prostaglandins

1. PROSTAGLANDINS
Samir ali albahrany
COOH
O
HO
OH
PGE2

2. Prostaglandins and related compounds are collectively known
as eicosanoids.
Most are produced from arachidonic acid, a 20-carbon
polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).
The eicosanoids are considered "local hormones."
 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.
But in addition to participating in intercellular signaling, there
is evidence for involvement of eicosanoids in intracellular
signal cascades.
INTRODUCTION

3. DISCOVERY OF PROSTAGLANDINS
• It was discovered by Ulf Von Euler
(1930)
• He extracted from human semen.
• It is secreted from prostate gland.
• Structure of prostaglandins -
proposed by Bergstrom (1950).

4.  Examples of eicosanoids:
prostaglandins
prostacyclins
thromboxanes
leukotrienes
epoxyeicosatrienoic acids.
 They have roles in:
inflammation
fever
regulation of blood pressure
blood clotting
immune system modulation
control of reproductive processes & tissue growth
regulation of sleep/wake cycle.

5. Arachidonic acid
COOH
PGE2
(prostaglandin E2)
is an example of a
prostaglandin,
produced from
arachidonic acid.
COOH
O
HO
OH
PGE2

6. Prostaglandin receptors:
 Prostaglandins & related compounds are
transported out of the cells that synthesize
them.
 Most affect other cells by interacting with
plasma membrane G-protein coupled
receptors.
♦ Depending on the cell type, the activated G-
protein may stimulate or inhibit formation of
cAMP, or may activate a phosphatidylinositol
signal pathway leading to intracellular Ca++
release.

7.  Prostaglandin receptors are specified by the same letter
code.
E.g., receptors for E-class prostaglandins are EP.
Thromboxane receptors are designated TP.
 Multiple receptors for a prostaglandin are specified by
subscripts (E.g., EP1, EP2, EP3, etc.).
Different receptors for a particular prostaglandin may
activate different signal cascades.
Effects of a particular prostaglandin may vary in different
tissues, depending on which receptors are expressed.
E.g., in different cells PGE2 may activate either
stimulatory or inhibitory or G-proteins, leading to either
increase or decrease in cAMP formation.

8. 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.
leukotrienes
phospholipids arachidonate diacylglycerol
prostaglandin H2
prostacyclins thromboxanes
other prostaglandins
Lipoxyganase
PGH2 Synthase
Prostacyclin
Synthase
Thromboxane
Synthase
Linear pathway
Cyclic pathway
Two major
pathways of
eicosanoid
metabolism.
Cyclic
pathway:

9. PGH2
Synthase is a
heme-containing
dioxygenase, bound
to ER membranes.
(A dioxygenase
incorporates O2
into
a substrate).
PGH2 Synthase
exhibits 2 activities:
cyclooxygenase &
peroxidase.
COOH
COOH
O
O
OH
COOH
O
O
OOH
2 O2
2 e−
arachidonic acid
PGG2
PGH2
Cyclooxygenase
Peroxidase

10. Ibuprofen and related compounds
block the hydrophobic channel by which
arachidonate enters the
cyclooxygenase active site.
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.
CH
COOHH3C
CH2
CH
CH3H3C
Ibuprofen

11. Aspirin acetylates a serine hydroxyl group near the
active site, preventing arachidonate binding.
The inhibition by aspirin is irreversible.
However, in most body cells re-synthesis of PGH2
Synthase would restore cyclooxygenase activity.
Aspirin
+
+
PGH2 Synthase (active)
COOH
O C CH3
O
Enz-Ser CH2 OH
COOH
OH
Salicylic acid
Enz-Ser CH2
Acetylated PGH2 Synthase (inactive)
O C CH3
O

12. 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.