This document summarizes the synthesis of fatty acids. Fatty acids are synthesized from acetyl-CoA, which is derived mostly from glucose and amino acids. Fatty acid synthesis occurs in the cytosol through a multi-enzyme complex called fatty acid synthase. The process involves repeated cycles of reactions that add two-carbon units from malonyl-CoA to an growing fatty acid chain. Triglycerides are then formed from fatty acids and stored in adipose tissue as an energy source. The synthesis is regulated by enzymes like acetyl-CoA carboxylase in response to energy levels.

1. Synthesis of Fatty Acids
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. Fatty acids are synthesized from acetyl
CoA
Acetyl CoA for fatty acid synthesis comes
mostly from glucose and amino acids
The capacity to store glucose and amino
acids is limited

3. An average adult can store 125-150 gm
glycogen and 5-6 kg protein
In terms of energy, this is less than 25,000
kcal
However, the capacity to store lipids is huge
When calorie intake exceeds its utilization,
the excess energy is stored as lipids

4. Glucose is oxidized to pyruvate by
glycolysis
Pyruvate is converted into acetyl CoA by
oxidative decarboxylation
Carbon skeletons of many amino acids are
converted into acetyl CoA

5. If there is need for energy, acetyl CoA is
oxidized in citric acid cycle
If energy is not required, acetyl CoA is
converted into fatty acids
Fatty acids are esterified with glycerol to
form triglycerides

6. Triglycerides are the major storage form
of lipids
They are stored in adipose tissue
In times of caloric insufficiency, stored
triglycerides are broken down
The fatty acids released are used as a
source of energy

7. Synthesis of fatty acids
The pathways for synthesis
of saturated fatty acids are:
Extramitochondrial fatty acid synthesis
Mitochondrial fatty acid synthesis
Microsomal fatty acid synthesis

8. Extra-mitochondrial fatty acid synthesis
occurs in cytosol
It results in de novo synthesis of fatty
acids from acetyl CoA
The other two pathways only elongate the
pre-existing fatty acids

9. A pathway for the synthesis of mono-
unsaturated fatty acids is present in
endoplasmic reticulum
However, polyunsaturated fatty acids
can't be synthesized in human beings,
and must be provided in diet

10. This pathway is present in many tissues
e.g. liver, kidneys, mammary glands,
adipose tissue, lungs, brain etc
The basic building block is acetyl CoA
which is the source of all the carbon
atoms of the fatty acid being synthesized
Extramitochondrial fatty acids synthesis

11. NADPH is required as a reductant
Carbon dioxide and biotin are required for
a carboxylation reaction
ATP is required as a source of energy for
the carboxylation reaction
The carboxylation reaction is catalysed by
acetyl CoA carboxylase

12. All the other enzymes required in the
pathway are present in the form of a
multi-enzyme complex (MEC)
The MEC is made up of two identical
subunits
MEC is also known as fatty acid synthase
(FAS)

13. Each subunit of MEC/FAS contains an
acyl carrier protein (ACP) and seven
different catalytic activities
The ACP is not a separate protein; it is
just a domain in the subunit
Seven different catalytic activities are also
present in seven domains

14. ACP contains 4'-phosphopantetheine as
a prosthetic group
4'-Phosphopantetheine has got a free
sulphydryl (–SH) group
Intermediates of fatty acid synthesis are
bound to the –SH group of ACP

15. The enzymatic
activities
present in each
subunit are:
Acyl transferase (AT)
Malonyl transferase (MT)
Condensing enzyme (CE)
b-Ketoacyl reductase (KR)
Dehydratase (DH)
Enoyl reductase (ER)
Thio esterase (TE)

16. AT, MT and CE of one subunit and KR,
DH, ER, TE and ACP of the other subunit
form one functional unit
There are two functional units in each
MEC
The two functional units synthesize two
fatty acid molecules simultaneously

17. CE has got a cysteine residue; its ‒SH
group binds an acetyl (or acyl) group
ACP has also got a ‒SH group in its
prosthetic group which is flexible
ACP moves the growing acyl chain from
one catalytic site of MEC to another

20. Malonyl CoA transfers its malonyl group
to ACP of one functional unit of MEC
Acetyl CoA transfers its acetyl group to
CE of one functional unit of MEC
Subsequent reactions leading to the
synthesis of fatty acid occur on the MEC

21. Malonyl group is decarboxylated and
condensed with acetyl group
This reaction is catalysed by CE
The product is a b-ketoacyl group,
bound to –SH group of ACP
The –SH group of CE becomes free

23. The b-ketoacyl group is reduced to
b-hydroxyacyl group
The reaction is catalysed by KR
The reducing equivalents are provided by
NADPH

25. The –OH group attached to b-carbon and
an –H atom from a-carbon atom are
removed as water
The reaction is catalysed by DH
The b-hydroxyacyl group is converted into
an a, b-unsaturated acyl (enoyl) group

27. The double bond between the a- and b-
carbon atoms is reduced to a single bond
The reducing equivalents are provided by
NADPH
This reaction is catalysed by ER
The product is a butyryl group

29. The butyryl group is transferred to the
–SH group of CE
This completes one cycle of reactions
The 2-carbon acetyl group has been
converted into a 4-carbon butyryl group

31. Another cycle begins with the binding of a
malonyl group to ACP
Two carbon atoms are added to the
butyryl group by the end of the cycle
These cycles continue until the acyl group
is converted into a palmityl group

32. The MEC is incapable of increasing the
length of the acyl chain beyond 16
carbon atoms
Palmitate is hydrolytically split off the
multi-enzyme complex by thio esterase

34. Acetyl CoA required for fatty acid synthesis
is obtained mostly from pyruvate
Pyruvate, formed mainly from glucose, is
converted into acetyl CoA in mitochondria
When the cells have sufficient energy,
acetyl CoA is used for fatty acid synthesis

35. While acetyl CoA is formed in mitochondria,
fatty acid synthesis occurs in cytosol
Acetyl CoA has to move out of mitochondria
for fatty acid synthesis
But mitochondrial membrane is not
permeable to acetyl CoA

36. Acetyl CoA combines with oxaloacetate to
form citrate
Citrate comes out of the mitochondria
It is cleaved into oxaloacetate and acetyl
CoA by ATP-citrate lyase

38. NADPH used in fatty acid synthesis
comes mainly from HMP shunt
Two other minor sources are:
Extramitochondrial oxidation
of isocitrate
Oxidative decarboxylation of
malate

39. Extramitochondrial oxidation of isocitrate
uses NADP+ as a coenzyme
It is catalysed by cytosolic isocitrate
dehydrogenase
Isocitrate a-Ketoglutarate + CO2
NADP+ NADPH + H+


40. Malate Pyruvate + CO2
NADP+ NADPH + H+

Oxidative decarboxylation of malate
also uses NADP+ as a coenzyme
It is catalysed by cytosolic malic
enzyme

41. This is a minor pathway for elongation of
medium-chain fatty acids
It is just a reversal of b-oxidation pathway
except for one reaction
a, b-Unsaturated acyl CoA is reduced by
a different enzyme
Mitochondrial synthesis (elongation)
of fatty acids

43. This is the major pathway for elongation
of fatty acids
Two carbon atoms are added to the
carboxyl end of a pre-existing fatty acid
in one cycle
Microsomal synthesis (elongation)
of fatty acids

44. The carbon atoms for elongation are
provided by malonyl CoA
NADPH is required as a reductant
Each cycle involves four reactions

46. This pathway also converts long-chain
fatty acids into very long-chain fatty acids
Very long-chain fatty acids are required in
brain for the synthesis of sphingolipids

47. Metabolism of fatty acids is regulated
according to availability of energy
During energy abundance, synthesis of
fatty acids in increased and their
oxidation is decreased
The reverse occurs during caloric
insufficiency
Regulation of fatty acid synthesis

48. Acetyl CoA carboxylase is the regulatory
enzyme of fatty acid synthesis
It catalyses the committed step of the
pathway which is also the rate-limiting step
Acetyl CoA is regulated by allosteric
mechanism and covalent modification

49. Citrate and palmitoyl CoA are allosteric
regulators of acetyl CoA carboxylase
Citrate is the allosteric activator of the
enzyme
Palmitoyl CoA is the allosteric inhibitor of
the enzyme

50. Concentration of citrate is high in times of
caloric sufficiency
Citrate activates acetyl CoA carboxylase;
synthesis of malonyl CoA is increased
Increased availability of malonyl CoA
increases fatty acid synthesis

51. If palmitic acid is not being used,
concentration of palmitoyl CoA increases
Palmitoyl CoA inhibits acetyl CoA
carboxylase
Inhibition of acetyl CoA carboxylase
decreases fatty acid synthesis
Palmitic acid is the end product of de
novo synthesis of fatty acids

52. Acetyl CoA carboxylase is also subject to
covalent modification
Covalent modification involves its
phosphorylation and dephosphorylation
The phosphorylated form is inactive, and
the dephosphorylated form is active

53. When availability of energy is low,
glucagon secretion rises
It activates adenylate cyclase in liver; the
concentration of cAMP increases
Increase in cAMP concentration activates
protein kinase A

54. Active protein kinase A phosphorylates
acetyl CoA carboxylase
As a result, acetyl CoA carboxylase
becomes inactive
Fatty acid synthesis decreases

55. In times of energy abundance, insulin
secretion is high
When insulin concentration is high, cAMP
level decreases
Protein kinase A remains inactive

56. Inactive protein kinase A cannot
phosphorylate acetyl CoA carboxylase
As the dephosphorylated enzyme is active,
fatty acid synthesis increases

59. Acetyl CoA carboxylase is regulated by
induction also
Insulin induces the synthesis of the
enzyme
Increased quantity of the enzyme
increases fatty acid synthesis

60. Unsaturated fatty acids include mono-
and poly-unsaturated fatty acids
Linoleic acid, linolenic acid and arachi-
donic acid are polyunsaturated fatty acids
(PUFA)
PUFA cannot be synthesized by
human beings
Synthesis of unsaturated fatty acids

61. Therefore, PUFA are known as essential
fatty acids, and must be supplied in diet
Their deficiency can impair lipid transport
and cause hypercholesterolaemia and
dermatitis
Presence of PUFA in membrane lipids
increases the fluidity of membranes

62. Several vegetable oils are good
sources of PUFA such as:
• Safflower oil
• Sunflower oil
• Cottonseed oil
• Wheat germ oil
• Soya bean oil
• Rice bran oil etc

63. Monounsaturated fatty acids can be
synthesized by human beings
They are synthesized from saturated
fatty acids
The synthesis occurs in endoplasmic
reticulum (microsomes) of liver cells

64. Microsomal hydroxylase system is
required to introduce a hydroxyl group in
the fatty acid
NADPH is required as a source of
hydrogen atoms
The complete system is known as the
desaturase system

65. The desaturase system
can synthesize:
Oleic acid from stearic acid
Palmitoleic acid from palmitic acid

67. The desaturase system cannot introduce
a double bond beyond carbon 9
Hence, linoleic acid and a-linolenic acid
cannot be synthesized by this system

68. Arachidonic acid (20:4;5,8,11,14) is an
important PUFA
Several eicosanoids are synthesized from
arachidonic acid
Human beings can synthesize arachi-
donic acid from linoleic acid
Synthesis of arachidonic acid

69. Linoleic acid is activated to linoleyl CoA
D6-Desaturase introduces a double bond
between carbon atoms 6 and 7
Two carbon atoms are added at the
carboxyl end by microsomal elongation

70. The fatty acid formed is 20: 3; 8, 11, 14
D5-Desaturase introduces a double bond
between carbon atoms 5 and 6
The fatty acid formed is 20:4; 5, 8, 11, 14
(arachidonic acid)

72. g-Linolenic acid is an intermediate in the
synthesis of arachidonic acid
Thus, both of these fatty acids can be
synthesized from linoleic acid
Linoleic acid and a-linolenic acid cannot
be synthesized by human beings
These two have to be provided in the
diet

73. Arachidonic acid, g-linolenic acid and
linoleic acid are w-6 PUFA
a-Linolenic acid is an w-3 PUFA
The dietary requirements of w-6 and w-3
PUFA are roughly in the ratio of 10:1