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
Some Differences Between Lipogenesis
and β-oxidation pathway
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
THE CITRATE – MALATE SHUTTLE SYSTEM
The acetyl CoA is the starting material for
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.
The outer mitochondrial matrix is freely
permeable to acetyl CoA, as well as many other
substances such as citrate, malate, and
The inner mitochondrial membrane, however is
not permeable to acetyl CoA.
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.
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.
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.
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
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
Acetyl CoA ATP ADP + Pi Malonyl CoA
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
o o o o
- 0—C—CH2—C—S—CoA + ACP—SH - 0—C—CH2—C—S—ACP +CoA—S—H
malonyl CoA ACP malonyl ACP CoA
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
STEP 1: CONDENSATION.
Acetyl ACP and malonyl ACP condense together
to form acetoacetyl ACP.
O O O
II II II
CH3—C—CH2—C—S—ACP + CO2 + ACP—SH
Acetyl ACP Malonyl ACP
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
NADPH/H+ NADP+Acetoacetyl ACP β-Hydroxybutyryl ACP
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
β-Hydroxybutyryl ACP Crotonyl ACPH2O
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
trans ll ll
Crotonyl ACP Butyryl ACP
C16 Fatty acid
C4 Fatty acid
CH3—CH2—CH2— CH2--CH2 C—S—ACP
C6 Fatty acid
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
OVERVIEW OF THE BIOSYNTHETIC PATHWAY FOR CHOLESTEROL
In the first phase of cholesterol synthesis, three
molecules of acetyl CoA are condensed into a
C6 mevalonate ion.
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.
The next stage of cholesterol biosynthesis
involves the condensation of six isoprene units
to give the C30 squalene molecule.
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 .
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.
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.