synthesis of eicosanoids, glycerolipids and isoprenoids
DESCRIPTION
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..)TRANSCRIPT
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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 (20:4D5,8,11,14) 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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NH2
CH CH2C OH
O
OO P
O-
O
H2C
CH
CH2O
O
C
C
O
O
R1
R2
O
N
NH2
ON
O
OHOH
HH
HH
OP
O-
O
O P
O-
O
H2C
CH
CH2O
O
C
C
O
O
R1
R2
NH2
CH CH2C OH
O
HO
OO P
O-
O
H2C
CH
CH2O
O
C
C
O
O
R1
R2
OH
OH
OH OH
OH
H
H H
H
H
CMP CMP
CDP-DAG
phosphatidylserinephosphatidylinositol
SerineInositiol
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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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Mev
alon
ate
kina
se
Phos
phom
eval
onat
eki
nase pyrohosphomevalonate
decarboxylase
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-phosphate (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
Dimethylallylpryophosphate
IPP isomerase
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IPP Isomerase
prenyltransferase
prenyltransferase
Squalene synthase
Cholesterol
Synthesis from IPP
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Squalenemonooxygenase
2,3-oxidosqualenelanosterol cyclase
cholesterol20 steps
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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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