Lipogenesis is the process by which fatty acids are synthesized from acetyl-CoA in the cytosol. Acetyl-CoA produced in mitochondria is transported to the cytosol via the citrate-malate shuttle. In the cytosol, acetyl-CoA and malonyl-ACP are condensed by fatty acid synthase to initiate the elongation cycle, which adds two carbon units in four steps utilizing NADPH. This cycle repeats until fatty acids of varying lengths are produced. Cholesterol synthesis is a 27 step process where acetyl-CoA is converted to mevalonate and then isopentenyl pyrophosphate, which condenses to form squalene and undergoes cyclization and

2. What is Lipogenesis?
 It is the metabolic pathway by which fatty acids
are synthesized from Acetyl-CoA.
 It is not simply a reversal of the steps of
degradation of fatty acids (the β-oxidation
pathway).

3. Some Differences Between Lipogenesis
and β-oxidation pathway
Oxidation Synthesis
Reaction site Mitochondria Cytosol
Enzymes involved (Independent ) Fatty acid synthase
Intermediates carrier Coenzyme A Acyl carrier protein
Coenzymes FAD, NAD+ NADPH
Carbon atoms Removed two at a time Added two at a time

4. THE CITRATE – MALATE SHUTTLE SYSTEM
 The acetyl CoA is the starting material for
lipogenesis.
 Because acetyl CoA is generated in mitochondria
and lipogenesis occurs in the cytosol, the acetyl
CoA must be transported to the cytosol.
 It exits the mitochondria through a transport
sytem that involves citrate ion.

5.  The outer mitochondrial matrix is freely
permeable to acetyl CoA, as well as many other
substances such as citrate, malate, and
pyruvate.
 The inner mitochondrial membrane, however is
not permeable to acetyl CoA.

6. THE CITRATE – MALATE SHUTTLE SYSTEM

7. THE CITRATE – MALATE SHUTTLE SYSTEM
 Mitochondrial acetyl CoA reacts with
oxaloacetate to produce citrate, which is then
transported through the inner mitochondrial
membrane by a citrate transporter.
 Once in the cytosol, the citrate undergoes the
reverse reaction to its formation to regenerate
the acetyl CoA and oxaloacetate, with ATP
involved in the process.

8.  The acetyl CoA so generated becomes the
“fuel” for lipogenesis; the oxaloacetate so
generated reacts further to produce malate, in
an NADH dependent change.
 The malate reenters the mitochondrial matrix
through a malate transporter, and is then
converted to oxaloacetate, which can then
react with another acetyl CoA molecule to form
citrate and the shuttle process repeats itself.

9. ACP COMPLEX FORMATION
 Two simple ACP complexes are neede to start
the lipogenesis process.
 They are acetyl ACP, a C2–ACP, and malonyl
ACP, a C3 --ACP .
 Additional malonyl ACP molecules are needed
as the lipogenesis process proceeds.

10.  Cytosolic acetyl CoA is the starting material for the
production of both of these simple ACP complexes.
Acetyl ACP is produced by direct reaction of acetyl CoA
with and ACP molecule.
O acetyl transferase O
CH3—C—S—CoA + ACP—S—H CH3—C—S—ACP + CoA—S—H
Acetyl CoA Acetyl ACP CoA

11.  The reaction to produce malonyl, ACP requires
two steps . The first step is a carboxylation
reaction with ATP involvement.
O O O
CH3—C—S—CoA + CO2
- 0—C—CH2—C—S--CoA
Acetyl CoA ATP ADP + Pi Malonyl CoA

12.  This reaction occurs only when cellular ATP levels are high. It is
catalyzed by acetyl CoA carboxylase complex, which requires
both Mn2+ ion and the B vitamin biotin for its activity. The
malonyl CoA so produced then reacts with ACP to produce
malonyl ACP.
o o o o
 malonyl transferase
- 0—C—CH2—C—S—CoA + ACP—SH - 0—C—CH2—C—S—ACP +CoA—S—H
malonyl CoA ACP malonyl ACP CoA

13. THE CHAIN ELONGATION
 Four reactions that occur in a cyclic pattern
within the multienzyme fatty acids synthase
complex constitute the chain elongation
process used for fatty acids.
 The reactions of the first turn of the cycle, in
general terms

14. Acetyl ACP Malonyl ACP
Crotonyl ACP
Acetoacetyl ACP
Butyryl ACP
β-Hydroxybutyryl ACP
+
1. CONDENSATION
2. HYDROGENATION
3. DEHYDRATION
4. HYDROGENATION
ACP CO2
NADPH/H+
NADP+
H2O
+
NADPH/H+
NADP+
CHAIN ELONGATION

15. STEP 1: CONDENSATION.
Acetyl ACP and malonyl ACP condense together
to form acetoacetyl ACP.
O O O
II II II
CH3—C—S—ACP+ -O—C—CH2—C—S—ACP
O O
II II
CH3—C—CH2—C—S—ACP + CO2 + ACP—SH
Acetyl ACP Malonyl ACP
Acetoacetyl ACP

16. STEP 2: FIRST HYDROGENATION.
The Keto group of the acetoacetyl complex,
which involves the β-carbon atom, is reduced to
the corresponding alcohol by NADPH.
O O OH O
II II I II
CH3—C—CH2—C—S—ACP CH3—CH—CH2—C—S—ACP
NADPH/H+ NADP+Acetoacetyl ACP β-Hydroxybutyryl ACP

17. STEP 3. DEHYDRATION
The alcohol produced in STEP 2 is dehydrated
to introduce a double bond into the molecule
(between α and β carbons.)
OH O O
l ll ll
CH3—CH—CH2—C—S—ACP CH3—CH=CH—C—S—ACP
β-Hydroxybutyryl ACP Crotonyl ACPH2O

18. STEP 4: SECOND HYDROGENATION
The double bond introduced in step 3 is
converted to a single bond through
hydrogenation. As in step 2, NADPH is the
reducing agent.
o o
trans ll ll
CH3—CH=CH—C—S—ACP CH3—CH2—CH2—C—S—ACP
Crotonyl ACP Butyryl ACP
NADPH/H+ NADP+

19. O
II
CH3—C—S—ACP
Acetyl ACP
O
ll
CH3--(C2)14—C—O-
C16 Fatty acid
O
II
CH3—CH2—CH2—C—S—ACP
C4 Fatty acid
O
Il
CH3—CH2—CH2— CH2--CH2 C—S—ACP
C6 Fatty acid
Cycle repeats
Malonyl ACP
CO2
Malonyl ACP
Malonyl ACP
Malonyl ACP
CO2
CO2
CO2

20. BIOSYNTHESIS OF CHOLESTEROL
 The biosynthesis of cholesterol, a C27 molecule
, occurs primarily in the liver.
 Its production consumes 18 molecules of
acetyl CoA and involves at least 27 separate
enzymatic steps.

21. Acetyl CoA
C2
Mevalonate
C6
Cholesterol
Multiring
C27
Lanosterol
Multiring
C30
Squalene
Acyclic
C30
Isopentyl
Pyrophosphate
C5
Several
Steps
Several
Steps
Several
Steps
Several
Steps
Several
Steps
OVERVIEW OF THE BIOSYNTHETIC PATHWAY FOR CHOLESTEROL
SYNTHESIS

22.  In the first phase of cholesterol synthesis, three
molecules of acetyl CoA are condensed into a
C6 mevalonate ion.

23. The C6 mevalonate undergoes a decarboxylation to yield a C5
isoprene derivative called isopentenyl pyrophosphate and CO2 .
Three ATP molecules are needed in accomplishing this process.

24. The next stage of cholesterol biosynthesis
involves the condensation of six isoprene units
to give the C30 squalene molecule.

25.  The multistep squalene-to-lanosterol transition involves the
formation of four ring systems.
 A decrease in double bonds from six to two.
 The migration of two methyl groups to new locations, and the
addition of an –OH group to the C30 system.
 Addition of the –OH group requires the use of molecular
oxygen; the O of the –OH group comes from the molecular O2 .
SQUALENE LANOSTEROL

26.  The transition from lanosterol to cholesterol involves
removal of three methyl groups (C30 to C27 ), reduction
of the double bond in the side chain, and migration of
the other double bond to a new location.

27.  Once the cholesterol has been formed,
biosyhthetic pathways are available to convert
it to each of the five major classes of steroid
hormones: progestins, androgens, estrogens,
glucocorticoids, and mineralocorticoids, as well
as to bile acids and vitamin D.

28. Cholesterol
C27
Progestins
C21
Mineralocorticoids
C21
Androgens
C19
Glucocorticoids
C21
Estrogens
C18
Biosynthetic Relationship among Steroid Hormones

29. THANK YOU… 
TO GOD BE THE GLORY
PREPARED BY:
LEIZEL A. DESPI
BSED 2C