Proteins

4. Lipid Biosynthesis
5. Regulation and pathology of
lipid metabolism

FATTY ACID SYNTHESIS :

Fatty Acids biosynthesis occurs in cytoplasm.
This process requires:

a source of carbons acetyl-CoA

a source of reducing equivalents NADPH
Fatty acid synthetase - a large complex of enzymes
which are responsible for the reactions of fatty acids
synthesis

The Fatty Acid Synthesis Pathway

involves the following stages :
1. Transport of Acetyl-CoA from mitochondria to cytoplasm
2. Synthesis of malonyl-CoA
3. Elongation - the malonyl-CoA pathway
condensation step ( I )
reduction step ( II )
dehydration step ( III )
another reduction step ( IV )
The steps then repeat.

1.Transport of Acetyl-CoA to
cytoplasm

2. Synthesis of malonyl-CoA

3. Elongation - the malonylCoA pathway

All the steps of elongation are catalyzed

by Fatty Acid Synthetase
Fatty Acid Synthetase is an enzyme
complex that consists from seven
enzymes.
At the centre of the multi-enzyme
complex an acyl carrier protein (ACP) is

Fatty acid
synthetase

Fatty Acid Synthase prosthetic

the first thiol group groups:
of a cysteine
residue. Acts as a

holding station for acetylor fatty acyl- groups.

the second thiol group - of

phosphopantetheine,
binds the growing fatty acyl
chain during the condensation
and reduction reactions of the

The Steps of elongation stage in fatty

acids biosynthesis :
I Condensation

1 acethyl-transacylase
2 malonyl-transacylase
3 beta-ketoacyl-ACP-synthase

Decarboxilation

The Steps of elongation stage in fatty

acids(isbiosynthesis
II Reduction
used NADPH). :
III Dehydration (is released water).
IV Reduction (is used again NADPH).

4 beta-ketoacyl-ACP-reductase
5 beta-hydroxyacyl-ACP-dehydrase
6 enoyl-ACP-reductase

The Steps of elongation stage in fatty

acids biosynthesis :
- Transfer of the acyl to the first thiol group (of cysteine), leaving
second thiol group available to pick up the next malonyl :

7 ACP-acyltransferase

Then a new molecule of malonyl-CoA

is added and the Synthetic Cycle is

In Palmitic Acid biosynthesis seven

Cycles are needed.

One Acetyl-CoA is required.
Seven Malonyl-CoA are required
Finally:

8 palmitoil-thio-esterase

Summary of Fatty Acid Synthesis

Reactions:
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH2

=
Palmitate + 7 CO2 + 14 NADP + 8 HSCoA

Elongation and desaturation

of fatty acids
The Fatty Acid Synthetase Complex only makes
palmitate
The rest of the fatty acids come from:

oElongation (for longer saturated acids)

oDesaturation ( for unsaturated acids)

Elongation of Fatty Acids

For longer fatty acids there is a fatty acid elongation system localized on
the ER. The same reactions occur as in the Synthetase, but now have
individual enzymes. Palmitate is first activated to palmitoyl-CoA, then
interact with malonyl-CoA. The major product is stearoyl-CoA.

Desaturation of fatty acid =

Synthesis of unsaturated Fatty Acid

Takes place in microsomes in

liver
enzyme monooxigenase

Biosynthesis of Triacylglycerols
and Glycerophospholipids
Triacylglycerols and
Glycerophospholipids are
synthesized from common
precursors:
Active Glycerol (Glycerol-3phosphate);
Active Fatty Acids (Acyl-CoA);

Glycerol-3-phosphate can be formed in two

ways:

1. From dihydroxyacetone phosphate generated

during glycolysis by the action of the cytosolic NADlinked glycerol-3-phosphate dehydrogenase
(liver, adipose tissue)
2. From glycerol by the action of glycerol kinase

The other precursors of triacylglycerols are

fatty acyl-CoAs, formed from fatty acids
by acyl-CoA synthetases

Phosphatidic acid is a central

intermediate in lipid biosynthesis:
it can be converted either to a
triacylglycerol or to a
glycerophospholipid:

Phosphatidic acid
Triacylglycerols Glycerophospholipids

In the pathway to
triacylglycerols:
1. Phosphatidic acid is
hydrolyzed to form a 1,2diacylglycerol
2. Diacylglycerols are then
converted into
triacylglycerols by
esterification with a third fatty
acyl-CoA.

Synthesis of
Glycerophospholipids

Synthesis of Phosphatidil
choline

Salvage
pathway
choline
is reused
("salvaged") by being
phosphorylated then
converted into CDPcholine by condensation
with CTP.
A diacylglycerol displaces

CMP from CDP-choline,

producing phosphatidylcholine
An analogous salvage

pathway converts
ethanolamine obtained in

Biosynthesis of Cholesterol
Cholesterol is an essential molecule in many
animals, including humans
Cholesterol is founded in the structure of many
membranes
Cholesterol is a precursor of steroid hormones
vitamin D and bile acids:

Biosynthesis of Cholesterol
Takes place in a liver of adult humans
Biosynthesis of cholesterol may be divided

into three steps:

1. Production of mevalonic acid from acetylCoA
2. Synthesis of an active isoprene from
mevalonic acid followed by the condensation
of the former of squalene

1. Production of mevalonic acid from acetylCoA

Cholesteryl esters are formed in

the liver

Acyl-CoA-cholesterol acyl
transferase (ACAT).
Acyl-CoAcholesterol acyl transferase

(ACAT). This enzyme catalyzes the

transfer of a fatty acid from coenzyme A to
the hydroxyl group of cholesterol ,
converting the cholesterol into a more
hydrophobic form.
Cholesteryl esters are transported in

secreted lipoprotein particles to other

tissues that use cholesterol

Plasma lipoproteins
Plasma lipoproteins, macromolecular
complexes of specific carrier proteins
called apoproteins with various
combinations of phospholipids,
cholesterol, cholesteryl esters, and
triacylglycerols
Differing combinations of lipids and
proteins produce particles of different
densities, ranging from very low-density
lipoproteins (VLDL) to high-density

Anatomy of a Lipoprotein
The principal lipid
components are
triglycerides,
cholesterol, cholesteryl
esters and
phospholipids. The
hydrophobic core of the
particle is formed by
the triglycerides and
cholesteryl esters. All

Lipoproteins
Various combinations of lipid and protein produce
particles of different densities. They are:

chylomicrons,
very low-density lipoproteins (VLDL),
low-density lipoproteins (LDL),
high-density lipoproteins (HDL).

The most distinguishing feature of each

class is the density and relative amounts of

Human plasma lipoproteins

chylomicro
n
Density (g/ml) <0.95

VLDL

IDL

LDL

HDL

0.950
1.006

1.006
1.019

1.019
1.063

1.063
1.210

Components (% dry weight)

protein

15

20

4055

triglycerides

83

50

31

10

free cholesterol 2

cholesteryl
esters
phospholipids

12

23

42

1220

22

22

22
A-I, A-II,
C-I, C-II,
C-III, D,
E

Apoprotein
composition

3
7

20
B-100, CA-I, A-II,
B-48, C-I, I,
C-II, C-III C-II, C-III,
E

B-100, C-I,
C-II, C-III, B-100
E

Chylomicrons
Chylomicrons are the
largest of the lipoproteins
and the least dense,
containing a high proportion
of triacylglycerols (80-90%)
Chylomicrons are
synthesized in the
endoplasmic reticulum of
epithelial cells of the small
intestine
Chylomicrons carry fatty

Very low-density lipoprotein,

VLDL

VLDLs contain a lot of endogenous

triacylglycerols (50-60%), cholesterol and
cholesteryl esters, as well as apoB-100
and other apoproteins.
These lipoproteins are synthesized in the
liver and are transported in the blood to
muscle and adipose tissue.

Low-density lipoproteins, LDL

Low-density lipoproteins, LDL are very rich
in cholesterol and cholesteryl esters and
contain apoB-100 as their major apoprotein
LDLs carry cholesterol to peripheral tissues
that have specific surface receptors that
recognize apoB-100. These receptors
mediate the uptake of cholesterol and
cholesteryl esters.

Structure of a low-density lipoprotein

(LDL)

High-density lipoprotein, HDL

HDL begins in the liver and small intestine as
small, protein-rich particles containing
relatively little cholesterol and no cholesteryl
esters
HDLs contain apoC-I and apoC-II, among
other apolipoproteins , as well as the enzyme
lecithin-cholesterol acyl transferase
(LCAT), which catalyzes the formation of
cholesteryl esters from lecithin

High-density lipoprotein, HDL

HDL collects cholesteryl esters from other
circulating lipoproteins, Chylomicrons and
VLDLs
HDL returns cholesterol to the liver for the
synthesis of bile acid and steroid hormones

Regulation of lipid metabolism

Metabolism of lipids is depended on dietary
supply of lipids and carbohydrates and on the
neuro-hormonal regulation
A large dietary intake of carbohydrate rich
food exerts a significant production of
triglycerides and cholesterol
Vegetable oils (rich in phospholipids and
poly-unsaturated fatty acids = lipotropic
factors) prevent an excessive accumulation
of cholesterol and its deposition in blood

Regulation of lipid metabolism

The lipotropic factors exercise a marked
effect on the biosynthesis of phospholipids
and triglycerides. The dietary deficiency of
lipotropic factors increase the triglyceride
production in the organism
The lipolysis in tissues is depended on the
activity of triglyceride lipase
Adrenaline and noradrenalin, glucagon,
thyroxin, somatotropin act as stimulators of

Regulation of Triacylglycerols
synthesis

Insulin promotes the conversion of

carbohydrate into triacylglycerols .
People with severe diabetes mellitus are
unable to synthesize fatty acids from
carbohydrates or amino acids.
They show increased rates of fat oxidation
and ketone body formation
As a consequence they lose weight

Pathology of lipid metabolism

Most lipid metabolism pathology is
manifest as HIPERLIPEMIA (elevated
concentration of lipids in blood) and tissue
lipidoses (excessive lipid deposition in
tissues)
Hyperlipemia may manifest itself by an
increased concentration of lipoproteins
and chylomicrons
Secondary Hyperlipemia are observed in

Familial hypercholesterolemia
In the human genetic disease known as
familial hypercholesterolemia, blood levels of
cholesterol are extremely high, and afflicted
individuals develop severe atherosclerosis in
childhood.
The LDL receptor is defective in these
individuals, and the receptor-mediated
uptake of cholesterol carried by LDL does not
occur.
Consequently, cholesterol obtained in the diet
is not cleared from the blood; it accumulates

Pathology of lipid metabolism.

Tissue Lipidoses

Lipidoses can arise from defects of the

enzymes involved in lipids metabolism
Atherosclerosis manifested by the
depozition of cholesterol in arterial walls,
which results in the formation of lipid
plagues.LDL exhibit atherogenic
properties
Fatty infiltration of the liver can be in
deficiency in lipotropic factors and excess

Atherosclerosis
When the cholesterol synthesized and
obtained in the diet exceeds the amount
required for the synthesis of membranes, bile
salts, and steroids
pathological accumulations of cholesterol in
blood vessels (atherosclerotic plaques) can
develop in humans, resulting in obstruction of
blood vessels (atherosclerosis).

Heart failure from occluded coronary arteries

Traditional risk factors include age, male sex, dyslipidemia,

hypertension, smoking, and diabetes. More recently identified
risk factors include obesity and a sedentary lifestyle.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis