De Novo Synthesis of fatty acids | Biosynthesis Of Fatty Acids |

Fatty acids
• Fatty acids are carboxylic acids with
hydrocarbon side chain.
• Simplest form of lipids.• Simplest form of lipids.
• Mainly occur in the esterified form.
• Some are present as free fatty acids (unesterified).

• Most fatty acids: Even carbons (usually 14C - 20C).
• Because the biosynthesis of fatty acids occurs with
the sequential addition of 2 carbon units.
Even Carbon fatty acids: Palmitic acid (16C) and
stearic acid (18C).
Odd chain fatty acids: Propionic acid (3C) and
Valeric acid (5C).

De novo synthesis of fatty acids
• Occurs in liver, kidney, adipose tissue and
lactating mammary glands.
• Enzyme for fatty acid production: Cytosomal
fraction of the cell.fraction of the cell.
Acetyl CoA: Source of carbon atoms
NADPH: provides the reducing equivalents
ATP: supplies energy.

3 stages of fatty acid synthesis
• Production of acetyl CoA and NADPH.
• Conversion of acetyl CoA to malonyl CoA.
• Reactions of fatty acid synthase complex.• Reactions of fatty acid synthase complex.

Production of acetyl CoA and NADPH
• Prerequisites: Acetyl CoA and NADPH.
• Acetyl CoA is produced in the mitochondria:
By the oxidation of pyruvate and fatty acidsBy the oxidation of pyruvate and fatty acids
Degradation of carbon skeleton of certain amino acids
From ketone bodies.

Production of acetyl CoA and NADPH
• Mitochondria are not permeable to acetyl CoA.
• That’s why acetyl CoA is converted to Citrate.
Acetyl CoA + Oxaloacetate Citrate.Acetyl CoA + Oxaloacetate Citrate.
• Citrate is freely transported to cytosol.
• In cytosol: Citrate  Acetyl CoA and Oxaloacetate
by “Citrate Lyase”
• And Oxaloacetate is converted to malate.

• Malate  Pyruvate by “Malic Enzyme”
• NADPH and CO2 generated in this reaction are
utilized for fatty acid synthesis.utilized for fatty acid synthesis.

Formation of malonyl CoA
• Acetyl CoA  Malonyl CoA by “Acetyl CoA
Carboxylase”
• Reaction requires ATP, CO2 and biotin.• Reaction requires ATP, CO2 and biotin.
• Acetyl CoA carboxylase: Regulatory enzyme in
fatty acid synthesis.

Reactions of fatty acid synthase
complex
• Remaining reactions: catalysed by a
multifunctional enzyme “fatty acid synthase
(FAS) complex”.
• It 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
catalysing all the seven reactions.catalysing all the seven reactions.
• Dissociation of the synthase complex results in
loss of the enzyme activities.

Reaction 1
• The two carbon fragment of acetyl CoA is
transferred to ACP of fatty acid synthase,
catalysed by the enzyme, acetyl CoA-ACP
transacylasetransacylase
• The acetyl unit is then transferred from ACP
to cysteine residue of the enzyme. Thus ACP
site falls vacant.

• The enzyme malonyl CoA-ACP transacylase
transfers malonate from malonyl CoA to bind
to ACP.
Reaction 2

• The acetyl unit attached to cysteine is transferred
to malonyl group (bound to ACP). The malonyl
moiety loses CO2 which was added by acetyl CoA
carboxylase. Thus, CO2 is never incorporated into
Reaction 3
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 β -ketoacyl ACP synthase.

• β-Ketoacyl ACP reductase reduces ketoacyl
group to hydroxyacyl group. The reducing
equivalents are supplied by NADPH.
Reaction 4

• β -Hydroxyacyl ACP undergoes dehydration. A
molecule of water is eliminated and a double
bond is introduced between α and β carbons.
Reaction 5

• A second NADPH-dependent reduction, catalysed 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
Reaction 6
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.

• The enzyme palmitoyl thioesterase separates
palmitate from fatty acid synthase. This
completes the synthesis of palmitate.
Reaction 7

Overall reactionOverall reaction

Summary of palmitate synthesis
• Of the 16 carbons present in palmitate, only
two come from acetyl CoA directly. The
remaining 14 are from malonyl CoA which, in
turn, is produced by acetyl CoA. The overallturn, is produced by acetyl CoA. The overall
reaction of palmitate synthesis is summarized
• 8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ 
Palmitate + 8 CoA + 7 ADP + 7 Pi + 6H2O

Regulation of fatty acid synthesis
Acetyl CoA carboxylase : Acetyl CoA carboxylase: protomer (monomer) or an
active polymer.
 Citrate promotes polymer formation, hence increases fatty acid synthesis.
 Palmitoyl CoA and Malonyl CoA cause depolymerization of the enzyme and
inhibit fatty acid synthesis.
Hormonal influence : Hormones regulate acetyl CoA carboxylase byHormonal influence : Hormones regulate acetyl CoA carboxylase by
phosphorylation (inactive form) and dephosphorylation (active form) of
the enzyme.
 Glucagon, epinephrine and norepinephrine inactivate the enzyme by
cAMPdependent phosphorylation.
 Insulin dephosphorylates and activates the enzyme.
 Thus, insulin promotes fatty acid synthesis while glucagon inhibits.
 Insulin stimulates tissue uptake of glucose, and conversion of pyruvate to
acetyl CoA. This also facilitates fatty acid formation.

Dietary regulation :
 Consumption of high carbohydrate or fat-free diet
increases the synthesis of acetyl CoA carboxylase and fatty
acid synthase, which promote fatty acid formation.
 Fasting or high fat diet decreases fatty acid production.
Availability of NADPH :
 The reducing equivalents for fatty acid synthesis are The reducing equivalents for fatty acid synthesis are
provided by NADPH which come either from citrate (acetyl
CoA) transport or hexose monophosphate shunt.
 About 50-60% of required NADPH is obtained from HMP
shunt, which significantly influences fatty acid synthesis.

De Novo Synthesis of fatty acids | Biosynthesis Of Fatty Acids |

De Novo Synthesis of fatty acids | Biosynthesis Of Fatty Acids |

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De Novo Synthesis of fatty acids | Biosynthesis Of Fatty Acids |