Download Cholesterol Synthesis Regulation of cholesterol synthesis pathway

Cholesterol Synthesis
Main function: formation of steroid
nucleus
Regulation of cholesterol
synthesis pathway
• HMG CoA reductase catalyzes the
rate-limiting step.
Substrate: cytoplasmic acetyl CoA
• The synthesis and the activity of
the HMG-CoA reductase enzyme
is controlled in the liver cell.
Endproduct: cholesterol
Location: cytoplasm
Cholesterol biosynthesis
cyto.acetyl CoA
NADP:H
HMG CoA
mevalonate
isopentenyl
PP (5C)
farnesyl
PP (15C)
geranylPP
(10 C)
CH2-C ~ S-CoA
O
HMG-CoA
2 NADP:H
+ 2 H+
OH
CH3-C-CH2-COO
HMG-CoA
OH
CH3-C-CH2-COO
CH2-CH2
OH
mevalonate
2 NADP+
CH3-C=O acetoacetyl CoA
CH2-C ~S-CoA
O
(30C)
HMG CoA reductase
CH3-C-CH2-COO
O
CH3-C ~ S-CoA
c. acetyl CoA
squalene
cholesterol
OH
Cholesterol synthesis
pathway
CH2-C ~ S-CoA
O
Regulation of HMG CoA
reductase activity
• cholesterol and mevalonate directly
inhibit HMG-CoA reductase activity
• insulin binding indirectly stimulates
HMG-CoA reductase activity
• glucagon binding indirectly inhibits
HMG-CoA reductase activity
Inhibition of HMG CoA
reductase synthesis
Inhibition of HMG CoA
reductase synthesis
1 cholesterol esters in blood bind to
Low Density Lipoprotein
LDL-chol.
2 LDL-cholesterol complex
binds LDL receptor protein
in liver cell membrane.
liver cell
Control of enzyme synthesis
• 3. LDL-cholesterol-ester complex
is transported into liver cell by
LDL receptor protein in
liver cell membrane .
• 4. LDL-chol.ester drops off LDL
receptor protein and binds to
cytoplasmic receptor protein.
Control of enzyme synthesis
LDL membrane receptors
LDL-cholesterol
cytoplasmic
receptor
protein
Controlling enzyme
synthesis
5. Cholesterol derivative and
c. recept. protein enter nucleus,
bind to DNA and
prevent RNA polymerase
from transcribing the gene
coding for HMG-CoA reductase .
Hormonal regulation of
cholesterol synthesis
• Glucagon binds to receptor in
liver cell membrane, stimulating
cAMP formation
LDL-cholesterol
binds to cyto.
receptor protein
and enters nucleus
cholesterol binds
to DNA; inhibits
transcription of
gsene coding for
HMG CoA reductase
• cAMP activates PROTEIN KINASE
which inactivates rate-limiting
HMG CoA reductase enzyme,
decreasing cholesterol synthesis
Hormone action
Hormonal regulation of
cholesterol synthesis
• Insulin binds to its receptor protein
in liver cell membrane, and
stimulates irs-1 formation.
insulin binds
cAMP
irs-1
• irs-1 activates HMG CoA reductase
enzyme, increasing rate of
cholesterol synthesis
HMG CoA reductase
active
form
glucagon binds
G
ATP
Glucagon binding results
in cAMP formation
inactive
P P form
P P
inactive
protein
kinase
HMG ~ S-CoA
2 NADP:H
+ H+
mevalonate +
2 NADP+
Insulin binding decreases
[cAMP] in cell
inactive
active
form
P P form
P P
cAMP
HMG CoA
Protein
reductase
kinase
HMG ~ S-CoA
P P
2 NADP:H P P
+ H+
Insulin binding to cell
stimulates cholesterol
synthesis
inactive
insulin binds
irs-1
G
no product
adenyl
cyclase
phosphocAMP diesterase
AMP
ATP
active
form
P P form
P P
HMG CoA
protein
reductase
kinase
HMG ~ S-CoA
2 NADP:H
+ H+
mevalonate
2 NADP+
Activated isoprenes
Activated isoprenes
isopentyl pyrophosphate
isopentyl
pyrophosphate
mevalonate
O
O
O-P-O~P-O
O
O
O
O
O-P-O~P-O
O
O
O
O
O-P-O~P-O
O
O
O
O
O-P-O~P-O
O
O
dimethylallyl pyrophosphate
dimethylallyl pyrophosphate
Condensation of
activated isoprenes
geranyl PP
O O
O-P-O~P-O
O
O
O O
O-P-O~P-O
O
O
P~P
+
cholesterol
HO
Derivatives of cholesterol
pathway intermediates
O O
O-P-O~P-O
O
O
•
•
•
•
ubiquinone
retinal (Vit. A)
cholecalciferol (Vit.D)
menadione (Vit. K)
cholesterol ester
CH3 - ( CH ) 14 - C - O
2
||
O
cholesterol palmitate
Steroid hormones
Bile acids
testosterone
OH
HO
cholesterol
C= O O
cholic acid
HO
O
HO
CH3
progesterone
HO
OH
OH
C=O
estradiol
- bile acids are derivatives
of cholic acid
HO
HO
O
C= O -
Bile acids
HO
OH
- glycine is condensed through
COO - to produce glycocholic acid
- 80% of cholesterol made in liver
is converted to bile acids
and stored in gall bladder
+
NH3
|
CH2
|
COO-
Function of bile acids
- bile acids are secreted from liver
and stored in the gall bladder
liver
gly
Function of bile acids
stomach
liver
- glycocholic acid emulsifies
triglycerides in the small intestine
Function of bile acids
fatty acids in blood stream cause gall
bladder to contract releasing bile
liver
gall bladder
small
intestine
Fatty acids absorbed into blood
through stomach wall stimulate gall
bladder to contract, releasing bile.
stomach
gall bladder
- glycocholic acid (bile acid)
emulsifies triglycerides
small
intestine
Gall stones
- gall stones are cholesterol & bile acids
- stones pass into hepatic duct
hypercholesterolemia
(too much cholesterol in blood stream)
High cholesterol levels may be due to:
liver
1. defective gene for LDL receptor protein
- affected individuals are slow to clear
cholesterol from blood stream
- passage of large gall
stones is extremely painful
normal
liver cell
hypercholesterolemic
liver cell
LDL receptor
protein
2. other factors: smoking, age, inactivity
Atherosclerosis
• atherosclerosis is the formation of
plaques in arteries and arterioles
• plaques are complex deposits of
cholesterol esters and dead cells
embedded in walls of artierioles
chol.-LDL
chol.-LDL chol.-LDL
chol.-LDL chol.-LDL
Plaque formation
Atherosclerosis
PLAQUE
• damaged regions in arteriole walls
trigger inflammatory response
• plaques form at these inflamed
areas more often in persons with
high blood cholesterol
• plaques form and remain when
circulation of blood is sluggish
damage & inflammation
of arteriole wall
healthy vessel
90% blocked
Pentose shunt
Pentose shunt
(phosphogluconate pathway)
• Main function: formation of NADP:H
and pentose PO4
• Location in cell: enzymes found in
cytoplasm
• Regulation: 1st enzyme, glu-6-P DHase
catalyzes rate-limiting step
OH
6-phosphoglucolactone
NADP:H
+ H+
G-6-P DHase
O - C=O
H -C-OH
O = C =O
HO-C - H
H -C-OH
+
H -C-OH NADP
H -C-O-P=O
H O
NADP:H
+ H+
=O
OH
6-phosphogluconolactone
..
H:O:H
..
- O - C=O
H -C-OH
HO-C-H
H -C-OH
H -C-OH
H -C-O-P=O
H O
6-phosphogluconate
rxn probably occurs spontaneously in cell
6-Phosphogluconate DHase
-
O
OH
OH
g-6-P
NADP+
in rapidly dividing cells,
pentose -PO4’s are required
for DNA synthesis
(Lactonase)
=O
OH
in adipose cells, NADP:H is
required for lipid synthesis
H
HC-OP=O
H
HC-OP
O
H
HC-OP
O OH
:H
• Substrate: glucose - 6 - P
• End-product: depends on cell needs
H
H -C-OH
O=C
H -C-OH
H -C-OH
H -C-O-P=O
H O
ribulose-5-P
Hereditary deficiency
of G-6-P DH
• at least 2 different G-6-P DHase
isozymes in humans
• one isozyme is absent in many
persons whose ancestors lived in
malarial regions (S. Italy, parts of
Africa, S.E. Asia)
• these individuals are asymptomatic
until large demand for NADP:H
NADP:H provides
reducing power in r.b.c.
LIPIDS
Classes
G-6-P DHase
g-6-P + NADP+
NADP:H + H+
6-phosphogluconate
NADP:H + H+
NADP+
oxidant
oxidant .H.H
(reduced acetyl
salicylate)
(acetyl salicylate)
glycogen
glu
glu
g-6-P
f-6-P
Carbon
skeleton
r-5-P
Components
• fatty acids
• triglycerides
acetyl units
3 f. a. + glycerol
• phosphoglycerides
• steroids
2 f.a. + glycerol-P
• sphingolipids
sphingosine + f.a.
glycogen
glu
glu
g-6-P
f-1,6-diP
OAA
malate
pyr
pyr
malate
OAA
glu
pyr
malate
3-PG
acetyl Co A
citrate
OAA
isocitrate
NADP:H
malate
r-5-P
c.citrate
glu
OAA
OAA
PEP
malate
malate
OAA
isocitrate
glu
g-6-P
NADP:H
G
c. acetyl CoA
r-5-P
f-6-P
c.citrate
gly.P
f-1,6-diP
DHAP gly.P
pyr
malate
m. acetyl Co A
citrate
OAA
succinate
succ.CoA
gly.P
pyr
pyr
glycogen
f-1,6-diP
3-PG
pyr
pyr
c. acetyl CoA
f-6-P
cAMP
PEP
c.citrate
gly.P
DHAP
Insulin
glycogen
g-6-P
OAA
malate
G
c. acetyl
CoA
phosphitidate
DHAP
succinate
succ.CoA
Glucagon
r-5-P
f-1,6-diP
DHAP gly.P
PEP
NADP:H
f-6-P
gly.P
3-PG
acetyl units
pyr
malate
DHAP
3-PG
acetyl Co A
citrate
OAA
succinate
succ.CoA
isocitrate
G
OAA
PEP
malate
malate
DHAP gly.P
pyr
pyr
OAA
pyr
malate
DHAP
acetyl Co A
citrate
OAA
succinate
succ.CoA
isocitrate
G