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
Synthesis of Eicosanoids, Glycerolipids and
Isoprenoids
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..)
Eicosanoids
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
• Arachidonic acid present in membrane lipids are released for eicosanoid synthesis in the cell interior by phospholipase A2
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
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
Glycerolipid
Biosynthesis• Phosphatidic
acid is the precursor for all other glycerolipids
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
Isoprenoid Synthesis• Involves formation of
isopentenyl pyrophosphate (IPP) monmers.
• IPP is conjugated in a head to tail manner to generate polyprenyl compounds.
•Formation of the isopentenyl pyrophosphate (IPP) via mevalonate pathway.•Primary pathway for isprenoid synthesis in animals and cytosolic isoprenoid synthesis in plants
Mev
alon
ate
kina
se
Phos
phom
eval
onat
eki
nase pyrohosphomevalonate
decarboxylase
Formation of the isopentenyl pyrophosphate (IPP)
Two Fates of HMG-CoA
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.
Very recent discovery (1996)
Pathway still not fully understood.
New pathway provides enzyme targets for new herbicidal and anti-microbial compounds
Condensation of IPP into Polyprenyl
Compounds
Dimethylallylpryophosphate
IPP isomerase
IPP Isomerase
prenyltransferase
prenyltransferase
Squalene synthase
Cholesterol
Synthesis from IPP
Squalenemonooxygenase
2,3-oxidosqualenelanosterol cyclase
cholesterol20 steps
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
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!