This document summarizes the biosynthesis of cholesterol in 5 steps: 1) Mevalonate is formed from acetyl-CoA in the cytosol. 2) Isoprenoid units are formed from mevalonate. 3) Six isoprenoid units condense to form squalene. 4) Squalene is cyclized to form lanosterol. 5) Lanosterol is modified through a series of changes to ultimately form cholesterol in the endoplasmic reticulum. Cholesterol biosynthesis is a major regulatory point for cholesterol levels and is the target of statin drugs.

1. BIOSYNTHESIS OF CHOLESTROL
M.Vharshini
4011450
4th
Year Biomedical Sciences
Sri Ramachandra University

2. Cholesterol- Biochemical
Importance
• Cholesterol is the major sterol in the animal tissues.
• Cholesterol is present in tissues and in plasma either as free
cholesterol or as a storage form, combined with a long-chain
fatty acid as cholesteryl ester.
• In plasma, both forms are transported in lipoproteins.
• Plasma low-density lipoprotein (LDL) is the vehicle of uptake
of cholesterol and cholesteryl ester into many tissues.
• Free cholesterol is removed from tissues by plasma high-density
lipoprotein (HDL) and transported to the liver, where it is
eliminated from the body either unchanged or after conversion to
bile acids in the process known as reverse cholesterol transport .

3. Cholesterol- Biochemical
Importance
• Cholesterol is the most abundant sterol in humans
• It is a major constituent of the plasma membrane and of plasma
lipoproteins.
• It is a precursor of bile salts.
• It is a precursor of steroid hormones that include adrenocortical
hormones, sex hormones, placental hormones etc. Also a
precursor of vitamin D.
• It is required for the nerve transmission.
• Cholesterol is a major constituent of gallstones.
• It has chief role in pathologic processes as a factor in the genesis
of atherosclerosis of vital arteries, causing cerebrovascular,
coronary, and peripheral vascular disease.

4. Sources
• Cholesterol is derived from
Diet
De novo synthesis and
From the hydrolysis of cholesteryl esters.
• More than half of the cholesterol of the body arises by
synthesis (about 700 mg/d), and the remainder is provided by
the average diet.
• The liver and intestine account for approximately 10% each of
total synthesis in humans.
• All tissues containing nucleated cells are capable of cholesterol
synthesis, which occurs in the endoplasmic reticulum and the
cytosol.

5. Biosynthesis of Cholesterol
• The biosynthesis of cholesterol may be divided into
five steps:
Biosynthesis of mevalonate occurs from acetyl-CoA.
Formation of Isoprenoid units formed from mevalonate by
loss of CO2.
Condensation of six isoprenoid units form squalene.
Cyclization of squalene give rise to the parent steroid,
lanosterol.
Formation of Cholesterol from lanosterol.

6. Step1: Biosynthesis of Mevalonate
•The first stage in the synthesis of cholesterol
is the formation of mevalonate from acetyl
CoA.
•This set of reactions takes place in the cytosol.
•Initially, two molecules of acetyl-CoA
condense to form Acetoacetyl-CoA catalyzed
by cytosolic thiolase.
•Acetoacetyl-CoA condenses with a further
molecule of acetyl-CoA catalyzed by HMG-
CoA synthase to form HMG-CoA, that is
reduced to mevalonate by NADPH catalyzed
by 3-hydroxy-3-methylglutaryl CoA
reductase (HMG-CoA reductase).

7. Step1: Biosynthesis of Mevalonate
• The synthesis of mevalonate is the principle regulatory step in
pathway of cholesterol synthesis.
• The enzyme catalyzing this irreversible step, (HMG-CoA
reductase), is an important control site in cholesterol biosynthesis,
and is the site of action of the most effective class of cholesterol-
lowering drugs, the HMG-CoA reductase inhibitors (Statins).

8. Step2: Formation of Isoprenoid
Units
•Mevalonate
is phosphorylated
sequentially by ATP
by three Kinases.
•After decarboxylation
(Figure 26–2) the
active isoprenoid unit,
isopentenyl
diphosphate,is
formed.

9. Step3: Condensation of six
isoprenoid units form squalene
• Squalene (C30) is synthesized from six molecules of
Isopentenyl Pyrophosphate (C5) and the reaction
sequence is:
C5 C10 C15 C30
• Isopentenyl diphosphate is isomerized by a shift of the
double bond to form dimethylallyl diphosphate, then
condensed with another molecule of isopentenyl
diphosphate to form the ten-carbon (C10) intermediate
geranyl diphosphate.

10. Step3: Condensation of six
isoprenoid units form squalene
(C10)
(C15)
(C30)

11. Step3: Condensation of six
isoprenoid units form squalene
• A further condensation with isopentenyl diphosphate
forms farnesyl diphosphate.
• Two molecules of farnesyl diphosphate condense at the
diphosphate end to form squalene.
• Initially, inorganic pyrophosphate is eliminated, forming
presqualene diphosphate, which is then reduced by
NADPH with elimination of a further inorganic
pyrophosphate molecule.

12. Step3: Condensation of six
isoprenoid units form squalene

13. Step4: Formation of Lanosterol
• Squalene can fold into a structure that closely resembles the
steroid nucleus .
• Before ring closure occurs, squalene is converted to squalene
2,3-epoxide by a mixed-function oxidase (i.e.) squalene
epoxidase in the endoplasmic reticulum.
• The methyl group on C14 is transferred to C13 and that on C8 to
C14 as cyclization occurs, catalyzed by oxidosqualene:
lanosterol cyclase.
• The newly formed cyclized structure is Lanosterol.

14. Step4: Formation of Lanosterol

15. Step5: Formation of Cholesterol
• The formation of cholesterol from lanosterol takes place in
the membranes of the endoplasmic reticulum and involves
changes in the steroid nucleus and side chain .
• The methyl groups on C14 and C4 are removed to form 14-
desmethyl lanosterol and then zymosterol.
• The double bond at C8–C9 is subsequently moved to C5–C6 in
two steps, forming desmosterol.
• Finally, the double bond of the side chain is reduced,
producing cholesterol.

16. Step5: Formation of Cholesterol

17. Bibbliography
• Harper’s Illustrated Biochemistry,
28th
edition, Section 2, Chapter 26, Pg224-
227.
• https://themedicalbiochemistrypage.org/choles