Fatty Acid Synthesis

Dr. Mehwish Hamid

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▪ liver adipocytes
▪ cytoplasm
▪ glucose is plentiful
fatty acid
synthesis
 ▪

Formation of ▪

malonyl CoA
▪
▪
acyl carrier protein (ACP-SH), fatty
acyl synthase complex.

The pantothenic acid is a

component of ACP.
Intermediates in the biosynthetic
pathway are attached to the
sulfhydryl terminus of
phosphopantotheine group.
Three stages of fatty acid synthesis:

❖ A. Transport of acetyl CoA into cytosol

❖ B. Carboxylation of acetyl CoA
❖ C. Assembly of fatty acid chain
▪ Fatty acids are synthesized in the cytoplasm, whereas acetyl CoA is formed
from pyruvate in mitochondria. Hence acetyl CoA must be transferred into
cytoplasm
▪ But inner mitochondrial membrane is impermeable to acetyl CoA.
▪ This problem is solved by citrate, which carries acetyl groups across the inner
mitochondrial membrane.
▪ Citrate is formed in mitochondrial matrix by condensation of acetyl CoA with
oxaloacetate (OAA)
▪ Thus, OAA and acetyl CoA are transferred from mitochondria to cytoplasm at
expense of 1 molecule of ATP
Citrate-Malate Shuttle
▪

malic enzyme

▪ from the pentose phosphate

pathway.
Enzyme: acetyl CoA carboxylase
Prosthetic group - biotin

A carboxybiotin intermediate is formed.

ATP is hydrolyzed.
The CO2 group in carboxybiotin is transferred to
acetyl CoA to form malonyl CoA.
Acetyl CoA carboxylase is the regulatory enzyme.
 C. The Reactions of Fatty Acid Synthesis
• Five separate stages:
(1) Loading of precursors via thioester derivatives
(2) Condensation of the precursors
(3) Reduction
(4) Dehydration
(5) Reduction
The elongation phase of fatty acid synthesis starts with
the formation of acetyl ACP and malonyl ACP.
Acetyl transacylase and malonyl transacylase catalyze
these reactions.
Acetyl CoA + ACP  acetyl ACP + CoA
Malonyl CoA + ACP  malonyl ACP + CoA
Condensation
reaction

Acetyl ACP and malonyl ACP

react to form acetoacetyl
ACP.

Enzyme - acyl-
malonyl ACP condensing
enzyme.
 Reduction

Acetoacetyl ACP is reduced

to D-3-hydroxybutyryl ACP.

NADPH is the reducing

agent

Enzyme: -ketoacyl ACP

reductase
 Dehydration

D-3-hydroxybutyryl ACP is
dehydrated to form
crotonyl ACP
(trans-2-enoyl ACP).

Enzyme: 3-
hydroxyacyl ACP
dehydratase
 Reduction
The final step in the cycle
reduces crotonyl ACP to butyryl
ACP.

NADPH is reductant.

Enzyme - enoyl ACP reductase.

This is the end of first elongation

cycle (first round).
In the second round
butyryl ACP condenses
with malonyl ACP to
form a C6--ketoacyl
ACP.

Reduction, dehydration,
and a second reduction
convert the C6--
ketoacyl ACP into a C6-
acyl ACP, which is ready
for a third round of
elongation.
• C16 palmitoyl group
• Palmitoyl-ACP thioesterase

Overall reaction of palmitate synthesis from acetyl

CoA and malonyl CoA
▪ palmitate (16:0).
▪

endoplasmic reticulum membrane

▪ Malonyl CoA

▪ elongation

▪
desaturases catalyze the formation of double bonds.
▪ synthase is dimer

▪ transacylases, ketoacyl-ACP synthase (condensing

enzyme)
▪ acyl carrier protein, -ketoacyl reductase,
dehydratase, enoyl reductase
▪ thioesterase
Schematic representation of single chain FA synthase present in animals.
▪ Acetyl CoA carboxylase

▪ carboxylase is controlled by hormones

➢

Another regulatory factors

➢

➢
Global Regulation is carried out by means of reversible phosphorylation
Acetyl CoA carboxylase is switched off by phosphorylation and activated
by dephosphorylation
Insulin stimulates fatty acid synthesis causing dephosphorylation of
carboxylase.
Glucagon and epinephrine have the reverse effect (keep the carboxylase in the
inactive phosphorylated state).

Protein kinase is
activated by AMP and
inhibited by ATP.

Carboxylase is
inactivated when the
energy charge is low.
▪ Acetyl CoA carboxylase stimulated by citrate
▪ citrate acetyl CoA ATP

▪ Palmitoyl CoA carboxylase

 Fed state:
• Insulin level is increased
• Inhibits hydrolysis of stored TGs
• Stimulates formation of malonyl CoA, which inhibits carnitine
acyltransferase I
• FA remain in cytosol (FA oxidation enzymes are in the mitochondria)
Starvation:
• Epinephrine and glucagon are produced and stimulate adipose cell lipase
and the level of free fatty acids rises
• Inactivate carboxylase, so decrease formation of malonyl CoA (lead to
increased transport of FA into mitochondria and activate the b-
oxidation pathway)