Synthesis of fatty acids in the body. Detailed pathway for de novo synthesis of fatty acids in the body including its energetic and regulation. also cover Multienzyme complex

2. Differenceinthetwopathways
Site Mitochondria Cytoplasm
Intermediates
Present as CoA
derivatives
Covalently linked to
SH group of ACP
Enzymes
Present as
independent
proteins
Multienzyme
complex
Sequential
units
2 carbon units split
off as acetyl CoA
2 carbon units
added, as 3 carbon
malonyl CoA
Co-enzymes
NAD+ & FAD are
reduced
NADPH used as
reducing power
Beta-oxidation Fatty acid synthesis

3. The majority of fatty acids required for the body is supplied
by the diet.
Fatty acids are synthesized whenever there is caloric excess
in the diet.
Excess amount of carbohydrate & protein from the diet can
be converted to fatty acids & stored as triacylglycerols.

4. 4
The sites of Fatty acid synthesis are…

5. It takes place in cytoplasm of the cell.
It is referred to as extramitochondrial or
cytoplasmic fatty acid synthase system.
The major fatty acid synthesized de novo is
palmitic acid, the 16C saturated fatty acid.
Source of carbon atoms-Acetyl CoA
Source of reducing equivalents-NADPH
Source of energy-ATP.

6. Steps in fatty acids synthesis
The fatty acids synthesis occurs in following stages....

7. Production (transport) of Acetyl CoA & NADPH.
Acetyl CoA is produced in the mitochondria by…
However, mitochondria is not permeable for acetyl CoA.
So, an alternate arrangement is made for the transfer of
acetyl CoA to cytosol in the form of citrate.

8. Acetyl CoA condenses with oxaloacetate in mitochodria to
form citrate.
Citrate is free transpoted to cytosol.
Here it is cleaved by citrate lyase to acetyl CoA and
oxaloacetate.
Oxaloacetate in the cytosol is converted to malate.
Malate dehydrogenase convert malate to pyruvate with
production of NADPH and CO2.
Transport of acetyl CoA from mitochondria to cytosol is
coupled with production of NADPH and CO2. both of them
are utilized for FA synthesis.

9. Acetyl-CoA
Acetyl-CoA
HMP shunt
pyruvate
pyruvate
oxaloacetate
CitrateCitrate
Oxaloacetate
Malate
Glucose
AAs Fatty
acids
Fatty acid
CoASH
NAD+
NADH+H
NADP+
NADPH+H
Citrate lyase
Citrate
synthase
Malate DH
Malic enzyme P.
carboxylasePDH
Transport of Acetyl CoA & NADPH.
Mitochondrial matrix

10. Formation of Malonyl CoA
Acetyl CoA is carboxylated to malonyl CoA by acetyl CoA
carboxylase.
ATP dependent and Biotin is required for CO2 fixation.
Acetyl CoA carboxylase is the regulatory enzyme in this
pathway.
Malonyl-CoA
CO2
ADP+Pi
CH3-C-SCoA
O
=
Acetyl-CoA
-OOC-CH2-C-SCoA
O
=
ATP,
BiotinAcetyl CoA
carboxylase

11. • It is a polypeptide containing seven enzyme activities & acyl carrier protein (ACP)
unit.
• it is dimer composed of 2 identical monomer units.
• Each monomer is identical having all 7 enzyme activity of fatty acid synthase.
• ACP-segment contain a 4-phosphopantetheine gr. This provide sulfhydryl (-SH)
group to which the growing fatty acid chain is attached.
• Thus, the function of ACP in FA synthesis is analogous to coenzyme A in fatty acid
oxidation.
• One more –SH group is contributed by a specific cysteine recidue of 3-ketoacyl
synthase.
• Both –SH groups participate in fatty acid synthesis.
• 2 functional subunit of FAS independently operate & two synthesize fatty acids
simultaneously.
Fatty acid synthase
multienzyme complex

12. Fatty acid synthase
multienzyme complex
Ketoacyl
synthase
Acetyl
transacylase
Malonyl
transacylase
Dehydratase
Enoyl
reductase Ketoacyl
reductase
ACP Thioesterase
Dehydratase
Enoyl
reductase
Ketoacyl
reductase
ACPThioesterase
Ketoacyl
synthase
Acetyl
transacylaseMalonyl
transacylase
Cys
Cys
4’-phospho-
pantetheine
4’-phospho-
pantetheine
SH
SH
SH
SH Subunit
division
Releasing
enzyme

13. Reactions of fatty acid synthase complex
 The 2 “C” fragment of acetyl CoA is transferred to ACP of FAS, by the enzyme
acetyl tranacylase.
 Acetyl unit is then transferred to cysteine –SH of the enzyme.
 Thus ACP site falls vacant.
 The enzyme malonyl transacylase transfer malonate from malonyl CoA to ACP
to form acetyl-malonyl enzyme.
 Now fatty acid synthase has two group attached to it.
 An acetyl group to cysteine –SH and malonyl group at ACP-SH.
 Enzyme complex is now ready for chain elongation process
 It done by following four steps……





14. Condensation
acetyl gr. which is
attached to cys-SH is
condenses with malonyl
gr Attached to ACP to
form β-Ketoacyl-ACP by
losing CO2 which was
added by carboxylase.
This reaction is catalysed
by ketoacyl synthase.
Reduction
Ketoacyl reductase
reduces ketoacyl
group to hydroxyacyl
group.
The reducing
equivalents are
supplied by NADPH.
Dehydration
β-hydroxyacyl-ACP
undergoes
dehydration by the
enzyme
dehydratase to
form enoyl-ACP.
Reduction
enoyl-ACP reduced by
the enzyme enoyl
reductase to acyl-ACP.
Here second molecule
of NADPH is used.
At the end of this
reaction 4 ”C” atom
butyryl group is
formed.

15. • The carbon chain attached to ACP is transferred to cys-SH
• the reaction of 2-6 are repeated 6 times.
• Each time, the fatty acid is elongated by 2 “C” unit.
• At the end of 7 cycles, a 16 carbon fatty acid (saturated) is
formed at ACP.
• The enzyme thioesterase separates palmitate from fatty
acid synthase.
• This complete fatty acid synthesis.

16. Malonyl-CoA
CH3-C-SCoA
O
=
Acetyl-CoA
-OOC-CH2-C-SCoA
O
=
CoA-SH
ACP SH
Cys SH
ACP S
Cys SH
-C-CH3
O
=
ACP SH
Cys S -C-CH3
O
=ACP S
Cys S-C-CH3
O
=
-C-CH2-COO-
O
=
Acylmalonyl-
enzyme
Acetyl S-enzyme
Acetyl S-ACP
Fatty acid
synthase
CoA-SH
1
2
Malonyl
trasacylase
Acetyl CoA
trasacylase
Transfer of
acetyl to cys

17. Acylmalonyl-enzyme
CO2
ACP S
Cys SH-C-CH3
O
=
-C-CH2
O
=
β-Ketoacyl-ACP
NADP+
NADPH+H+
ACP S
Cys SH
-CH-CH3
OH
-
-C-CH2
O
=
β-Hydroxyacyl-ACP
β-Ketoacyl
reductase
H2O
ACP S
Cys SH
=CH-CH3
OH
--C-CH
O
=
Trans-enoyl-ACP
β-hydroxyacyl
dehydratase
3
4
5
β-Ketoacyl
synthatase

18. ACP S
Cys SH
=CH-CH3
OH
-
-C-CH
O
=
NADP+
NADPH+H+
Enoyl reductase
ACP S
Cys SH
-CH2-CH3-C-CH2
O
=Acyl-ACP
Trans-enoyl-ACP
ACP SH
Cys S -CH2-CH3-C-CH2
O
=
Acyl-S-enzyme
Transfer of C
chain to cys-SH
ACP S
Cys SH
-CH2-CH3-C-(CH2)13
O
=
Acyl-ACP
ACP SH
Cys SH
CH3-CH2 -(CH2)13-COO-
palmitateThioesterase
6 more Cycles
Of reac. 2-6
6

19. Summary of β-oxidation of palmitoyl CoA
Palmitoyl-coA
CO-S-coA
CH3
1
2
3
4
5
6
7
8
9
10121416
15 13 11
1 acetyl coA + 7 Malonyl coA = 8 Acetyl-coA
CH3-CO-SCoA
14 NADPH+H+
7 Cycles of
Fatty acid synthesis
7 ATP
7 ADP+Pi
14 NADP+ 6 H2O

20. •Two type of control mechanism regulate the fatty
acid synthesis……
Regulation of fatty acid synthesis

21. Short-term Control Mechanism
•Short-term control mechanism by…

22. Allosteric regulation
 The conc. of citrate in the cytosol is most imp. short term regulator.
 Citrate stimulates acetyl CoA carboxylase, which catalyzes
formation of malonyl CoA(rate limiting step).
 The level of citrate is high when both acetyl CoA & ATP are
abundant.
 The effect of citrate on carboxylase is opposes by palmitoyl CoA
 palmitoyl CoA also inhibits the transfer of citrate from
mitochondria to cytosol and G6PD which generate NADPH

23. •Allosteric regulation
• The activity of acetyl CoA carboxylase is also controlled by
phosphorylation.
• Phosphorylated enzyme is inactive.
• Dephosphorylated enzyme is active.
• Glucagon & epinephrine stimulate phosphorylation.
• Insulin stimulate dephosphorylation.

24. Insulin
phosphatase
Acetyl CoA
carboxylase
(inactive)
Acetyl CoA
carboxylase
(active)
Protein
kinase
Glucagon, Epinephrine
ATPADP
P
-
+
Malonyl-CoA
Acetyl-CoA
Glucose
Citrate
palmitate
Palmitoyl CoA
NADPH
-
-
+
G6PD
Covalent modification
Allosteric regulation
Pentose phosphate
pathway

25. • It exerts its effect slowly.
• It is by induction and repression of the enzyme synthesis.
• This involves change in the gene expression which controls
the rate of synthesis of these enzymes.
• The production of enzyme of FAS is stimulated in liver when
carbohydrate and ATP are available.
• And it is decreased during starvation, diabetes.
LONG TERM CONTROL MECHANISM
+
High fat diet
Starvation
DM
-
All the enzymes of
fatty acid synthesis
High
carbohydrate
diet

26. 27 of 75
Contact no. – 07418831766
E mail – ashokkt@gmail.com
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Asst. Professor
Dept. of Biochemistry,
Dhanalakshmi Srinivasan Medical College,
Perambalur