Fatty acid synthesis

Reactions 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++
 Steps of fatty acid synthesis
Step-1
The input to fatty acid synthesis is acetyl-CoA, which is carboxylated to malonyl-
CoA. The reaction is catalyzed by Acetyl co A carboxylase
 Enzyme-biotin
-
HCO3 + ATP
1
ADP + Pi
-
Enzyme-biotin-CO 2
O
ll 2
CH3-C-SCoA
Enzyme-biotin
acetyl-CoA
O
-
ll
O2C-CH2-C-SCoA
malonyl-CoA

The overall reaction, which is spontaneous, may be summarized as:

HCO3- + ATP + acetyl-CoA → ADP + Pi + malonyl-CoA

This is the rate limiting step of fatty acid synthesis and acetyl CoA carboxylase is considered
the regulatory enzyme of the pathway
 Fatty acid synthase complex
• After conversion of acetyl CoA to malonyl CoA, all other
reactions of fatty acid synthesis are catalysed by FAS complex
• FAS complex exists as dimer with two identical polypeptide
chains which run antiparallel to each other
• Each polypeptide monomer contains seven different enzyme
activities and an acyl carrier protein (ACP) bound to
phosphopantetheine
• Both subunits are organised in ‘head to tail’ orientation in
such a fashion that the –SH group of phosphopantetheine of
one sununit lies in close proximity to the –SH group of
cysteine residue of the other subunit
• Though each subunit contains all the enzyme activities
required for fatty acid synthesis, only the dimer is
functionally active
• Two functional subunits of FAS operate simultaneously and
can synthesise two fatty acids at once
Reactions of FAS complex
• First, the acetyl group of acetyl
CoA is transferred to the cys-SH
group of the ketoacyl synthase
• This reaction is catalysed by
acetyl transacylase
• Second reaction involves the
transfer of malonyl group from
malonyl CoA to the –SH group of
ACP
• This reaction is catalysed by
malonyl transacylase
• In next reaction, acetyl group
binding to cys-SH group on
Ketoacyl synthase is transferred to
malonyl group on the -SH of ACP,
where both condense to form β-
ketoacyl ACP. Reaction catalysed by
ketoacyl synthase

• During this reaction, a molecule of

carbondioxide is released. The
carbon atom in carbondioxide is
the same carbon atom that was
inserted into malonyl CoA from
bicarbonate by acetyl CoA
carboxylase
• Now ketoacyl reductase reduces
the carbonyl group at C-3 of β-
ketoacyl ACP and convert it to β-
hydroxyacyl ACP.
• Reducing equivalents are
supplied by NADPH

• In next step, dehydratase

removes a water molecule from
C-2 and C-3 of β- hydroxyacyl
ACP and introduces a double
bond in the molecule to form
unsaturated acyl ACP ( trans-Δ2
enoyl ACP)
• The double bond is reduced by enoyl
reductase to form acyl ACP.
• This is the second reaction of the
pathway utilising NADPH
• By this time, the acyl radical attached
to ACP is a 4- carbon, saturated fatty
acyl group (Butyryl ACP)

• The butyryl chain attached to ACP is

now transferred to the cys- SH group
of ketoacyl synthase leaving
unattached the phosphopantetheine
–SH group of ACP

• With this, one cycle of the pathway is

completed
• In the next cycle, another malonyl
group is attached to now
unattached phosphopantetheine –
SH group of ACP and reaction 2-7
are repeated, lengthening the fatty
acid chain by two more carbons.

• Reactions of the pathway are

repeated seven times (including
first cycle) adding a two- carbon
moiety each time, which finally
yields a 16-carbon saturated acyl
group (Palmitic acid)

• The newly synthesised palmitate,

still bound to ACP is freed and
released into the cytosol by the
enzyme, thioesterase
Comparison of β-Oxidation & Fatty Acid
Synthesis
Βeta Oxidation pathway Fatty acid Synthesis

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 product/donor Acetyl co A Acetyl co A/ Malonyl co A

Regulation of fatty acid synthesis
• Acetyl CoA carboxylase converting acetyl CoA to malonyl CoA : chief
regulatory enzyme of the pathway
• Nutritional state of the individual regulates fatty acid synthesis
• When Carbohydrate rich diet is consumed, the surplus glucose is
converted to fat via acetyl CoA
• Fat rich diet and starvation depresses fatty acid synthesis
• Insulin promotes fatty acid synthesis, while glucagon and epinephrine
switch it off
Fatty acid elongation
❑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.
Fatty acid elongation
The desaturation of Fatty Acids
Palmitate and stearate serve as precursors of the
two most common monounsaturated fatty acids of
animal cells: palmitoleate (16:1D9), and Oleate
(18:1D9).

The double bond is introduced by fatty acyl-CoA

desaturase in the smooth endoplasmic reticulum.
The desaturation of Fatty Acids
Essential fatty acids
❑Mammalian hepatocytes readily introduce double
bonds at the D9 position of FAs but cannot between
C-10 and the methyl-terminal end.
❑Linoleate, 18:2D9,12 and linolenate 18:3D9,12,15
cannot be synthesized by mammals, but plants can
synthesize both.
❑Arachidonic acid is semi essential, since it can be
synthesized from Linoleic acid
Essential fatty acids