Transcript Eicosanoid Metabolism Medical Biochemistry Lecture #50 METABOLISM OF UNSATURATED FATTY ACIDS AND EICOSANOIDS • Animals have limited ability in desaturating fatty acids. • Dietary intake of certain polyunsaturated fatty acids derived.

Eicosanoid Metabolism
Medical Biochemistry
Lecture #50
METABOLISM OF UNSATURATED
FATTY ACIDS AND EICOSANOIDS
• Animals
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.
Some polyunsaturated fatty acids
are essential:
• Double bonds are present in cisconfiguration.
• Palmitoleic and oleic acids are not essential
in the diet, because the tissues are capable
of introducing a double bonds at the ∆9
position into the corresponding fatty acids.
• In most mammals, double bonds can be
introduced at the ∆4, ∆5, ∆6, and ∆9 positions
but never beyond the ∆9 position.
• Linoleic and a-linolenic acids are known as
nutritionally essential fatty acids. Arachidonic
acid can be formed from linolenic acid in most
Monounsaturated fatty acids are
synthesized by a ∆9 desaturase
system:
• Several tissues including the liver is
responsible for formation of monounsaturated
fatty acids from saturated fatty acids.
• ∆9 desaturase system in the endoplasmic
reticulum will catalyze conversion of
palmitoyl-CoA
or
stearoyl-CoA
to
palmitoleoyl-CoA or oleoyl-CoA, respectively.
• The enzyme appear to be similar to
cytochrome b5, and consists of three
component proteins, NADH-cytochrome b5
reductase, cytochrome b5, and a cynamidesensitive desaturase containing non-heme
iron.
Synthesis of
polyunsaturated fatty acids
involves desaturase and
elongase enzyme systems
• In higher animals, additional double
bonds are introduced between the
existing double bond and the carboxyl
group. However, in plants they are
introduced between the existing double
bond and the w (methyl terminal)
carbon.
Linoleate may be
converted to
arachidonate
• Desaturation and chain elongation
system is greatly diminished in the
fasting state, upon glucagon and
epinephrine administration, and in
the absence of insulin as in type I
diabetes mellitus.
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
• Docosahexaenoic acid (DHA; w3, 2:6) which is
synthesized from a-linolenic acid or obtained directly
from fish oils, is present in high concentrations in
retina, cerebral cortex, testis, and sperm. DHA is
needed for development of the brain and retina and is
supplied via the placenta and milk.
• Patients with retinitis pigmentosa have low blood
levels of DHA. Premature infants have a low ∆4
desaturase ability, reducing their potential for
synthesizing DHA from n-3 fatty acids precursors.
• In essential fatty acid deficiency, nonessential
polyenoic acids of the w9 family replace the essential
fatty acids in phospholipids, particularly with ∆5,8,11eicosatrienoic acid.
• The triene:tetraene ratio in plasma lipids can be used
to diagnose the extent of essential fatty acid
deficiency.
Trans-fatty acids compete with cis-fatty
acids
• Large amonuts of trans-unsaturated fatty
acids in partially hydrogenated vegetable oils
(e.g., margarine) raises the question of their
safety as food additives.
They are
metabolized more like saturated than like the
cis-unsaturated fatty acids.
• Up to 15% of tissue fatty acids are in trans
configuration.
• Trans-polyunsaturated fatty acids do not
possess essential fatty acid activity and may
antagonize the metabolism of essential fatty
acids and enhance essential fatty acid
deficiency.
• Trans-fatty acids raise plasma LDL levels and
EICOSANOIDS:
• Formed from C20 polyunsaturated fatty
acids
• Arachidonate and some other C20 give rise
to
eicosanoids;
prostaglandins
(PG),
thromboxanes (TX), leukotrienes (LT), and
lipoxins (LX).
• Eicosanoids are pharmacologically and
physiologically active compounds.
• Act as hormones functioning through Gprotein linked receptors to elicit their
biochemical effects.
CYCLOOXYGENASE pathway:
• Prostaglandin H synthase (PGHS) and two
molecules of oxygen.
• There are two PGHS isoenzymes, PGHS-1
and PGHS-2.
Each isoenzyme has
cyclooxygenase and peroxidase activities.
• Each cell type produces only one type of
prostanoid.
• "Switching off" of prostaglandin formation is
partly achieved by self-catalyzed destruction,
i.e., it is a "suicide enzyme."
• Aspirin , a nonsteroidal anti-inflammatory
drug (NSAID), inhibits cyclooxygenase of
both PGHS-1 and PGHS-2 by acetylation.
• Most other NSAIDs, such as indomethacin
and ibuprofen, inhibit cyclooxygenases by
competing with arachidonate.
• Transcription of PGHS-2 but not of PGHS-1
is completely inhibited by anti-inflammatory
corticosteroids.
LIPOXYGENASE pathway:
• –Produce leukotrienes from eicosanoic
acids in leukocytes, mastocytoma cells,
platelets, and macrophages in response
to
both
immunologic
and
nonimuunologic stimuli.
CLINICAL ASPECTS:
• Infants receiving formula diets low in fat developed
skin symptoms that were cured by giving linoleate.
• Patients maintained for long periods exclusively by
intravenous nutrition low in essential fatty acids. It can
be prevented by an essential fatty acid intake of 1-2%
of the total caloric requirement.
• Abnormal metabolism of essential fatty acids has been
noted in cystic fibrosis, acrodermatitis enteropathica,
hepatorenal syndrome, Sjogren-Larsson syndrome,
multisystem neuronal degeneration, Crohn's disease,
cirrhosis and alcoholism, Zellweger's and Reye's
syndrome.
• Thromboxanes are synthesized in platelets and upon
release
cause
vasoconstriction
and
platelet
CLINICAL ASPECTS (cont.)
• Prostaglandins (PGI2) are produced by blood
vessel walls and are potent inhibitors of platelet
aggregation.
• Greenland Eskimos have low incidence of heart
disease probably due to high intake of fish oils
containing 20:5 w3 (EPA, or eicosapentaenoic
acid), which gives rise to the series 3
prostaglandins (PG3) and thromboxanes (TX3).
PG3 and TX3 inhibit the release of arachidonate
from phospholipids and the formation of PG2 and
TX2.
• Mixture of leukotrienes C4, D4, and E4 are 1001000 times more potent than histamine or
prostaglandins as a constrictor of the bronchial