Biosynthesis of Fatty Acids
Biosynthesis of Fatty Acids
The dietary carbohydrates and amino acids, when consumed in excess, can be converted to fatty acids
and stored as triacylglycerols. De novo (new) synthesis of fatty acids occurs predominantly in liver,
kidney, adipose tissue and lactating mammary glands. The enzyme machinery for fatty acid production is
located in the cytosomal fraction of the cell. Acetyl CoA is the source of carbon atoms while NADPH
provides the reducing equivalents and ATP supplies energy for fatty acid formation. The fatty acid
synthesis may be learnt in 3 stages
i. Production of acetyl CoA and NADPH
ii. Conversion of acetyl CoA to malonyl CoA
iii. Reactions of fatty acid synthase complex.
Malic enzyme converts malate to pyruvate. NADPH and CO2 are generated in this reaction.
Both of them are utilized for fatty acid synthesis.
Advantages of coupled transport of acetyl CoA and NADPH:
The transport of acetyl CoA from mitochondria to cytosol is coupled with
the cytosomal production of NADPH and CO2 which is highly advantageous
to the cell for optimum synthesis of fatty acids.
2. Formation of malonyl CoA:
Acetyl CoA is carboxylated to malonyl CoA by the enzyrne acetyl CoA
carboxylase. This is an ATP-dependent reaction and requires biotin for CO2
fixation. The mechanism of action of acetyl CoA carboxylase is similar to
that of pyruvate carboxylase Acetyl CoA carboxylase is a regulatory enzyme
in fatty acid synthesis.
3. Reaction of Fatty acid synthase comples:
The remaining reactions of fatty acid synthesis are catalysed by a
multifunctional enzyme known as fatty acid synthase (FAS) complex. ln
eukaryotic cells, including man, the fatty acid synthase exists as a dimer
with two identical units. Each monomer possesses the activities of seven
different enzymes and an acyl carrier protein (ACP) bound to 4'-phosphopantetheine. Fatty acid
synthase functions as a single unit catalyzing all the seven reactions. Dissociation of the synthase
complex results in loss of the enzyme activities. In the lower organisms (prokaryotes), the fatty acid
synthesis is carried out by a multienzyme complex in association with a separate acyl carrier protein.
This is in contrast to eukaryotes where ACP is a part of fatty acid synthase. The sequence of reactions of
the extramitochondrial synthesis of fatty acids (palmitate).
1. The two carbon fragment of acetyl CoA is transferred to ACP of fatty acid synthase, catalysed by the
enzyme, acetyl CoA-ACP transacylase. The acetyl unit is then transferred from ACP to cysteine residue of
the enzyme. Thus, ACP site falls vacant.
2. The enzyme malonyl CoA-ACP transacylase transfers malonate from malonyl CoA to bind to ACP.
3. The acetyl unit attached to cysteine is transferred to malonyl group (bound to ACP). The malonyl
moiety loses CO2which was added by acetyl CoA carboxylase. Thus, CO2 is never incorporated into fatty
acid carbon chain. The decarboxylation is accompanied by loss of free energy which allows the reaction
to proceed forward. This reaction is catalyzed by p-ketoacyl ACP synthase.
4. p-Ketoacyl ACP reductase reduces ketoacyl group to hydroxyacyl group. The reducing equivalents are
supplied by NADPH.
5. B-Hydroxyacyl ACP undergoes dehydration. A molecule of water is eliminated and a double bond is
introduced between a and p carbons.
6. A second NADPH-dependent reduction, catalyzed by enoyl-ACP reductase occurs to produce acyl-ACP.
The four-carbon unit attached to ACP is butyryl group. The carbon chain attached to ACP is transferred
to cysteine residue and the reactions 2-6 are repeated 6 more times. Each time, the fatty acid chain is
lengthened by a two-carbon unit (obtained from malonyl CoA). At the end of 7 cycles, the fatty acid
synthesis is complete and a 16-carbon fully saturated fatty acid-namely palmitate-bound to ACP is
produced.
7. The enzyme palmitoyl thioesterase separates palmitate from fatty acid synthase. This completes the
synthesis of palmitat.