fatty acid biosynthesis

1. DR MUHAMMAD MUSTANSAR
Fatty Acid Synthesis

2. Fatty acids
 Fatty acids are a class of compounds containing a long
hydrophobic hydrocarbon chain and a terminal
carboxylate group
 They exist free in the body as well as fatty acyl esters in
more complex molecules such as triglycerides or
phospholipids.
 Fatty acids can be oxidized in all tissues, particularly
liver and muscle to provide energy
 They are also structural components of membrane
lipids such as phospholipids and glycolipids.
 Esterified fatty acids, in the form of triglycerides are
stored in adipose cells
 Fatty acids are also precursors of Eicosanoids

3. Sources of Fatty acids
 Diet
 Adipolysis
 De novo synthesis(from precursors)-
Carbohydrates, protein, and other
molecules obtained from diet in
excess of the body’s need can be
converted to fatty acids, which are
stored as triglycerides

4. Biosynthesis of Fatty acids
The excess dietary Carbohydrates & Proteins
can be converted to fatty acids and are stored as
Tri acyl Glycerol.
Denovo synthesis of Fatty acids takes place in
Liver, Kidney, adipose tissue and Lactating
Mammary glands.
Site: Cytoplasm of the cell
Requirements:
Acetyl CoA – source of Carbon atoms
NADPH – provides reducing equivalents
ATP – energy

5. ═ Fatty acid synthesis in 3 stages
(i) Production of Acetyl CoA & NADPH
(ii) Conversion of acetyl CoA to Malonyl CoA
(iii) Reactions of Fattyacid synthase complex.

6. De novo fatty Acid Synthesis-extra
Fatty acids are synthesized by an Introduction
mitochondrial system
This system is present in many tissues, including
liver, kidney, brain, lung, mammary gland, and
adipose tissue.
Acetyl-CoA is the immediate substrate, and free
palmitate is the end product.
Its cofactor requirements include NADPH, ATP,
Mn2+, biotin, and HCO3– (as a source of CO2).

7. Location of fatty acid synthesis
FA synthase
complex is found
exclusively in
the cytosol.
The location
segregates
synthetic
processes from
degradative
reactions.

8. Sources of NADPH
NADPH is involved as donor of reducing
equivalents
The oxidative reactions of the pentose phosphate
pathway are the chief source of the hydrogen
required for the reductive synthesis of fatty acids.
Tissues specializing in active lipogenesis—ie, liver,
adipose tissue, and the lactating mammary gland—
possess an active pentose phosphate pathway.
Other sources of NADPH include the reaction that
converts malate to pyruvate catalyzed by the "Malic
enzyme" (NADP malate dehydrogenase) and the extra
mitochondrial isocitrate dehydrogenase reaction
(probably not a substantial source, except in
ruminants).

9. Acetyl co A- Sources and Fate
Acetyl co A, the
precursor for fatty
acid synthesis is
produced from
pyruvate,
ketogenic amino
acids, fatty acid
oxidation and by
alcohol
metabolism
It is a substrate
for TCA cycle and a
precursor for fatty
acids, ketone
bodies and sterols.

10. Transportation of Acetyl co A
Fattyacid synthesis requires considerable
amounts of acetyl-CoA
Nearly all acetyl-CoA used in fatty acid
synthesis is formed in mitochondria
 Acetyl co A has to move out from the
mitochondria to the cytosol
Cytosol – site of acetate utilization
Mitochondria – site of acetate synthesis

11. Transportation of Acetyl co A
Acetate is shuttled out of mitochondria as citrate
The mitochondrial inner membrane is
impermeable to acetyl-CoA
Intra-mitochondrial acetyl-CoA first reacts with
oxaloacetate to form citrate, in the TCA cycle
catalyzed by citrate synthase
Citrate then passes into the cytosol through
the mitochondrial inner membrane on the
citrate transporter.
In the cytosol, citrate is cleaved by citrate
lyase regenerating acetyl-CoA.

12. Transportation of Acetyl co A

13. Enzymes and cofactors involved in the
process of Fatty acid synthesis
Two main enzymes-
Acetyl co A carboxylase
Fatty acid Synthase
Both the enzymes are multienzyme complexes
Coenzymes and cofactors are-
Biotin
NADPH
Mn++
Mg++

14. Steps in Fatty acid synthase complex
1) Acetyl CoA is transferred to ACP by
Acetyl CoA ACP transacylase (CoA is
removed). The two carbon unit acetate
which is attached to ACP is shifted to
cysteine residue of keto acyl synthase
enzyme.

15. 2) Now Malonyl CoA is transferred to ACP by
Malonyl CoA ACP transacylase where Co A
is removed

16. 3) The acetyl unit (2) which is attached to
cysteine combines with malonyl unit (3 ‘C’)
where Co2 is released to form keto acyl,
ACP, Enzyme is keto acyl synthase.

17. 4) Ketoacyl ACP undergoes reduction to
form β-hydroxy acyl ACP, enzyme is keto
Acyl reductase NADPH provides
Hydrogens.

18. 5) β-hydroxy acyl ACP undergoes
dehydration where one water molecule is
removed to form Enoyl ACP (double bond
between 2 & 3 Carbons) enzyme is
dehydratase.

19. 6) Enoyl ACP undergoes reduction to form
acyl ACP or butryl ACP, enzyme is enoyl
ACP reductase, NADPH provides
Hydrogens.

20. 7) The 4 carbon butryl acid attached to ACP is
shifted to cysteine residue and reactions 2 –
6 are repeated

22.  For 1 cycle carbon chain length increase by
2 carbons
(2) Acetyl acid
1 cycle
(4) Butyric acid
2 cycle
(6) Caproic acid
3 cycle
(8) Caprylic acid

23. Series of Reactions
After activation, the processes involved are-
1. Condensation
2. Reduction
3. Dehydration
4. Reduction
These steps are repeated till a fatty acid with 16 carbon
atoms is synthesized

24. Repetition of these four steps leads
to fatty acid synthesis

25. The overall reaction for the
synthesis of palmitate from
acetyl-CoA can be considered
in two parts.

26. Part 1
First, the formation of seven malonyl-CoA molecules:
7Acetyl-CoA + 7CO2 + 7ATP
7malonyl CoA + 7ADP + 7Pi

27. Part 2
Then the seven cycles of condensation and
reduction
Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+
palmitate + 7CO2 + 8CoA +
14NADP+ + 6H2O
The biosynthesis of FAs requires acetyl-CoA and
the input of energy in the form of ATP and reducing
power of NADPH.

28. Rxn for palmitate synthesis is:
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 7 H+
palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6H2O
But malonate is made from acetyl CoA
7 acetyl-CoA + 7 CO2 + 7 ATP 7 malonyl-CoA
+ 7 ADP + 7 Pi + 7 H+
So overall:
8 acetyl-CoA + 7 ATP + 14 NADPH palmitate
+14 NADP+ + 8 CoASH + 6 H2O + 7 ADP + 7 Pi
The NADPH comes from the pentose phosphate
shunt. The source of acetyl-CoA is more complex.

30. Comparison of β-Oxidation & Fatty Acid
Synthesis
Βeta Oxidation Fatty acid Synthesis
pathway
Location Mitochondrial Cytoplasmic
Acyl Carriers(Thiols) Coenzyme A 4’ Phosphopantetheine
and Cysteine
Electron acceptors and FAD/NAD NADPH
donors
OH Intermediates L D
2 Carbon Acetyl co A Acetyl co A/ Malonyl co
product/donor A