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
Serine
H2
C
HO
NH2
O
CH
C
NH2
O
R1
C
O
CH2
R2
C
O
CH
CMP
O
H2C
O
O
P
O-
N
O
O
P
O
CDP-DAG
O
C
O
CH2
R2
C
O
CH
O
H2C
CMP
O
O
O-
H
H
OH
OH
H
R1
Inositiol
N
OH
H
O
R1
C
O
CH2
R2
C
O
CH
O
O
O
P
O
H2
C
NH2
O
CH
C
H2C
O
O
P
H
OH
OH
OH
OH
O
H
OH
O-
OH
phosphatidylserine
OH
H
H
phosphatidylinositol
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
Phosphomevalonate
kinase
Mevalonate
kinase
Formation of the isopentenyl pyrophosphate (IPP)
pyrohosphomevalonate
decarboxylase
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-3phosphate (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
IPP
isomerase
Dimethylallyl
pryophosphate
Cholesterol
Synthesis
from IPP
IPP Isomerase
prenyltransferase
prenyltransferase
Squalene synthase
Squalene
monooxygenase
2,3-oxidosqualene
lanosterol cyclase
20 steps
cholesterol
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!