Download - 11 Biosynthesis of Other Lipids 20141115
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Biosynthesis of Membrane Lipids
Glycerolipids and Sphingolipids Synthesis of new membrane requires production of phospholipids On smooth ER surfaces
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CTP
PPi Phosphatic acid phosphatase
Pi
CMP
Glycerophospholipids
Head group HO
CTP
PPi
CMP
Biosynthesis of Glycerolipids (glycerol backbone)
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Glycerophospholipids
Phosphodiester linkage
Examples of head groups: - inositol in phosphatidylinositol - glycerol in phosphatidylglycerol
Non-polar (hydrophobic)
Polar (hydrophilic)
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Amide linkage
N-acylation
(C-18)
Biosynthesis of sphingolipids (backbone: C-18 amino alcohol)
(C-16)
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C
O
R
C
O
R
(N-acyl-sphingosine)
choline
Head-group attachment
(Sphingophospholipid)
(Glycosphinolipid)
Desaturation
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(ARA)
ARA is a precursor for Eicosanoids
Eicosanoids - Potent signaling molecules - e.g. Prostaglandins and thromboxanes
Arachidonic acid (ARA)
Prostaglandins - Trigger pain and inflammation - Regulate the release of mucins for stomach protection
Thromboxanes - Induces constriction of blood vessels, platelet aggregation,
blood clotting
Biosynthesis of Eicosanoids
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Prostaglandin H2 synthase (COX) - 2 enzyme activities (1 and 2) - 2 isozymes: COX-1 and COX-2, very similar in structure (both with
activities 1 and 2) - COX-1: making prostaglandins for regulation of gastric mucin secretion - COX-2: making prostaglandins for induction of inflammation, pain, fever
Thromboxanes
Prostagladin H2 Other prostaglandins
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Different pain killers/anti-inflammatory drugs targeting COX
- Inhibition of cycloxygenase of COX-1 and COX-2 - Side effects: stomach ulcers - Low dosage of aspirin: reduces risks of heart attack and stroke due to
lowered thromboxane production - Vioxx: COX-2 specific; no side effects on stomach but increased risks
of cardiovascular disease; taken off the market - Structural analysis of COX-1 and COX-2 for design of COX-2 specific
pain killers.
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Salicylic acid - Natural pain-killer found in bark of willow trees used by ancient Greek - Structure similar to aspirin - Bitter tasting and unpleasant side effects including severe stomach irritation - Plant hormone to suppress diseases and wilting
Salicylic acid
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Cholesterol Biosynthesis
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Condensation of 3 acetate units
Conversion to a C-5 unit
(C-6 intermediate)
condensation of 6 isoprene units
3 acetyl-CoAs to 1 isoprene 6 isoprenes to 1 cholesterol 18 acetyl CoAs
Ring closure
4 fused rings: steroid nucleus
OVERVIEW OF BIOSYNTHESIS (acetyl-CoA)
(C-30)
(C-27)
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Formation of mevalonate and activated isoprene units
3 acetyl-CoA 1 activated isoprene unit
Target for cholesterol-
lowering drug
CO2
Same as the first 2
steps in ketone body
formation
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Cholesterol-lowering drugs - Statins - Competitive inhibitor of HMG-CoA reductase - HMG-CoA reductase converts HMG-CoA to mevalonate
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5 3
Isomerization
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Formation of Squalene
(C-10)
(C-15)
Tail Head Tail Head
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Head
Head
Tail Tail
(C-15)
(C-15)
(C-30 unit, first discovered in sharks, Squalus spp.)
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HO
Ring closure converts squalene to steroids
3 3 3
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~20 rxns
Removal of methyl groups (CH3)
Reduction of double bonds
Cholesterol
3
3
Fatty acyl-CoA
CoA-SH
Acyl-CoA-cholesterol
acyl transferase
Lipoprotein
particles
(chylomicrons,
VLDL, LDL, HDL)
(C-30)
(C-27)
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