Ecosinoid Metabolism

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Eicosanoid Metabolism

• M.Prasad Naidu
• MSc Medical Biochemistry, Ph.D,.

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METABOLISM OF UNSATURATED FATTY ACIDS AND
EICOSANOIDS

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• 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. 

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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.

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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.

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Synthesis of polyunsaturated fatty acids involves
desaturase and elongase enzyme systems

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• 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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Linoleate may be converted to arachidonate
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• 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.

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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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• 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.

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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.

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EICOSANOIDS

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• 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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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."

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• 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.

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LIPOXYGENASE pathway

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

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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.

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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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