BIOC 462B: Dr' Tischler

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BIOC 462B Dr. Tischler
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SYNTHESIS OF EICOSANOIDS AND CHOLESTEROL
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Objectives   1. Identify sources of precursors
for synthesis of prostaglandins, describe the
role of phospholipase A2. 2. Discuss the
mechanisms by which glucocorticoids, NSAIDs
including aspirin control synthesis of
eicosanoids 3. Describe the significance of
HMG-CoA reductase in pharmacologically
controlling hypercholesterolemia. 4. Discuss how
intracellular pool of cholesterol is controlled
via storage or excretion.
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The Actions of Prostaglandins, Thromboxanes and
Leukotrienes

• inflammatory response involving primarily the
  joints and skin -PG
• b. production of pain and fever - PG
• c. regulation of blood pressure
  (vasoconstrictors/vasodilators) and blood
  clotting (platelet function) PG, TX, LT
• d. decreased gastric acid secretion PG
• e. reproductive functions such as induction of
  labor and delivery PGs
• f. the regulation of the sleep/wake cycle PG
• g. hypersensitivity allergic reactions LT.

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2-double bonds
A.
Linoleic Acid (?6 essential fatty acid) for
membrane integrity in phospholipids
Elongation Desaturation twice
4-double bonds
Figure 1A. The eicosanoids and their
biosynthetic origins - synthesis from ?6
precursors
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An extra double bond compared to linoleic acid
B.
?-Linolenic Acid (?3 essential fatty acid) for
membrane integrity in phospholipids
Elongation Desaturation twice
plant sources
Diet ?3 fatty acids
Eicosapentaenoic Acid EPA (?3) for membrane
integrity in phospholipids
Benefit of eating fish PGI favors prevention
of clots compared to weak TXA action in causing
clotting
Docosahexaenoic Acid DHA (?3) in breast milk
required for infant brain development
Figure 1B. The eicosanoids and their
biosynthetic origins - synthesis from ?3
precursors
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Phospholipase A2 (PLA2)
GC induce lipocortin that inhibits PLA2
Prostaglandins and thromboxanes (Cyclic/ring
product)
Leukotrienes (Linear product)
Figure 2. Liberation of arachidonic acid and its
metabolism to prostaglandins/ thromboxanes or to
leukotrienes
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Scaly dermatitis caused by essential fatty acid
deficiency
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Arachidonic Acid (?6) derived from membrane
phospholipids
X
Prostaglandin endoperoxide synthase
PGH2 central intermediate (Head of pathway)
Figure 3. Conversion of arachidonic acid to PGH2
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Aspirin Reduces Inflammation Caused By
Prostaglandins Knee thermograms from lateral
aspect of a patient with arthritis before and
after treatment 4 months with aspirin higher
temperatures are green and dark purple
Figure 4. Structure and mechanism of action of
aspirin
CH2
OH
Ser
?
Cyclooxygenase (active)
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PGH2 central intermediate (Head of pathway)
PGF2? labor induction (Fetus)
Figure 3. Conversion of PGH2 to prostaglandins
and thromboxane of the 2-series
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PHYSIOLOGICAL ROLES OF CHOLESTEROL
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Fatty acids
MITOCHONDRION
Acetyl CoA
Statins
Figure 5. Formation of mevalonate from HMG-CoA is
the rate limiting and regulated step in the
biosynthesis of cholesterol
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Figure 6. The stages of cholesterol biosynthesis

• NADPH required all stages derived from malic
  enzyme and pentose pathway
• 18 ATP consumed step 2
• molecular O2 in 2 stages

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ACAT acyl CoAcholesterol acyltransferase
O R-C
O R-C
O R-C
O R-CO
O R-CO
O R-C
O R-C
O R-C
Figure 7. Cholesterol Metabolism - Esterification
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Figure 7. Cholesterol Metabolism - Bile Acid
Synthesis and its Regulation