Synthesis%20of%20Eicosanoids,%20Glycerolipids%20and%20Isoprenoids - PowerPoint PPT Presentation

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Synthesis%20of%20Eicosanoids,%20Glycerolipids%20and%20Isoprenoids

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Glycerolipid Biosynthesis. Important for the synthesis of membrane lipids and triacylglycerol ... Glycerolipid Biosynthesis. Phosphatidic acid is the precursor ... – PowerPoint PPT presentation

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Title: Synthesis%20of%20Eicosanoids,%20Glycerolipids%20and%20Isoprenoids


1
  • Synthesis of Eicosanoids, Glycerolipids and
    Isoprenoids

2
Eicosanoids
  • Eicosanoids are important regulatory molecules
  • Referred to as local regulators. Function where
    they are produced.
  • Two classes Prostaglandins/thromboxanes, and
    Leukotrienes
  • Prostaglandins mediate pains sensitivity,
    inflammation and swelling
  • Thromboxanes involved in blood clotting,
    constriction of arteries
  • Leukotrienes attract white cells, involved
    inflammatory diseases (asthma, arthritis, etc..)

3
Eicosanoids
4
Eicosanoid Synthesis
  • C20 unsaturated fatty acids (i.e. arachidonic
    acid (204D5,8,11,14) are precursors
  • Prostaglandins and Thromboxanes are synthesized
    by a cyclooxygenase pathway
  • Leukotirenes are synthesized by a lipoxygenase
    pathway

cyclooxygenase
5
  • Arachidonic acid present in membrane lipids are
    released for eicosanoid synthesis in the cell
    interior by phospholipase A2

6
Cyclooxygenase (COX) Inhibitors
  • Two COX isozymes COX-1 and COX-2.
  • COX-1 important in regulating mucin secretion
    in stomach
  • COX-2 promotes pain and inflammation and fever
    (involved in prostaglandin synthesis).
  • Asprin (acetylsalicylate) non-specific COX
    inhibitor. Acts by acetylating an essential
    serine residue in the active site.
  • Because asprin inhibits COX-1, causes stomach
    upset and other side effects.
  • New drugs (Vioxx and Celebrex) specifically
    inhibit COX-2

7
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8
Glycerolipid Biosynthesis
  • Important for the synthesis of membrane lipids
    and triacylglycerol
  • Synthesis occurs primarily in ER
  • Phosphatidic acid (PA) is the precursor for all
    other glycerolipids in eukaryotes
  • PA is made either into diacylglycerol (DAG) or
    CDP-DAG

9
Glycerolipid Biosynthesis
  • Phosphatidic acid is the precursor for all other
    glycerolipids

10
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11
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12
Isoprenoid Synthesis
  • Involves formation of isopentenyl pyrophosphate
    (IPP) monmers.
  • IPP is conjugated in a head to tail manner to
    generate polyprenyl compounds.

13
  • Formation of the isopentenyl pyrophosphate (IPP)
    via mevalonate pathway.
  • Primary pathway for isprenoid synthesis in
    animals and cytosolic isoprenoid synthesis in
    plants

14
Formation of the isopentenyl pyrophosphate (IPP)
15
Two Fates of HMG-CoA
16
Bacteria and Plants Synthesize IPP via
Non-Mevalonate Pathway
  • In plants and most bacteria, IPP is synthesized
    from the condensation of glyceraldehyde-3-phosphat
    e (3 carbons) and pyruvate (3 carbons).
  • Forms a 5 carbon intermediate through
    transketolase type reaction (transfer of 2 carbon
    aldehyde from pyruvate to G-3-P).
  • Occurs in chloroplast of plants. Involved in
    synthesis of chlorophyll, carotenoids, Vitamins
    A, E and K.

17
Very recent discovery (1996) Pathway still not
fully understood. New pathway provides enzyme
targets for new herbicidal and anti-microbial
compounds
18
Condensation of IPP into Polyprenyl Compounds
IPP isomerase
Dimethylallyl pryophosphate
19
Cholesterol Synthesis from IPP
20
Squalene monooxygenase
2,3-oxidosqualene lanosterol cyclase
20 steps
cholesterol
21
Regulation of HMG-CoA Reductase
  • As rate-limiting step, it is the principal site
    of regulation in cholesterol synthesis
  • 1) Phosphorylation by cAMP-dependent kinases
    inactivates the reductase
  • 2) Degradation of HMG-CoA reductase - half-life
    is 3 hrs and depends on cholesterol level
  • 3) Gene expression (mRNA production) is
    controlled by cholesterol levels

22
Inhibiting Cholesterol Synthesis
  • HMG-CoA reductase is the key - the rate-limiting
    step in cholesterol biosynthesis
  • Lovastatin (mevinolin) blocks HMG-CoA reductase
    and prevents synthesis of cholesterol
  • Lovastatin is an (inactive) lactone
  • In the body, the lactone is hydrolyzed to
    mevinolinic acid, a competitive (TSA!) inhibitor
    of the reductase, Ki 0.6 nM!

23
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