fatty acid synthesis

1. By
DR KHALED SALEH ALGARIRI
JANUARY 2018

2. INTRODUCTION
 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. There are three systems for the synthesis
of fatty acids
1. De novo synthesis of FAs in cytoplasm
2. Chain elongation in mitochondria
3. Chain elongation in microsomes

4. SYNTHESIS OF FATTY
ACIDS
De Novo synthesis of
fatty acids
Elongation of fatty acids Desaturation of
fatty acids
• Saturated fatty acids
are synthesized from
acetyl CoA derived
from glucose
• Occur in cytoplasm
• Acetyl fragments are
added to the existing
fatty acids
• Occur in both
cytoplasm and
mitochondria
• Double bonds are
introduced into the
fatty acids
•Occur in
microsomes

5.  In mammals fatty acid synthesis occurs primarily in the cytosol of
the liver and adipose tissues .It also occurs in mammary glands
during lactation.
 Acetyl-CoA is the starting material for FA synthesis. However, most
acetyl-CoA in mitochondria(from the breakdown of sugars, some
amino acids and other fatty acids).
So, acetyl-CoA must be transferred from the mitochondria to the
cytosol
BUT Mitochondria not permeable to acetyl CoA
De novo synthesis of FA

6. TRANSPORTATION OF ACETYL CoA
Acetate is shuttled out of mitochondria as citrate
The mitochondrial inner membrane isimpermeable
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.

7. TRANSPORTATION OF ACETYL CoA

8. De novo synthesis of fatty acid is the
synthesis of saturated fatty acids
from acetyl CoA that is primarily
derived from glucose
Definition
DE NOVO SYNTHESIS OF FATTY ACIDS

9. carbohydrate intake -
acetyl CoA -
fatty acids synthesis
» Occurred in cytosol
» Need - acetyl CoA
- NADPH ( from HMP
shunt )

10. Enzymes and Cofactors involved in
fatty acids synthesis
Two main enzymes-
Acetyl co A carboxylase
Fatty acid Synthase
Both the enzymes are multi enzyme complexes
Coenzymes and cofactors are-
Biotin
NADPH
Mn++
Mg++

11. Fatty acid synthase complex
 Is a polypeptide
containing
seven enzyme
activities and
acyl carrier
protein (ACP)
segment
Acetyl transacylase AT
Malonyl transacylase MT
3-ketoacyl synthase KS
3-ketoacyl reductase KR
Enoyl reductase ER
Thioesterase
ACP contains the vitamin pantothenic acid in the form of 4'-
phosphopantetheine (Pant). ACP is the part that carry the acyl groups
during fatty acid synthesis

12. Fatty acid synthase complex
 Synthesis of all enzymes in
the complex is coordinated
since it is encoded by a
single gene.
The use of one multienzyme functional unit has
the advantages of achieving the effect of
compartmentalization of the process within the
cell without the erection of permeability barriers

13. The first a round in fatty acids synthesis
 To initiate FA biosynthesis, malonyl and acetyl groups are
activated on to the enzyme fatty acid synthase.
 Initially, a priming molecule of acetyl-CoA combines with
a cysteine —SH group catalysed by acetyl transacylase.
 Malonyl-CoA combines with the adjacent —SH on the 4'-
phosphopantetheine of ACP of the other monomer,
catalyzed by malonyl transacylase (to form acetyl
(acyl)-malonylenzyme.

14. The activation of molnyl group
 The acetyl group from
acetyl-CoA is transferred to
the Cys-SH group of the-
ketoacyl ACP synthase
 This reaction is catalyzed by
acetyl- CoA transacetylase.

15. 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

16. Step 1- Condensation
Condensation of the
activated acetyl and
malonyl groups takes place
to form Acetoacetyl-ACP.
The reaction is catalyzed
by β- ketoacyl-ACP
synthase.

17. Step 2 - Reduction
 The Acetoacetyl- ACP is
reduced to β-hydroxybutyryl-
ACP, catalyzed by β-ketoacyl-
ACP reductase.
 NADPH + H+ are required

18. Step 3- Dehydration
Dehydration yields a double bond in the product,
trans-Δ2-butenoyl-ACP,
Reaction is catalyzed by β-hydroxybutyryl-ACP
dehydratase.

19. Step 4- Reduction
 Reduction of the double
bond takesplace to form
butyryl-ACP,
 Reaction is catalysed by
enoyl-reductase.
 Another NADPH
dependent reaction.

20. The growing chain is transferred from
the acyl carrier protein
• This reaction makes way for the next incoming
malonyl group.
• The enzyme involved is acetyl-CoAtransacetylase

21. Beginning of the second round of the fatty
acids synthesis
• The butyryl group is on the Cys-
SH group.
• The incoming malonyl group is
first attached to ACP.
• In the condensation step, the
entire butyryl group is exchanged
for the carboxyl group on the
malonyl residue

22. Repetition of these four steps leads to fatty
acids synthesis

23. The result of fatty acyl synthase
activity
 Seven cycles of condensation and reduction produce the
16-carbon saturated palmitoyl group, still bound toACP.
 Chain elongation usually stops at this point, and free
palmitate is released from the ACP molecule by hydrolytic
activity in the synthase complex.
 Smaller amounts of longer fatty acids such as stearate
(18:0) are also formed
In mammary gland, there is a separate Thioesterase specific
for acyl residues of C8, C10 or C12, which are subsequently found
in milk lipids.

24. The overall reactions for the synthesis of palmitate
from acety-CoA can divided in two parts
First, the formation of seven malonyl-CoA molecules:
7Acetyl-CoA + 7CO2 + 7ATP 7malonyl CoA + 7ADP + 7Pi
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.
8Acetyl-CoA + 7ATP + 14NADPH + 14H+
palmitate + 7CO2 + 8CoA + 14NADP+ + 7ADP + 7Pi + 6H2O
The overall reactions

25. RGULATION OF FATTY ACIDS SYNTHESIS
Enzymes Metabolites End products Hormones Diet
Enzymes • Acetyl CoA carboxylase
Metabolites • Citrate
End
products
• Palmitoyl CoA
Hormones
• Insulin
• Glucagon
Diet • High carbohydrate diet

26. RGULATION OF FATTY ACIDS SYNTHESIS
Allosteric control
Palmitoyl-CoA acts as a feedback
inhibitor of the enzyme, and citrate is
an activator.
When there is an increase in
mitochondrial acetyl-CoA and ATP,
citrate is transported out of
mitochondria,
Citrate becomes both the precursor
of cytosolic acetyl-CoA and a signal
for the activation of acetyl-CoA
carboxylase

27. RGULATION OF FATTY ACIDS SYNTHESIS
Phosphorylation
Acetyl-CoA carboxylase is also
regulated by hormones such as
glucagon,
epinephrine, and
insulin via changes in its
phosphorylation
state

28. RGULATION OF FATTY ACIDS SYNTHESIS

29. FATTY ACID ELANGATION
Palmitate in animal cells is the
precursor of other long-chained
FAs.
By further additions of acetyl
groups, fatty acid chain length
is elongated through the action
of FA elongation systems
present in the smooth
endoplasmic reticulum and the
mitochondria.

30. THE DESATURATION OF FATTY ACIDS
 Palmitate and stearate serve
as precursors of the two most
common monounsaturated
fatty acids of animal cells:
palmitoleate (16:1 9), and
Oleate (18:1 9).
 The double bond is
introduced by fatty
 acyl-CoA desaturase in the
smooth endoplasmic
reticulum

31. THE FATE OF FATTY ACIDS
Most of the FAs synthesized or ingested by an
organism have one of two fates:
Incorporated into triacylglycerols for the storage
of metabolic energy
Incorporated into the phospholipid components
of membranes

32. THANK YOU