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METABOLISM of

UNSATURATED
FATTY ACIDS
and
EICOSANOIDS
Marion G. Rivera, M.D.

OBJECTIVES

Describe the structure


and synthesis of the
unsaturated fatty acids

Enumerate some
important
polyunsaturated fatty
acids and their
physiological roles
Trace the cyclooxygenase
and lipooxygenase
pathways responsible for
the formation of the
various classes of
eicosanoids
Describe the homeostatic
functions and the role in
pain control and
inflammation of
eicosanoids

IMPORTANCE
OF
UNSATURATED
FATTY ACIDS

Unsaturated fatty acids in


phospholipids of the cell
membrane are important in
maintaining membrane
fluidity

Presence in diet is a major


factor in lowering plasma
cholesterol concentration
which is beneficial in
preventing heart disease
As precursor of
prostaglandins, tromboxanes
and leukotrienes which have
important physiologic
functions

UNSATURATED
FATTY ACIDS

Occurs mostly in cis


configuration
Small amounts in trans
form are found in
ruminant fats where they
arise from the action of
microorganisms in the
rumen but the main
source in the human diet
is from partially
hydrogenated vegetable
oils

GEOMETRIC
ISOMERISM OF C18
MONOUNSATURATED
FATTY ACIDS

TRANSUNSATURATED
FATTY ACIDS

Metabolized more like


saturated fatty acids due
to their similar straight
chain conformation
Compete with essential
fatty acids and may
exacerbate essential
fatty acid deficiency

TRANSUNSATURATED
FATTY ACIDS

Have comparable effects


in the promotion of
hypercholesterolemia and
atherosclerosis as
saturated fatty acids
Found mostly in partially
hydrogenated vegetable
oils

ESSENTIAL
FATTY ACIDS

Fatty acids that cannot


be synthesize by the
body and must
therefore be supplied
in the diet

Linoleic acid

Linolenic acid

Arachidonic acids

Are polyunsaturated
fatty acids

DEFICIENCY OF
ESSENTIAL
FATTY ACIDS

In animals

Poor growth, dermatitis,


learning disabilities,
reproductive failure

In humans

Skin symptoms,
impairment in lipid
transport
Reported in infants
receiving formula low in
fats and in adults on
parenteral feeding without
fats
Prevented by an essential
fatty acid intake of 1-2% of
the total caloric
requirement

UNSATURATED
FATTY ACIDS

Double bonds present in


naturally occurring fatty
acids of mammals are of
cis configuration

In animals, double bonds


can be introduced at 4,
5, 6 and 9 positions
but never beyond 9
In plants, double bonds
can be introduced at 6,
9
12
15
, and positions

MONOUNSATURA
TED FATTY ACIDS

Are synthesized from


saturated fatty acids
First double bond is
9
always introduced in
position by enzyme
system, 9 Desaturase
found in the endoplasmic
reticulum
Examples:

Palmitic acid (C16)


palmitoleic acid
Stearic acid (C18)
oleic acid

POLYUNSATURAT
ED FATTY ACIDS

family

Synthesized with 9
desaturase enzyme
system in combination
with chain elongation
and desaturation

6 and 3 families

Derived from linoleic


(6) and -linolenic (3)
acids supplied in the
diet

Desaturation and
chain elongation
system is greatly
diminished:

In the starving state


In response to glucagon
and epinephrine
administration
In the absence of
insulin as in type I DM

DOCOSAHEXAEN
OIC ACID (DHA)

High levels are found in


rod cell membrane in
animal retina and in
neural tissue
Approximately 22% of
total fatty acids in animal
retina and 35-40% of the
fatty acids in retinal
phosphatidylethanolamin
e
Important in the neural
and visual development
of infants

EICOSANO
IDS
EICOSANOIDS

Mostly derived from


arachidonic acid
Made up of:

Prostaglandins (PG)

Tromboxanes (TX)

Leukotrienes (LT)

Lipoxins (LX)

EICOSANOIDS

Are local hormones


Usually act near their
site of synthesis
Exert their effects at
very low
concentrations
Have half-lives of only
30 seconds to few
minutes

EICOSANOIDS

Membrane Phospholipids

Arachidonate

Leukotrienes
Prostaglandins
and Lipoxins
and Tromboxanes

ARACHIDONA
TE

May be obtained from the


diet or derived from the 2
position of phospholipids
in the plasma membrane
by the action of
Phospholipase A2
Is the substrate for the
synthesis of PG2, TX2
series by the
cyclooxygenase pathway
or the LT4 and LX4 series
by the lipoxygenase
pathway

CYCLOOXYGE
NASE
PATHWAY

Catalyzed by
Prostaglandin H
Synthase which
possess 2 separate
enzyme activities: (1)
Cyclooxygenase and
(2) Peroxidase

Products:
Prostaglandins,
Prostacyclins and
Tromboxanes

CYCLOOXYGENAS
E PATHWAY

CYCLOOXYG
ENASE

Present as two
isoenzymes

COX-1 responsible for


the synthesis of
prostaglandins with
homeostatic functions
COX-2 responsible for
the synthesis of
prostaglandins that
mediates inflammation,
pain and fever

Is a suicide enzyme
capable of selfcatalyzed destruction

PROSTAGLAN
DINS

Capital letter refers to


type of ring substitution
Number denotes
number of double bonds
in side chain
Subscript or refers
to orientation of OH
group at C9 of ring

BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S

Cardiovascular

Lowers arterial blood


pressure thereby
increasing local blood
flow and decreasing
peripheral resistance;
maintains the
patency of the ductus
arteriosus in the fetus
prior to birth

Renal

Dilates renal blood


vessels and increase
blood flow through
the kidneys; regulates
sodium excretion and
glomerular filtration
rate

BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S

Gastrointestinal

Increases peristaltic
action in intestine;
regulates secretion of
mucin; inhibits gastric
acid secretion

Reproductive

Stimulates uterine
activity leading to
expulsion of fetus and
placenta

BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S

Nervous system

Produces sedation and


tranquilizing effect

Metabolic

Increases formation of
cAMP in platelets,
thyroid, corpus luteum,
fetal bone,
adenohypophysis and
lungs but reduces cAMP
in renal tubule cells and
adipose tissue

BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S

Induces the signs of


inflammation

Redness and heat due to


arteriolar vasodilation
Swelling due to increased
capillary permeability

Evokes chemokinesis of T
cells

When generated by
immune cells
(macrophages, mast cells,
B cells)

Produces fever when


released in the region of
the hypothalamus where
body temperature is
regulated

BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S

Tromboxane (TXA2)

Synthesized in platelets
Causes vasoconstriction
and platelet
aggregation

Prostacyclin (PGI2)

Produced by endothelial
cells in blood vessel
walls
Inhibits platelet
aggregation

REGULATION OF
PROSTAGLANDIN
METABOLISM

Control of biosynthesis
is poorly understood
Prostaglandins are
rapidly inactivated by
15hydroxyprostaglandin
dehydrogenase

ASPIRIN

A non-steroidal, antiinflammatory drug


Inhibits COX-1 and COX-2

Irreversibly inactivates
cyclooxygenase activity
by acetylating a Ser
residue and blocking the
enzymes active site
At low doses, reduces the
probability of heart
attacks and stroke by
inhibiting the synthesis of
tromboxane

MECHANISM OF
ACTION OF
ASPIRIN

NON-STEROIDAL
ANTIINFLAMMATORY
AGENTS (NSAIDS)

Inhibit both COX-1 and


COX-2.

Inhibition of COX-2 is
responsible for the antiinflammatory effects of
these drugs
Inhibition of COX-1 is
responsible for the
recognized toxicities of
NSAIDs

Peptic ulcers and the


associated risks of
bleeding, perforation and
obstruction

Prolonged bleeding time

Renal insufficiency

COX-2 SPECIFIC
INHIBITORS

Includes Celecoxib (Celebrex)


and Etoricoxib (Arcoxia)
Highly desirable since
inflamed tissues could be
targeted without disturbing
the homeostatic functions of
prostaglandins

Causes less gastric irritation


than other NSAIDs
Was specifically designed to
selectively fit COX-2 and
therefore inhibits COX-2 more
effectively than COX-1

COX-1 and COX-2 differs in


the structure of the
hydrophobic channel that
contains both the active
site and binding site for
arachidonate

COX-2 SPECIFIC
INHIBITORS

Two COX-2 inhibitors


Vioxx and Bextra have
been withdrawn from the
market

Due to clinical findings


indicating that it was
associated with an
increased risk of
cardiovascular events;
increased number of MI
noted on patients taking
Rofecoxib

Data indicate that COX-2,


rather than COX-1, is the
dominant source of
prostacyclin in the human
endothelium

LIPOXYGENASE
PATHWAY

Insert oxygen at 5, 12
and 15 position of
arachidonic acid giving
rise to hydroperoxides

5-lipoxygenase forms
leukotrienes
Combined action of 15lipoxygenase and
5lipoxygenase forms
lipoxins

LIPOOXYGENAS
E PATHWAY

SRS-A (Slow Reacting


Substance of
Anaphylaxis)

Mixture of leukotrienes
C4, D4, E4
100-1000x more potent
than histamine or
prostaglandin as
constrictor of bronchial
musculature; among
the principal mediators
of asthma

With B4, causes


vascular permeability
and attraction and
activation of leukocytes

Antagonists to
leukotriene receptors
has been used as
treatment for
bronchial asthma
(e.g. Montelukast)

LIPOOXYGENAS
E PATHWAY

Lipoxins

Has anti-inflammatory
role
Inhibits the chemotactic
responses and
degranulation induce by
leukotrienes
Inhibits neutrophil and
eosinophil migration
and adhesion

OMEGA-3 FATTY
ACIDS

Includes linolenic acid


and eicosapentaenoic
acid
The low incidence of
heart disease seen in
Greenland Eskimos has
been attributed to their
high intake of fish oil
which contain EPA

EICOSAPENTAE
NOIC ACID

Give rise to series 3


prostaglandins (PG3) and
tromboxane (TX3) and
series 5 leukotrienes

PG3 and TX3 inhibits the


release of arachidonate
from phospholipids and the
formation of PG2 and TX2
PGI3 is as potent an antiaggregator of platelet as
PGI2 but TXA3 is a weaker
aggregator than TXA2; thus
the balance of activity is
shifted towards nonaggregation

KEY POINTS

Biosynthesis of
unsaturated fatty acids is
catalyzed by desaturase
and elongase enzymes

Animals have 4, 5, 6
and 9 desaturases but
cannot insert double
bonds beyond 9 thus
the essential fatty acids
linoleic, linolenic and
arachidonic must be
obtained from the diet

KEY POINTS

The cyclooxygenase
pathway produces
prostaglandins,
thromboxane and
prostacyclin

The lipoxygenase
pathway produces
leukotrienes and lipoxins
Non-steroidal antiinflammatory agents
(NSAIDs) inhibit
cyclooxygenase
Aspirin irreversibly
inhibits cyclooxygenase
by acetylating a serine
residue in the active site

KEY POINTS

Arachidonic acid give rise


to series 2 prostaglandins
and series 4 leukotrienes;
Eicosapentaenoic acid
(EPA) give rise to series 3
prostaglandins and series
5 leukotrienes
Docosahexaenoic acid
(DHA) promotes visual
and neural development
EPA promotes nonaggregation of platelets
by giving rise to weaker
TX3