The process of lipid synthesis is described in the slides

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Celullar Biochemistry and
Metabolism
Metabolic Pathways for Lipids:
Fatty Acid Synthesis
Dr. Syazwani Itri Amran
FBME

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FA
metabolism
Breakdown
Synthesis

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Revisit fatty acids degradation
Category of biochemical
reaction
Catabolism Anabolism
Pathway location Cytosol Mitochondria
Type of redox reaction Oxidation Reduction
Shuttle mechanism Carnitine shuttle Citrate shuttle
Electron carriers NADPH NAD+ / FAD

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Excess
Prots
Excess
Carbs
Diet
LIVER
Mammary gland
Adipose cells

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Fatty acids synthesis
● Reduction process that builds up the
hydrocarbon chain of fatty acids utilizing
activated acyl unit and malonyl unit
● Occurs in the cytoplasm
● Catalyzed by fatty acid synthase containing
7 catalytic sites
● Incorporates carbon atoms from acetyl CoA
into the growing fatty acid chain
●

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Fatty acids synthesis
● Reverse process of FA degradation
● Driven by the release of CO2 in a decarboxylation
step
● Energetically unfavourable process
● Reduction process involves NADPH
● Extension of fatty acid chain stops at 16C (saturated
palmitate)
Condensation Reduction Dehydration Reduction

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Structure of Fatty acid synthase
Acetyl
CoA
Acetyl
CoA
Acetyl
CoA
Acetyl
CoA
Elongation process occurs
by attaching acetyl Co-A
on the sulfhydryl group
Fatty acid
synthase
Acyl carrier
protein (ACP)
-S-H
phosphopentethiene
-S-HCys

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Localization of acetyl CoA into cytosol
Activation of acetyl CoA to malonyl CoA
Synthesis of fatty acid chain via addition of activated acetyl
CoA

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Fatty acid
synthase
Acyl carrier
protein
(ACP) -S-H
phosphopentethiene
Acetyl
CoA
Acetyl
CoA
Acetyl
CoA
Acetyl
CoA
Elongation process occurs
by attaching acetyl Co-A
on the sulfhydryl group
Acetyl
CoA
Acetyl
CoA
Mitochondria
Cytoplasm
Acetyl CoA is synthesized in the matrix of the
mitochondria but fatty acids are synthesized
in the cytosol. How acetyl CoA is made
available in the cytoplasm?
-S-HCys
Localization of acetyl CoA into cytosol
β-oxidation
Pyruvate
Decarboxylation
Ketogenesis
Amino acids
catabolism

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Citrate shuttle : acetyl CoA transporter
● Acetyl CoA (water soluble)  citrate (1st reaction of the TCA
cycle)
● In the cytosol, citrate undergo the reverse reaction producing
oxaloacetate and acetyl CoA
● If the conditions favor, FA synthesis begins
● [ATP] allosterically inhibits
isocitrate dehydrogenase
(isocitrate is not converted
to α-ketoglutarate &
TCA stops)
Builds up isocitrate, convert to
citrate in the matrix

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● FAs are synthesised in the cytoplasm from acetyl-CoA.
● Acetyl-CoA generated from pyruvate by the action
of PDH and β-oxidation of FAs, is in the mitochondria.
● So, acetyl-CoA has to be transported from the
mitochondria to the cytoplasm. This is done via a
shuttle system called the Citrate shuttle.
● Acetyl-CoA reacts with oxaloacetate to give citrate. A
tricarboxylate translocase transports citrate from
mitochondria to cytosol.
● In the cytosol, citrate is cleaved back to
oxaloacetate and acetyl-CoA. This reaction is
catalysed by ATP-citrate lyase and requires the hydrolysis
of one molecule of ATP.
FA Synthesis
Regenerate acetyl CoA in the cytoplasm

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For every 1 Acetyl-CoA transported into the cytosol, 1 NADPH results
Q: Is that enough NADPH?
We’re going to be making Palmitate (16C). So, we need ______ Acetyl-CoA (2C each)
8 Transported Acetyl-CoA ____ NADPH Q: Will that be enough?
2C + 2C + 2C + 2C + 2C + 2C + 2C + 2C
A: Yes? No?
8
8
1 2 83 764 5
2 22 2222 = 14 NADPH
Covered NOT covered
A: The Pentose Phosphate Pathway
Q. Where do the other 6 required NADPH molecules comes from?

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Pentose Phosphate Pathway
● Another metabolic fate for glucose (other
than glycolysis)
● Function of this alternative pathway
1. Synthesis of the coenzyme NADPH needed in
lipid biosynthesis
2. Production of ribose 5-phosphate, a pentose
derivative needed for the synthesis of nucleic
acids and many coenzymes
Pentose Phosphate Pathway is the metabolic pathway by
which glucose is used to produce NADPH, ribose 5-phosphate
(a pentose phosphate), and numerous other sugar phosphates.
NADPH  used in anabolic reactions requiring electrons

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● FAs are synthesised in the cytoplasm from acetyl-CoA.
● Acetyl-CoA generated from pyruvate by the action
of PDH and β-oxidation of FAs, is in the mitochondria.
● So, acetyl-CoA has to be transported from the
mitochondria to the cytoplasm. This is done via a
shuttle system called the Citrate shuttle.
● Acetyl-CoA reacts with oxaloacetate to give citrate. A
tricarboxylate translocase transports citrate from
mitochondria to cytosol.
● In the cytosol, citrate is cleaved back to
oxaloacetate and acetyl-CoA. This reaction is
catalysed by ATP-citrate lyase and requires the hydrolysis
of one molecule of ATP.
FA Synthesis
Glu
NADP+ NADPH
Ri-5-P(Pentose Phosphate Pathway)

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Localization of acetyl CoA into cytosol
Activation of acetyl CoA
Synthesis of fatty acid chain via addition of acetyl CoA

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Activation of acetyl CoA
● Initiation of fatty acid synthesis
● Formation of malonyl CoA through irreversible carboxylation of
acetyl CoA
● A CO2 is attached to acetyl CoA producing a 3C molecule
● Hydrolysis of ATP supply the energy needed to attach the CO2
Mn2+, Biotin

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The intermediate: Malonyl-CoA
● Malonyl-CoA is an “activated” form of acetyl-CoA
used for fatty acid biosynthesis.

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● Malonyl CoA
inhibits CAT1 to
prevent the
entry of fatty
acid into
mitochondria
carnitine
acyltransferase I

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Localization of acetyl CoA into cytosol
Activation of acetyl CoA
Synthesis of fatty acid chain via addition of acetyl CoA

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* also bind to
propionyl
CoA in odd
chain FA

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Initiation of fatty acid synthesis
• Attachment of acetyl group of acetyl CoA onto the sulfhydryl
group on phosphopentediene (ACP domain)
• Catalyzed by Acetyl transacylase
•Release CoA
Acetyl
Acetyl
CoA
Acetyl
CoA
Elongation process occurs
by attaching acetyl Co-A
on the sulfhydryl group
Fatty acid
synthase
Acyl carrier
protein (ACP)
-S-H
phosphopentethiene
-S-HCys
CoA-SH
Acetyl
CoA

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Acetyl
Initiation of fatty acid synthesis
Acetyl
CoA
Malonyl
Acetyl
CoA
Fatty acid
synthase
Acyl carrier
protein (ACP)
-S-H
phosphopentethiene
-S-HCys
CoA-SH
•Transfering the acetyl group from phosphopentetiene to Cysteine residue (temporary)
•Formation of linkage between malonate group of malonyl CoA and
phosphopentediene sulfhydryl group (ACP domain)
• Catalyzed by Malonyl transacylase (substrate specific)
• Prepares for the elongation of fatty acid chain

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Fatty acid synthesis
Condensation Reduction Dehydration Reduction

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Condensation
• Decarboxylation reaction
involves cleavage of high
energy thioester bond *
which supply enough energy
to drives the whole reaction
forward
• The acetyl group moves
from cystein residue onto
malonate group on ACP
• Product : acetoacetyl
attached to ACP, CO2 released
*
Acyl-malonyl ACP
condensing enzyme
*Nucleophilic attack breaks
the thioester bond

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Reduction by NADPH
• Acetoacetyl is transformed to D-3-
hydroxybutyryl by converting the the
carbonyl group into alcohol group
• Reducing agent : NADPH + H+  NADP+
• Catalyzing enzyme : β-ketoacyl ACP
reductase

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Dehydration
• Removal of hydroxyl group as H2O and
formation of C=C
• Catalyzed by 3-hydroxyacyl ACP
dehydratase
D-3-hydroxybutyryl-ACP
crotonyl-ACP
(Trans-∆2-enoyl )

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Reduction by NADPH
• Butyryl group is generated on ACP
• NADPH reduced the C=C because
the ultimate fatty acid chain
produced is a saturated fatty acid
• This completes the first elongation
process containing 4C atoms
Enoyl ACP reductase
● This whole cycle takes place 7 times in
total to generate a 16C palmitate
Butyryl-ACP
crotonyl-ACP
(Trans-∆2-enoyl )

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Restarting the cycle
Malonyl
Fatty acid
synthase
Acyl carrier
protein (ACP)
-S-H
phosphopentethiene
-S-HCys
CoA-SH
Butyryl

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Cleavage of 16C palmitate from ACP

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From the 16C in palmitate, ____ C
are from Malonyl-CoA
the other ____ C are from __________.
14
2 Acetyl-CoA

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THE END