
C
CH
H2C
cleavage by
Phospholipase C
R2
O
O
P
O
O
H
OPO32
OH
H
OH
PIP2
OH
H
H
H
phosphatidylinositol4,5-bisphosphate
H
OPO32
After PI is phosphorylated to PIP2, cleavage via
Phospholipase C yields diacylglycerol (and IP3).
COOH
Arachidonic acid
O
COOH
HO
OH
PGE2
Prostaglandins all have a cyclopentane ring.
 A letter code is based on ring modifications (e.g.,
hydroxyl or keto groups).
 A subscript refers to the number of double bonds in
the two side-chains.
Thromboxanes are similar but have instead a 6-member
ring.
CLINICAL ASPECTS:
• Thromboxanes are similar but have instead a 6-member
ring.
• Thromboxanes are synthesized in platelets and upon
release cause vasoconstriction and platelet
aggregation. Their synthesis is inhibited by low-dose
aspirin.
Prostaglandin H2
Synthase
catalyzes the
committed step in the
“cyclic pathway” that
leads to production of
prostaglandins,
prostacyclins, &
thromboxanes.
Different cell types
convert PGH2 to
different compounds.
Mast cells attracts
immune cells
Corticosteroids are anti-inflammatory because they
prevent inducible Phospholipase A2 expression, reducing
arachidonic acid release.
There are multiple Phospholipase A2 enzymes, subject to
activation via different signal cascades.
 The inflammatory signal platelet activating factor is
involved in activating some Phospholipase A2 variants.
 arachidonic acid may give rise to inflammatory or
anti-inflammatory eicosanoids in different tissues.
Non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and derivatives of
ibuprofen, inhibit cyclooxygenase activity
of PGH2 Synthase.
 They inhibit formation of prostaglandins
involved in fever, pain, & inflammation.
 They inhibit blood clotting by
blocking thromboxane formation
in blood platelets.
Ibuprofen and related compounds block the
hydrophobic channel by which arachidonic acid
enters the cyclooxygenase active site.
H3C
CH3
CH
CH2
CH
H3C
COOH
Ibuprofen
There are at least two isozymes of PGH2 Synthase (COX-1 and COX2)
COX-1 is constitutively expressed at low levels in many cell types
Specifically, COX-1 is known to be essential for maintaining the
integrity of the gastrointestinal epithelium.
COX-2 expression is stimulated by growth factors, cytokines, and
endotoxin
COX-2 levels increase in inflammatory disease states such as arthritis
and cancer
Up-regulation of COX-2 is responsible for the increased formation of
prostaglandins associated with inflammation
Next generation NSAIDs
• Older NSAIDs inhibit both COX-1 & COX-2:
– acetylsalicylate (Aspirin®, Disprin®, etc.)
– ibuprofen ( Brufen®, etc.)
• Newer generation drugs are specific COX-2 inhibitors:
– Celebrex®
– Vioxx®
Thromboxane A2 stimulates blood platelet aggregation,
essential to the role of platelets in blood clotting.
 Many people take a daily aspirin for its anti-clotting
effect, attributed to inhibition of thromboxane
formation in blood platelets.
 This effect of aspirin is long-lived because platelets
lack a nucleus and do not make new enzyme.
LIPOXYGENASE PATHWAY:
• –Produces leukotrienes from eicosanoic
acids in leukocytes, mast cells, platelets,
and macrophages in response to both
immunologic and nonimuunologic stimuli.
SYNTHESIS OF LEUKOTRIENES FROM ARACHIDONIC ACID
• Leukotrienes are
produced from
arachidonic acid via a
different enzyme:
lipoxygenase
•
HPETE Hydroxyperoxytetraenoic
LEUKOTRIENES HAVE ROLES IN INFLAMMATION.
They are produced in areas of inflammation
in blood vessel walls as part of the pathology
of atherosclerosis.
Leukotrienes are also implicated in asthmatic
constriction of the bronchioles.
ANTI-ASTHMA MEDICATIONS INCLUDE:
 inhibitors of 5-Lipoxygenase, e.g., Zyflo
(zileuton)
 drugs that block leukotriene-receptor
interactions e.g., Singulair (montelukast) &
Accolate (zafirlukast) block binding of
leukotrienes to their receptors on the plasma
membranes of airway smooth muscle cells.
Therapeutic Uses of Eicosanoids
•
•
•
•
•
Induction of midtrimester abortion
Treatment of peptic ulcer
Maintain patency of ductus arteriosus
(?) Ischemic disease .
Impotence (intracavernous injection of PGE2)
leukotrienes
Linear pathway Lipoxyganase
phospholipids
arachidonate
diacylglycerol
Cyclic pathway PGH2 Synthase
Cyclic
pathway:
Prostacyclin prostaglandin H2 Thromboxane
Synthase
Synthase
prostacyclins
thromboxanes
other prostaglandins
Prostaglandin H2 Synthase catalyzes the committed step in
the “cyclic pathway” that leads to production of
prostaglandins, prostacyclins, & thromboxanes.
Different cell types convert PGH2 to different compounds.