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Must know: target product to be

synthesized, pathway, starting
substrate, product, rate limiting step and Five Step in the
Synthesis of Cholesterol

enzyme, what cellular compartment is 1.

Biosynthesis of mevalonate
involved
2. Formation
of isoprenoid units

3. Formation
of squalene
Biosynthesis of Cholesterol
4.
Cyclization of squalene to

lanosterol
General considerations
5.
Conversion of lanosterol to
1. Liver, intestine, adrenal cortex, cholesterol

gonads, placenta have the greatest

capacity to synthesize cholesterol

2. All carbon atoms of cholesterol are Step -1 :

Formation of Mevalonate
derived from acetyl CoA (Rate-limiting
Step)

3. Cholesterol synthesis takes place in

the cytosol and endoplasmic reticulum
(2)
Acetyl Co-A
4. Among all lipid synthesis, cholestorol
is the most expensive because it entail
the usage of 18 ATPs per mecule of

Thiolase Co-A
cholesterol
5. The reducing power in the form of

NADPH is provided by the HMP shunt

Acetoacetyl Co-A

-the proton that will be added will come

from NADPH.
HMG-CoA
synthase Acetyl Co-A

(Cytosolic)
Co-A
Cholesterol
3-
Hydroxy-3-methylglutaryl CoA
-have a cyclic ring structure

(HMG-CoA)
NOTE: the ring will be formed at some
point of the pathway Therefore it is From
HMG-CoA to Mevalonic
important to know that the esterification Acid
or the addition of fatty acid will occur at
C3 of the ring structure

HMG-CoA

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activate the rate limiting enzyme

for
cholesterol to be synthesized.
NADPH
Thus
it favours the
HMG-CoA reductase
dephosphorylated form of an

enzyme which is an active form.

(committed enzyme) NADP

Mevalonate
b.) Glucagon
inhibits the production
(favour
phosphorylated

inactive
form of enzyme)
Regulation of HMG-CoA Reductase

Since
glucagon is a catabolic
HMG-CoA reductase is an intrinsic
enzyme, it will have a role that is
membrane protein of the endoplasmic
entirely opposite. So it will make
reticulum and its active site extends into the
enzyme inactive by providing
the cytosol. a
phosphorylated form, which is
an
inactive form.
 1.) Feedback inhibition by

cholesterol. 3.)
Cholesterol-mediated inhibition
of
gene transcription

2.) Hormonal regulation

a.) Insulin stimulates the

production(favours dephosphorylated

active form of enzyme)

It is an anabolic enzyme. It
removes the glucose form the
blood stream, and enters it into
the glycolytic pathway, to form
Pyruvic acid, Acetyl Co-A. Thus it
being a synthetic hormone, it will

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o 1
mevalonate to 1 isoprenoid

unit = 3 ATPs
o 6
isoprenoid units to 1

cholesterol = 18 ATPs

Step - 3 :
Formation of Squalene

Involves
initial isomerization of
isopentenyl
pyrophosphate (5C).

Followed by a
series of condensation
reactions forming
geranyl
pyrophosphate
(10C) and

farnesylpyrophosphate (15C)
 Condensation
of two

farnesylpyrophosphates forming the 30-

carbon atom
squalene.

4.) Inhibition by drugs : Pyrophosphate

is released in each
condensation
step.

Statins - eg. simvastatin, Farnesyl-PP is

a precursor of
lovastatin, pravastatin, important
compounds like ubiquinone
atorvastatin, etc. and dolichol.

Step - 4 :
Formation of Lanosterol

Step 2 : Formation of isopentenyl Involves

cyclization of squalene to
pyrophosphate form
lanosterol by endoplasmic

reticulum-
bound squalene

oxidocyclase
Sequential phosphorylation of Squalene
oxidocyclase has two
mevalonate by kinases utilizing enzymatic
activities: epoxidase
ATP.
(monooxygenase) and cyclase
Take place several times.
(oxidosqualene: lanosterol cyclase)
Need 6 isoprenoid units to form Lanosterol
has also 30 carbon
one cholesterol. atoms
Most expensive stage : Step - 5 : From
Lanosterol to
Cholesterol

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Take place in the membrane of Because in fasted

state glycolysis, B-
endoplasmic reticulum oxidation and
ketogenesis are more
The major pathway in mammals active.
proceeds through 7-

dehydrocholesterol involving a
series of double bond reductions Two forms of
cholesterol

and demethylations. 1.Free cholesterol

Alternative pathway involves:

1. three demethylations to - un-
esterified to fatty acid;
give zymosterol amphipathic

2. Isomerization of double - found

in membranes and outer
bond to form desmosterol layer of
lipoproteins
3. Reduction of double
- 30% of
total cholesterol in the
bond to form cholesterol
blood

-
biologically more active form

2. Cholesterol
ester

- fatty
acid is esterifed to OH grp
at C-3

- found
in lipid core of lipoproteins

- 70% of
total cholesterol in the
blood

- storage
form of cholesterol in
the tissue

Cholesterol Values

Plasma
150-200
mg/100mL (mostly as

cholesterol ester)
Bile

Digestive
fluid that is synthesized
Cholesterol synthesis using a synthetic in the
liver and stored in the
pathway, takes place in fed state.

gallbladder
390 mg /
100 mL

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96% of cholesterol is free 1.cortisol -

important in the regulation of
cholesterol; 4% is cholesterol carbohydrate, fat and
protein
ester metabolism
Total Cholesterol 2.aldosterone -
mineralocorticoid that is
Estimated by Lieberman- important in water
and electrolyte
Burchard Reaction (chemical balance in the body
as it promotes
reaction involved in the tubular reabsorption
of sodium in the
quantitative determination of distal tubules of the
nephron of the
cholesterol in body fluids kidney (structural
and functional unit of
especially in the blood; produces the urinary system)
a green color which is determined 3.biosynthesis of a
number of
spectrophotometrically) androgenic hormones
such as
androstenedione and
When asked about the metabolic fates dehydroepiandosterone
in which some
of cholesterol in our body mention the are converted to
estrogen.
functions of cholesterol in our body. 4.Progesterone - an
intermediate
Served by Free Cholesterol NOT metabolite in the
biosynthesis of other
by Cholesterol Ester. steroids, important
in the menstrual
cycle of females.
Importance of Cholesterol (Free 5.Testosterone -
responsible for
Cholesterol) secondary sexual
characteristics of
Makes up outer layer of males
lipoprotein (chylomicron, VLDL, 6.Estradiol -
responsible for secondary
LDL and HDL) together with sexual
characteristics of females
 phospholipids.

Important component of cell Protects the

gallbladder
membranes and contributes to its membrane
from irritating and
fluidity harmful
effects of bile salts (minor
Precursor of function)
- Vitamin D - An
obstruction in the
3

(Cholecalfciferol in the
common bile duct may
skin)
cause jaundice as bile
- Bile acids (primary Bile
pigments (particularly
Acids: Cholic acid and
bilirubin) may be
chenodeoxycholic acids in
regurgitated back in the
the liver)
blood stream from the liver
- Steroid hormones in the and
this will be deposited
adrenal cortex and gonads in
the sclera of the eyes
(testis in males ; ovary in
(yellowish discoloration of
females) the
white of the eyes)

cause icterus of the skin

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(jaundice). Patients with - Primary:

formed in the Liver from
jaundice may verbalize Cholesterol

itching Cholic
and chenodeoxycholic
which may be due to the acid
irritating effects of bile - Secondary:
formed in the
salts.
intestines
from the primary bile
acids
Foods Rich in Cholesterol
Organ meats (liver, intestines,
Deoxycholic acid and
 adrenal gland, gonads, brain) and
lithocholic acid
skin -
Conjugatedwith Glycine or
Egg Yolk and meat Taurine
- Conserved
through enterohepatic
circulation

TRIACYLGLYCEROL

- Storage form of fat

Chenodeoxycholic
acid Primary bile
- For future metabolic requirements
- Most of
them 95% are
- most abundant lipid in the diet reabsorbed

- 95% of them
excreted along the
- Foods rich in TAG: butter, margarine, feces
animal fats, fish oils and cooking oils

Pancreatic lipase

Factors involved in Fat Digestion

-very important
enzyme (given at board
1. Enzymes - for degradation exams)
a. Lingual lipase - tongue (Ebners
-is the enzyme that
will be part of fat
gland)
digestion.
b. Gastric lipase stomach
c. Pancreatic lipase most This part does not
happen during fasted
important state
- aka steapsin
Tag breakdown or
lipolysis is a
- requires colipase (found in
degradative path but
it happens during
pancreatic secretion) for
Fed State because
you need to absorb
optimum activity
your triacylglycerol

2. Bile Salts and Bile Acids for It is different from

the lipase that is the
emulsification; not digestive enzymes enzyme in your
lipolysis
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Lipolysis- breakdown of TAG but in the

adipose tissue.

-So this part is the digestion of your

triacylglycerol but we cannot digest and
we cannot absorb TAG as TAGs so
some part of it has to be degraded first
then resynthesized again.

Pancreatic lipase- this is the enzyme

when we breakdown your dietary TAGs
that is different from the breakdown of
fats stored in your adipose tissues.

Pancreatic lipase has a distinct function:

-it can only hydrolyze your SN1 and SN3

of your TAG meaning carbon 1 and

For clearer image
refer to Pg: 540 in
carbon 3 of your TAG
th
Harpers
Biochemistry 30 edition.
Product of pancreatic lipase 2
Absorption of the
Products of Fat
monoacylglycerol ( Glycerol Alcohol + 1
Digestion
Fatty Acid to your carbon 2 or SN2 )
IMAGINATION. Short- and
medium-chain fatty
What could be achieved in the Reaction: acids are
absorbed by the portal
circulation
in liver (small and
Fat digestion -> absorb Fatty Acids easily
digested)
(simple form) -> absorb and digest
Long-chain
fatty acids and 2-
glycerol part ( at this point Pancreatic

monoacyglycerols are used to

lipase can also catabolize or breakdown

resynthesized TAGs in the

the bonds at one entry)
intestinal
cells (De novo
-> what is left is 2 monoacylglycerol ( synthesis)
monoacylglycerol = 1 glycerol
Apoproteins
are added to TAGs
compound with 1 Fatty acid)
and other
lipids from the diet to
form
chylomicrons

Chylomicrons are absorbed by

the
lymphatic circulation
Digestion and Absorption of eventually
to systemic circulation.
Triacylglycerol

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In the
muscles and adipose
tissue
these TAGs are reformed.
Formation
of TAGs require-

1. Rx-1
Activated fatty acids. How
will you
activate the fatty acids?
By adding
thiokinase to the fatty
acids,
which forms fatty acyl co-
A.
2. Rx-2 And
you require glycerol-3-

phosphate, and this glycerol-3-

phosphate
you will get from the
DHAP.

(For one fatty

acids we require three
activated
fatty acids.)
 Long chain fatty acids undergo
formation of TAGs in our body - All the
important substances such
and these TAGs then inform the as as
triacylglycerols,
chylomicrons to participate in
phosphatidylcholine,
general circulation (20%). These
phosphatidylethanolamine,
are later broken down in into
phosphatidylinositol, and
simpler components, which make
cardiolipin,
up fatty acids and glycerol in the a
constituent of mitochondrial
adipose tissue and muscle.
membranes, are formed from
glycerol-
3-phosphate.

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- Glycerol 3-phosphate and

dihydroxyacetone phosphate are
intermediates in glycolysis,
making a very important
connection between carbohydrate
and lipid metabolism
- Glycerol kinase catalyzes the
activation of glycerol to sn-
glycerol 3-phosphate.
If the activity of this enzyme is
absent or low, as in muscle or
adipose tissue, most of the
glycerol-3-phosphate is formed
from dihydroxyacetone
phosphate by glycerol-3-
phosphate dehydrogenase

Biosynthesis of Triacylglycerols
- Two molecules of acyl-CoA,
formed by the activation of fatty
acids by acyl-CoA synthetase
(see Chapter 22), combine with
glycerol-3-phosphate to form
phosphatidate (1,2-
diacylglycerol phosphate). TAG
Metabolism

- This takes place in two stages,

Biomedical Importance:
catalyzed by glycerol-3-
1. TAG is a major form
by w/c
phosphate acyltransferase and
energy is STORED.
1-acylglycerol-3-phosphate
Fat store (70kg) =
15kg(fat)
acyltransferase.

=15kg x
- Phosphatidate is converted by
1,000=15,000g
phosphatidate

=15,000g x 9kcal/g
phosphohydrolase (also called

=135,000 kcal
phosphatidate phosphatase
*Protein and Carbs=
4kcal/g
(PAP)) and diacylglycerol
acyltransferase
2. INCREASE synthesis
& storage
(DGAT) to 1,2-diacylglycerol and of TAG = OBESITY
then triacylglycerol.
*measured through
BMI

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BMI=weight(kg)/height(m2)
*Adipose tissue
releases free fatty acids
Classifications: in starvation, and
these are used by
BMI of 25-30= Overweight/grade I many tissues as fuel.
Furthermore, in
obesity the liver they are the
substrate for
>30= grade II obesity synthesis of ketone
bodies.
>40= morbid/grade III obesity
Protein energy
(calorie) malnutrition
INTERNATIONAL Classification of
(PEM)
adult overweight and obesity accdg
to BMI In developed
countries, PEM is
most
frequently seen in patients
with medical
conditions that
 Classification BMI
decrease
appetite or alter how
Normal 18.50-24.99
nutrients are
digested or
Overweight >/= 25.00 absorbed, or
in hospitalized
Pre-obese 25.00-29.99 patients with
major trauma or
Obese >/= 30.00 infections.
Class I 30.00-34.99 Affected
individuals show a
Class II 35.00-39.99 variety of
symptoms, including a
Class III >/= 40.00 depressed
immune system with a
reduced
ability to resist infection.
*The body can interconvert the majority Death from
secondary infection is
of foodstuffs. However, there is no net common. Two
extreme forms of
conversion of most fatty acids (or other PEM are
kwashiorkor and
acetyl-CoA-forming substances) to marasmus.
glucose. Most amino acids, arising from
the diet or from tissue protein, can be 1. Kwashiorkor:

used for gluconeogenesis, as can the

glycerol from TAG. Kwashiorkor

occurs when protein
deprivation
is relatively greater
*In starvation, glucose must be provided than the
reduction in total
for the brain and erythrocytes; initially, calories.
this is supplied from liver glycogen Protein
deprivation is associated
reserves. To spare glucose, muscle and with severely
decreased
other tissues reduce glucose uptake in synthesis of
visceral protein.
response to lowered insulin secretion; Typical
symptoms include stunted
they also oxidize fatty acids and ketone growth,
edema, skin lesions,
bodies preferentially to glucose. depigmented
hair, anorexia,
enlarged
fatty liver, and

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 decreased plasma albumin
concentration.
Edema results from the lack of
adequate plasma proteins to
maintain the distribution of water
between blood and tissues.

2. Marasmus:

Marasmus occurs when

calorie deprivation is relatively

greater than the reduction in Biosynthesis of

Phosphoglycerides
protein. The first step in
the synthesis of
It usually occurs in children both
phospholipids for membranes
younger than 1 year of age
and
triacylglycerols for energy
when breast milk is
storage is the
synthesis
supplemented with watery
gruels of native cereals that of phosphatidate
(diacylglycerol 3-
are usually deficient in protein phosphate).
and calories.
It is formed by
the addition of two
Typical symptoms include fatty acids to
glycerol 3-
arrested growth, extreme
phosphate, which
in turn is formed
muscle wasting (emaciation),
primarily by the
reduction of
weakness, and anemia.
Victims of marasmus do not dihydroxyacetone
phosphate, a
show the edema or changes glycolytic
intermediate, and to a
in plasma proteins observed lesser extent by
the phosphorylation
in kwashiorkor. of glycerol.

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 Phospholipid synthesis requires the
combination of a diacylglyceride with
1. DE NOVO
SYNTHESIS OF
an alcohol. As in most anabolic

PHOSPHOGLYCERIDES
reactions, one of the components
must be activated.
Starting substrate:

PHOSPHATIDYL SERINE
In this case, either of the two
Synthesis of
components may be activated,
Phosphatidylserine:
depending on the source of the (1)
Addition of
reactants.
NUCLEOTIDE (2)

Addition of AMINO
The de novo pathway starts with the

ACID SERINE
reaction of phosphatidate with cytidine
2. SALVAGE PATHWAY
FOR
triphosphate (CTP) to form cytidine
SYNTHESIS OF
diphosphodiacylglycerol (CDP-

PHOSPHOGLYCERIDES
diacylglycerol) .
Taking
of intermediates
This reaction, like those of many from
other pathways to
biosyntheses, is driven forward by the form
bigger products
hydrolysis of pyrophosphate. What
you have: 1,2 DAG
(1,2
Diacylglycerol)

CEPHALIN leads to the

synthesis of LECITHIN;

immediate precursor
METHYL
GROUP donor
to
Cephalin to become

Lecithin
 DEGRADATION PRODUCTS OF

PHOSPHOGLYCERIDES
WHAT YOU WISH TO ACHIEVE
A. PHOSPHOLIPASE
A1 LCSFA
+
Lysophosphoglyceride (Long
Chain Saturated
Fatty Acid)
B. PHOSPHOLIPASE
A2 UFA +

Lysophosphoglyceride
(Unsaturated
Fatty Acid)

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C. PHOSPHOLIPASE B LCSFA +

UFA