3. Cholesterol Synthesis
• Perhydrocyclopentanophenanthrene structure consists of four fused
rings
• Cholesterol contains a hydroxyl group at C3, double bond between C5 &
C6, eight-membered hydrocarbon chain at C17, & methyl groups at C10
& C13
Cholesterol
Perhydrocyclopentanophenanthrene
Fig. 1
Fig.2
7. •All the carbon atoms of
cholesterol are derived from
acetyl CoA
•Liver and Intestine are
major sites of cholesterol
8. STEPS OF DE NOVO
CHOLESTEROL SYNTHESIS
• Step 1—Biosynthesis of Mevalonate
• Step 2—Formation of Isoprenoid Units
• Step 3—Six Isoprenoid Units Form
Squalene
• Step 4—Formation of Lanosterol
• Step 5—Formation of Cholesterol
12. Cholesterol Synthesis Stage 2:
Mevalonate to 2 Activated Isoprenes
• Transfer 3 ATP to Mevalonate in
order to activate C5 & OH-group of
C3
• Phosphate group at C3 & Carboxyl
group of C1 leave, which produces a
double bound
• This allows for two active isoprenes
Fig.5
13. Cholesterol Synthesis Stage 3:
Condensation of Isoprenes to for Squalene
• 1) Head to tail attachment of
isoprenes to form Geranyl
pyrophosphate
• 2) Head to tail condensation of
Geranyl pyrophosphate and
isopentenylpyrophosphate to form
Farnesyl pyrophosphate
• 3) Head to head fusion of two
Farnesyl pyrophosphate to form
squalene
Fig.6
14. Cholesterol Synthesis Stage 4:
Squalene to Four-Ring Steroid Nucleus
• Squalene monooxygenase adds oxygen to form an epoxide
• Unsaturated carbons (double bonds) are aligned to allow cyclization and
formation of lanosterol
• After many reaction get cholesterol
Fig. 7
17. Cholesterol Esters
• Acyl-CoA:cholesterol acyl
transferase (ACAT) is an ER
membrane protein
• ACAT transfers fatty acid of
CoA to C3 hydroxyl group of
cholesterol
• Excess cholesterol is stored as
cholesterol esters in cytosolic
lipid droplets
Fig. 8
18. Bile Salts
• Bile acids & salts are effective detergents
• Synthesized in the liver
• Stored & concentrated in the gallbladder
• Discharged into gut and aides in absorption of
intraluminal lipids, cholesteral, & fat soluble vitamines
• Bile acid refers to the protonated form while bile salts
refers to the ionized form
– The pH of the intestine is 7 and the pKa of bile salts is 6, which
means that 50% are protonated
• These terms are sometimes used interchangeably
19. Synthesis of Bile Salts
• Rate-limiting step performed by the 7α-hydroxylase (CYP7A1) and is
regulated by bile salt concentration
• End product: Cholic acid series & Chenocholic acid series
• Bile salts can be conjugated & become better detergents
Fig. 9 Fig. 10
39. EXCRETION OF CHOLESTREROL
• Cholesterol is excreted in faeces
• Cannot be destroyed by oxidation to CO2
and H2O, because of absence of enzyme
capable of catabolising the steroid nucleus
• About 1gm of cholesterol is eliminated
from the body per day
