section 18.9
Metabolism of Eicosanoids
391
Esterified essential
fatty acid in cell lipid
{e.g., glycerophospholipid)
Stimulus
(physical,
chemical,
hormonal, or
neuronal)
Activation of
phospholipase A2
(or phospholipase C, followed by the
action of diacylglycérol lipase)
Inhibited by glucocorticoids
12-Lipoxygenase^
12-HPETE
I
12-HETE
Arachidonic acid.
5-Lipoxy-
genase
Leukotrienes
^Cyclooxygenase (inhibited by
gspirin, indomethacin)
‘pgg2, pgh2
(cyclic endoperoxides)
\TXA? synthase
^inhibited by
D_.
\ analogues of
.
syn!has\im toole>
Prostaglandins
PGL
TXA,
FIGURE 18-19
Pathways of arachidonate metabolism in eicosanoid synthesis and their inhibitors. HPETE =
Hydroperoxyeicosatetraenoic acid; HETE = hydroxyeicosatetraenoic acid; PG = prostaglandin; PGI = prostacyclin;
TX = thromboxane. Conversions of arachidonic acid by various enzymes can be inhibited by analogues of the natural
fatty acid, e.g., the acetylenic analogue 5,8,11,14-eicosatetraynoic acid.
arachidonic acid is through action of phospholipase A2. It
may also be derived through action of phospholipase C,
which liberates diacylglycérol; the latter is then acted on
by diacylglycérol lipase. Stimuli that increase the biosyn-
thesis of eicosanoids cause increased mobilization of in-
tracellular calcium, which with calmodulin is thought
to activate membrane-bound phospholipases A
2
and C
(phagocytosis, Chapter 15; and mechanism of hormone
action, Chapter 30).
Glucocorticoids (e.g., cortisol) inhibit phospholipase
A
2
activity by induction of synthesis of a phospholi-
pase inhibitor protein, which partly explains their anti-
inflammatory effects.
The major metabolites of arachidonic acid (Figure
18-19) arise from the 12-lipoxygenase, the 5-lipoxy-
genase, and the fatty acid cyclooxygenase pathway. The
5-lipoxygenase pathway yields leukotrienes, and the cy-
clooxygenase pathway yields cyclic endoperoxides, which
are converted to PGs, TXs, and PGIs.
Prostaglandins
(PG) were discovered in human semen
more than 50 years ago. Their name derives from the
prostate gland, but they are produced in many tissues.
In fact, the high concentrations found in semen arise in
the seminal vesicles rather than the prostate. The chemi-
cal parent compound is a
2 0
carbon unnatural fatty acid
known as
prostanoic acid
that contains a five-membered
(cyclopentane) ring. Derivatives that contain this struc-
ture (PGs, TXs, and PGIs) are known collectively as
prostanoids.
Prostanoic acid
Differences among various PGs are attributable to differ-
ences in substituents and in their positions on the five-
membered ring (Figure 18-20). PGs are identified by a
letter (e.g., PGE, PGF), characteristic for ring substituents,
and by a numerical subscript (e.g., PGEi, PGF2), which
indicates the number of double bonds (Figure 18-17).
The location and type of double bonds are as follows:
PGi,
tran s-C
13; PG2,
tran s-
C13
cis-
C5; PG
3
,
tran s-C
13
CW-C
5
C
1 7
. All PGs have a hydroxy group at C
15
except
PGG, which has a hydroperoxy group (-OOH). The hy-
droxy group at C
15
is in the S-configuration in the natu-
rally occurring prostaglandins. The
a
and
f3
notations (e.g.,
PGF2„) designate the configuration of the substituent at C
9
on the cyclopentane moiety, as used in steroid chemistry
(a for below and /3 for above the plane of the projec-
tion of the cyclopentane ring). The natural compounds are
«-derivatives.
PGs are synthesized in a stepwise manner by micro-
somal enzymes. The metabolic pathways discussed here
use arachidonic acid as an example. Similar pathways
are applicable to other polyenoic fatty acids. PG synthe-
sis is started by microsomal prostaglandin endoperoxide
