Title: Synthesis%20of%20Eicosanoids,%20Glycerolipids%20and%20Isoprenoids
1- Synthesis of Eicosanoids, Glycerolipids and
Isoprenoids
2Eicosanoids
- 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..)
3Eicosanoids
4Eicosanoid 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
6Cyclooxygenase (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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8Glycerolipid 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
9Glycerolipid Biosynthesis
- Phosphatidic acid is the precursor for all other
glycerolipids
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12Isoprenoid 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
14Formation of the isopentenyl pyrophosphate (IPP)
15Two Fates of HMG-CoA
16Bacteria 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.
17Very recent discovery (1996) Pathway still not
fully understood. New pathway provides enzyme
targets for new herbicidal and anti-microbial
compounds
18Condensation of IPP into Polyprenyl Compounds
IPP isomerase
Dimethylallyl pryophosphate
19Cholesterol Synthesis from IPP
20Squalene monooxygenase
2,3-oxidosqualene lanosterol cyclase
20 steps
cholesterol
21Regulation 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
22Inhibiting 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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