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

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• Synthesis of Eicosanoids, Glycerolipids and
  Isoprenoids

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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..)

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

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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

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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

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Glycerolipid Biosynthesis

• Phosphatidic acid is the precursor for all other
  glycerolipids

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Isoprenoid Synthesis

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

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

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Formation of the isopentenyl pyrophosphate (IPP)
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Two Fates of HMG-CoA
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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.

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Very recent discovery (1996) Pathway still not
fully understood. New pathway provides enzyme
targets for new herbicidal and anti-microbial
compounds
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Condensation of IPP into Polyprenyl Compounds
IPP isomerase
Dimethylallyl pryophosphate
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Cholesterol Synthesis from IPP
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Squalene monooxygenase
2,3-oxidosqualene lanosterol cyclase
20 steps
cholesterol
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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

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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!

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