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 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

1. BIOSYNTHESIS OF
CHOLESTEROL
PREPARED BY; MISS RABIA KHAN BABER
COURSE TITLE : BIOCHEMISTRY

2. LEARNING OBJECTIVES OF PPT
CHOLESTROL
METABOLISM
STRUCTURE
METABOLISM
AND
BIOSYNTHESIS
VARIATIONIN
SERUM
UTILIZATION
DEGREDATION
REGULATION
FUNCTIONS
AND SOURCES

3. INTRODUCTION TO
CHOLESTROL METABOLISM
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
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

4. STRUCTURE OF
CHOLESTROL
 4 non aromatic rings
named as A,B,C,D
 27 Carbon compound
 1 double bond between
C 5&6
 1 side chain
 1 hydroxyl group at C-3

5. SOURCES OF CHOLESTROL
Cholesterol is derived from
Diet
 De novo synthesis
From the hydrolysis of cholesteryl esters
The liver and intestine account for approximately
10% each of total synthesis in humans.
Virtually all tissues containing nucleated cells are
capable of cholesterol synthesis, which occurs in
the endoplasmic reticulum and the cytosol.

6. FUNCTIONS OF
CHOLESTROL
Cholesterol is the most abundant sterol in humans and
performs a number of essential functions.
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

7. STEROID HORMONE
PRODUCTION
 All steroid hormones are derived form
cholesterol
 In the cortex of adrenal glands two classes of
hormones are synthesized –
mineralocorticoids and glucocorticoids
 In the male and female gonads – sex hormones
are produced
 Sex hormones include – progesterone,
androgens and estrogens

8. BIOSYNTHESIS OF
CHOLESTROL
Slightly less than half of the cholesterol in the body derives
from biosynthesis de novo. Biosynthesis in the liver
accounts for approximately 10%, and in the intestines
approximately 15%, of the amount produced each day. The
cholesterol biosynthesis pathway involves enzymes that
are in the cytoplasm, microsomes (ER), and peroxisomes.
Synthesis of cholesterol, like that of most biological lipids,
begins from the two-carbon acetate group of acetyl-CoA.
The initial steps in the pathway of cholesterol biosynthesis
are collectively called the mevalonate pathway which itself
culminates with the synthesis of the isoprenoid molecule,
isopentenyl pyrophosphate (IPP).

10. The process of cholesterol synthesis can be considered to be composed of five major
steps where the reactions that culminate in the synthesis of isopentenyl
pyrophosphate, and its isomeric form dimethylallyl pyrophosphate, are commonly
referred to as the mevlonate pathway:
Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
HMG-CoA is converted to mevalonate
Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate
(IPP)
IPP molecules are converted to squalene
Squalene is converted to cholesterol

11. STEP#1
HMG-COA SYNTHESIS
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

13. HMG-CoA is then converted to mevalonate by HMG-
CoA reductase.
HMGR is bound in the endoplasmic reticulum.
HMGR requires NADPH as a cofactor and two moles
of NADPH are consumed during the conversion of HMG-
CoA to mevalonate
 The final step the reduction of HMG-CoA to
mevalonate, catalyzed by HMG-CoA reductase.
STEP#2
MEVALONATE SYNTHESIS

15. STEP#3 IPP SYNTHESIS
Conversion of mevalonate into activated isoprene
units
Isoprene containing molecules are important
intermediates in cholesterol biosynthesis

16. Mevalonate is
phosphorylated by 2
sequential Pitransfers
from ATP,
yielding the
pyrophosphate
derivative.
ATP-dependent
decarboxylation, with
dehydration, yields
isopentenyl
pyrophosphate.
H2C
C
CH3
HO
2
C

O O
2CH CH OH
O
O O
H2C CH2 CH2 O P O P
O
O
CH3
C
H2C
C
CH3
HO
2
C

O O
2 O
O O
CH CH O P O P
O
O
CO2
5-pyrophosphomevalonate
ATP
ADP + Pi
mevalonate
2ATP (2 steps)
2ADP
isopentenyl pyrophosphate

17. Isopentenyl Pyrophosphate Isomerase inter-converts
isopentenyl pyrophosphate & dimethylallyl pyrophosphate.
O
O O
CH3
C
H2C CH2 CH2 O P O P
O O
O
O O
CH3
C
H3C CH CH2 O P O P
O O
isopentenyl
pyrophosphate
dimethylallyl
pyrophosphate

18. STEP#4 SYNTHESIS OF
SQUALENE
Polymerization of
six 5-carbon
isoprene units to
form the 30-carbon
linear structure of
squalene

19. O
O O
O
O O
H2C
CH3
C CH2 CH2 O P O P
CH3
H3C C CH CH2 O P O P
O
O
O
OCH3
H3C C CH CH2 CH2
CH3
C CH CH2 O P O P
O
O
PPi
O
O O
H2C
CH3
C CH2 CH2 O P O P
CH3
H3C C CH CH2 CH2
PPi
O
CH3 CH3
C CH CH2 CH2 C CH CH2 O P O P
O
O
dimethylallyl pyrophosphate
O
O
isopentenyl pyrophosphate
O
O
O
isopentenyl pyrophosphate
O O
geranyl pyrophosphate
farnesyl pyrophosphate
Each condensation involves a carbocation formed as PPi is eliminated.

20. O
O O
CH CH2 O P O P
O
O
CH3 CH3
CH2 C CH CH2 CH2 C
CH3
2 H3C C CH CH2
O
O2 H2O
HO
H+
NADPH
NADP+
+ 2 PPi
NADP+
NADPH
2 farnesyl pyrophosphate
squalene 2,3-oxidosqualene lanosterol
Squalene Synthase: Head-to-head condensation of 2 farnesyl
pyrophosphate, with reduction by NADPH, yields squalene.

21. Cyclization of
squalene forms the
four rings of the
steroid nucleus.
Subsequent
modifications leads to
the final product,
cholesterol.
STEP#5 SYNTHESIS OF
CHOLESTROL

22. Conversion of lanosterol to cholesterol involves
19 reactions, catalyzed by enzymes in ER
membranes.
Additional modifications yield the various
steroid hormones or vitamin D.
HO HO
lanosterol cholesterol
19 steps

23. REGULATION OF
CHOLESTEROL SYNTHESIS
Normal healthy adults synthesize cholesterol at a rate of
approximately 1g/day and consume approximately
0.3g/day. A relatively constant level of cholesterol in the
blood (150–200 mg/dL) is maintained primarily by
controlling the level of de novo synthesis. The level of
cholesterol synthesis is regulated in part by the dietary
intake of cholesterol. Cholesterol from both diet and
synthesis is utilized in the formation of membranes and in
the synthesis of the steroid hormones and bile acids. The
greatest proportion of cholesterol is used in bile acid
synthesis.

24. VARIATION OF SERUM
CHOLESTEROL LEVELS
High cholesterol concentration is found in:
Diabetes mellitus
Nephrotic syndrome
Obstructive jaundice
Familial hypercholesterolemia
Biliary cirrhosis
Hypothyroidism

25. HYPOCHOLESTEROLEMIA
Low serum cholesterol concentration is
observed in-
Hyperthyroidism
Malnutrition
Malabsorption
Anemia
Physiologically lower levels are found in children
Persons on cholesterol lowering drugs

26.  The rate limiting
step in the pathway
to cholesterol is
catalyzed by HMG-
CoA reductase
 Its activity is
modulated over a
100-fold range
REGULATION OF HMGR
ACTIVITY AND LEVELS.

27. CHOLESTEROL MADE IN THE
LIVER IS EXPORTED
 Much of cholesterol synthesis takes place in the liver
 Cholesterol is exported in two forms
1. Bile salts – amphipathic cholesterol derivatives that aid
lipid digestion
2. Cholesteryl esters – transported and secreted in
lipoprotein particles to other
tissues that use cholesterol or
are stored in the liver

28. THE UTILIZATION OF
CHOLESTEROL
Cholesterol is transported in the plasma predominantly
as cholesteryl esters associated with lipoproteins.
Dietary cholesterol is transported from the small
intestine to the liver within chylomicrons.
Cholesterol synthesized by the liver, as well as any
dietary cholesterol in the liver that exceeds hepatic needs,
is transported in the serum within LDL.
The liver synthesizes VLDL and these are converted to
LDL through the action of endothelial cell-associated
lipoprotein lipase.
Cholesterol found in plasma membranes can be
extracted by HDL

29. DEGRADATION OF
CHOLESTEROL
The ring structure of cholesterol cannot
bemetabolized to CO2and H20 in humans.
The intact sterol ring is eliminated from
the body by:
1. Conversion to bile acids, which are excreted in
feces
2. Secretion of cholesterol into the bile, which
transports it to the intestine for elimination