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Eicosanoid Metabolism

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Eicosanoid Metabolism Medical Biochemistry Lecture #50 METABOLISM OF UNSATURATED FATTY ACIDS AND EICOSANOIDS Animals have limited ability in desaturating fatty acids. – PowerPoint PPT presentation

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Title: Eicosanoid Metabolism


1
Eicosanoid Metabolism
  • Medical Biochemistry
  • Lecture 50

2
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. 

3
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4
Some polyunsaturated fatty acids are essential
  • Double bonds are present in cis-configuration. 
  • 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
    mammals.

5
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 cynamide-sensitive desaturase containing
    non-heme iron.

6
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7
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.

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9
Linoleate may be converted to arachidonate
10
  • 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.

11
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.

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13
  • Docosahexaenoic acid (DHA w3, 26) 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 ?5,8,11-eicosatrienoic acid. 
  • The trienetetraene ratio in plasma lipids can be
    used to diagnose the extent of essential fatty
    acid deficiency. 
  • These fatty acids are found in high
    concentrations in vegetable oils.

14
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
    lower HDL levels.

15
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 G-protein
    linked receptors to elicit their biochemical
    effects.

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17
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."

18
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19
  • 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.

20
LIPOXYGENASE pathway
  • Produce leukotrienes from eicosanoic acids in
    leukocytes, mastocytoma cells, platelets, and
    macrophages in response to both immunologic and
    nonimuunologic stimuli.

21
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22
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
    aggregation. Their synthesis is inhibited by
    low-dose aspirin.

23
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 205 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
    100-1000 times more potent than histamine or
    prostaglandins as a constrictor of the bronchial
    airway musculature. 
  • Leukotrienes are vasoactive, and 5-lipoxygenase
    has been found in arterial walls.
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