1. METABOLISM OF LIPIDS:
SYNTHESIS OF
FATTY ACIDS

2. Fatty Acid Synthesis
• Occurs mainly in liver and adipocytes, in
mammary glands during lactation
• Occurs in cytoplasm
• FA synthesis and degradation occur by
two completely separate pathways
• When glucose is plentiful, large amounts
of acetyl CoA are produced by glycolysis
and can be used for fatty acid synthesis

3. Three stages of fatty acid
synthesis:
A. Transport of acetyl CoA into
cytosol
B. Carboxylation of acetyl CoA
C. Assembly of fatty acid chain

4. A. Transport of Acetyl CoA to
the Cytosol
• Acetyl CoA from catabolism of
carbohydrates and amino acids is
exported from mitochondria via the
citrate transport system
• Cytosolic NADH also converted to NADPH
• Two molecules of ATP are expended for
each round of this cyclic pathway

5. Sources of NADPH for Fatty Acid Synthesis
1. One molecule of NADPH is generated for each
molecule of acetyl CoA that is transferred from
mitochondria to the cytosol (malic enzyme).
2. NADPH molecules come from the pentose
phosphate pathway.

6. B. Carboxylation of Acetyl CoA
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.

7. 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

8. During the fatty acid synthesis all intermediates are linked
to the protein called acyl carrier protein (ACP-SH), which
is the component of 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.

9. 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

10. Condensation
reaction.
Acetyl ACP and
malonyl ACP react to
form acetoacetyl
ACP.
Enzyme -
acyl-malonyl ACP
condensing enzyme.

11. Reduction.
Acetoacetyl ACP is
reduced to D-3-
hydroxybutyryl ACP.
NADPH is the
reducing agent
Enzyme: β-ketoacyl
ACP reductase

12. Dehydration.
D-3-hydroxybutyryl
ACP is dehydrated
to form crotonyl
ACP
(trans-∆2-enoyl
ACP).
Enzyme:
3-hydroxyacyl
ACP dehydratase

13. 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).

14. In the second round
butyryl ACP condenses
with malonyl ACP to
form a C6-β-ketoacyl
ACP.
Reduction, dehydration,
and a second reduction
convert the C6-β-
ketoacyl ACP into a C6-
acyl ACP, which is ready
for a third round of
elongation.

15. Final reaction of FA synthesis
• Rounds of synthesis continue until a
C16 palmitoyl group is formed
• Palmitoyl-ACP is hydrolyzed by a thioesterase
Overall reaction of palmitate synthesis from
acetyl CoA and malonyl CoA
Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+
Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O

16. Organization of Multifunctional Enzyme
Complex in Eukaryotes
The synthase is dimer with antiparallel subunits.
Each subunit has three domains.
ACP is located in domain 2.
Domain 1 contains transacylases, ketoacyl-ACP
synthase (condensing enzyme)
Domain 2 contains acyl carrier protein, β-ketoacyl
reductase, dehydratase, and enoyl reductase.
Domain 3 contains thioesterase activity.

18. Fatty Acid Elongation and Desaturation
The common product of fatty acid synthesis is
palmitate (16:0).
Cells contain longer fatty acids and unsaturated
fatty acids they are synthesized in the endoplasmic
reticulum.
The reactions of elongation are similar to the ones
seen with fatty acid synthase (new carbons are
added in the form of malonyl CoA).
For the formation of unsaturated fatty acids there
are various desaturases catalizing the formation of
double bonds.

19. THE CONTROL OF FATTY ACID METABOLISM
Acetyl CoA carboxylase plays an essential role
in regulating fatty acid synthesis and
degradation.
The carboxylase is controlled by hormones:
 glucagon,
 epinephrine, and
 insulin.
Another regulatory factors:
 citrate,
 palmitoyl CoA, and
 AMP

20. 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.

21. Local Regulation
Acetyl CoA carboxylase is allosterically stimulated by
citrate.
The level of citrate is high when both acetyl CoA and ATP
are abundant (isocitrate dehydrogenase is inhibited by
ATP).
Palmitoyl CoA inhibits carboxylase.

22. Response to Diet
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)

23. LIPID METABOLISM:
BIOSYNTHESIS OF TRIACYLGLYCEROLS
AND PHOSPHOLIPIDS

24. Synthesis of Triacylglycerols (TGs)
and Glycerophospholipids (GPLs)
Glycerol 3-phosphate can be obtained either by the
reduction of dihydroxyecetone phosphate (primarily) or
by the phosphorylation of glycerol (to a lesser extent).

25. Formation of phosphatidate
Two separate acyl transferases (AT) catalyze the
acylation of glycerol 3-phosphate.
The first AT (esterification at C1) has preference for
saturated fatty acids;
the second AT (esterification at C2) prefers
unsaturated fatty acids.

26. • Phosphatidic acid (phosphatidate) is an
common intermediate in the synthesis of
TGs and GPLs
Phosphatidate can be converted to two precursors:
- diacylglycerol (precursor for TGs and neutral
phospholipids) - cytidine diphosphodiacylglycerol (CDP-
diacylglycerol) (precursor for acidic phospholipids)

27. Synthesis of TGs and neutral phospholipids
Phospha-
Triacyl- tidyl-
glycerol
etha-
nolamine
Phosphatidylcholine

28. Synthesis of TGs
Diacylglycerol can
be acylated to
triacylglycerol (in
adipose tissue
and liver)
Enzyme:
acyltransferase

29. Synthesis of neutral phospholipids
CDP-choline or CDP-ethanolamine are formed from
CTP by the reaction:
CTP + choline phosphate → CDP-choline + PPi
CTP + ethanolamine phosphate →
CDP-ethanolamine + PPi
Diacylglycerol react with CDP-choline or CDP-
ethanolamine to form phosphatidylcholine or
phosphatidylethanolamine

31. Synthesis of acidic phospholipids

32. Phosphatidylinositol can be converted to phosphatidylinositol
4,5-biphosphate which is the precursor of the second
messenger inositol 1,4,5-triphosphate

33. • Interconver
-sions of
phosphati-
dylethanol-
amine and
phospha-
tidylserine