2. BIOSYNTHESIS OF CHOLESTEROL
Site of Synthesis
Liver is the major site of cholesterol biosynthesis; also
other tissues are active in this regard, e.g. adrenal cortex,
gonads, skin, and intestine are most active.
Low order of synthesis: Adipose tissue, muscle, aorta and
neural tissues.
3. Enzymes:
Enzyme system involved in cholesterol biosynthesis
are associated with:
• Cytoplasmic particles “microsomes”
• Soluble fraction—cytosol.
4. Acetate
‘Active’ acetate (acetyl-CoA) is the starting material and
principal precursor.
The entire carbon skeleton, all 27 C of cholesterol in
humans can be synthesized from active acetate.
5. Steps of biosynthesis:
Cholesterol biosynthesis can be thought of as occurring
in Five groups of reactions.
They are:
I. Synthesis of mevalonate: A 6-C compound from acetyl-
CoA.
II. Formation of “Iso-Prenoid units” (C-5) from Mevalonate:
By successive phosphorylations and followed by loss of CO2.
III. Formation of Squalene: A 30-carbon aliphatic chain,
formed by condensation of six isoprenoid units.
IV. Cyclisation of Squalene to form Lanosterol.
V. Conversion of Lanosterol → to form cholesterol.
6. I. Synthesis of Mevalonate from Acetyl-CoA
Consists of two steps:
• Formation of HMG-CoA: HMG-CoA can be formed in the
cytosol from acetyl-CoA in two steps catalyzed by the enzyme
thiolase and HMG-CoA synthase.
7. In the next step, which is the rate-limiting step, HMG-
CoA is converted to Mevalonic acid (Mevalonate)
catalyzed by the enzyme HMG-CoA reductase.
8. Characteristics of this reaction:
Most important and rate limiting step and irreversible
reaction
Enzyme contains—SH group
NADPH required as cofactor—supplied by HMPPathway.
Hormones: Insulin and thyroid hormones— increases
reductase activity; Glucagon and glucocorticoids—
reduces the activity.
Also inhibited by cyclic AMP
9. II. Formation of Isoprenoid Units
• Mevalonate is phosphorylated by ATP to form
several ‘active’ phosphorylated intermediates.
• Three such phosphorylated compounds are formed
and it is followed by decarboxylation to form first
“active” iso-prenoid unit: ”Iso-pentenyl
pyrophosphate” (5 C).
• Iso-pentenyl pyrophosphate undergoes
isomerisation to form another 5 C iso-prenoid unit,
called “3-3’-Dimethyl allyl pyrophosphate”.
10.
11. III. Formation of squalene
The pyrophosphorylated isoprenoid units condense
to form ultimately a 30-carbon aliphatic chain called
Squalene
12.
13. IV. Cyclisation of squalene to form lanosterol:
The formation of lanosterol from squalene takes place
in two steps:
In the first step squalene-2,3-epoxide is formed
catalysed by the enzyme squalene mono-oxygenase;
which requires NADPH and molecular O2.
In the next step, an enzyme cyclase brings about the
cyclisation of squalene to form lanosterol.
14.
15. V. Conversion of lanosterol to cholesterol:
Main changes that are brought about are:
Removal of three angular –CH3 groups. This involves
a series of reactions, mechanism of demethylation is
not properly known. CH3 group at C14 is first
eliminated.
• Shift of double bond between C8 and C9 to C5 and
C6,and
• Saturation of double bond in side chain.
20. Average diet contains about 300 mg of cholesterol per
day.
Body synthesizes about 700 mg/day.
About 500mg of cholesterol is excreted through bile.
Some of this partly reabsorbed from intestine.
Remaining is converted to bile acids, which are
excreted in the bile as bile salts.
