Chapter 16 (Part 3)
Fatty acid Synthesis
Fatty Acid Synthesis
• In mammals fatty acid synthesis occurs
primarily in the liver and adipose tissues
• Also occurs in mammary glands during
lactation.
• Fatty acid synthesis and degradation
go by different routes
• There are four major differences
between fatty acid breakdown and
biosynthesis
The differences between fatty
acid biosynthesis and breakdown
• Intermediates in synthesis are linked to -SH
groups of acyl carrier proteins (as compared
to -SH groups of CoA)
• Synthesis in cytosol; breakdown in
mitochondria
• Enzymes of synthesis are one polypeptide
• Biosynthesis uses NADPH/NADP+; breakdown
uses NADH/NAD+
ACP vs. Coenzyme A
•Intermediates in synthesis are linked to -SH
groups of acyl carrier proteins (as compared to SH groups of CoA)
Fatty Acid Synthesis Occurs in
the Cytosol
• Must have source of acetyl-CoA
• Most acetyl-CoA in mitochondria
• Citrate-malate-pyruvate shuttle provides cytosolic
acetate units and reducing equivalents for fatty
acid synthesis
Citrate synthase
Citrate Lyase
Malate
dehydrogenase
Pyruvate
carboxylase
Malate Enzyme
Fatty Acid Synthesis
• Fatty acids are built from 2-C units derived
from acetyl-CoA
• Acetate units are activated for transfer to
growing FA chain by conversion to malonylCoA
• Decarboxylation of malonyl-CoA and reducing
power of NADPH drive chain growth
• Chain grows to 16-carbons (eight acetylCoAs)
• Other enzymes add double bonds and more
Cs
Acetyl-CoA Carboxylase
Acetyl-CoA + HCO3- + ATP Æ malonyl-CoA + ADP
• The "ACC enzyme" commits acetate to
fatty acid synthesis
• Carboxylation of acetyl-CoA to form
malonyl-CoA is the irreversible, committed
step in fatty acid biosynthesis
Acetyl-CoA
Carboxylase
Regulation of Acetyl-CoA
Carboxylase (ACCase)
• ACCase forms long, active filamentous
polymers from inactive protomers
• Accumulation of palmitoyl-CoA (product)
leads to the formation of inactive
polymers
• Accumulation of citrate leads to the
formation of the active polymeric form
• Phosphorylation modulates citrate
activation and palmitoyl-CoA inhibition
Regulation of Acetyl-CoA
Carboxylase (ACCase)
• Unphosphorylated ACCase
has low Km for citrate and
is active at low citrate
• Unphosphorylated ACCase
has high Ki for palmitoylCoA and needs high
palmitoyl-CoA to inhibit
• Phosphorylated E has high
Km for citrate and needs
high citrate to activate
• Phosphorylated E has low Ki
for palmitoyl-CoA and is
inhibited at low palmitoylCoA
Fatty Acid Synthesis
• Step 1: Loading – transferring acetyl- and
malonyl- groups from CoA to ACP
• Step 2: Condensation – transferring 2 carbon
unit from malonyl-ACP to acetyl-ACP to form 2
carbon keto-acyl-ACP
• Step 3: Reduction – conversion of keto-acylACP to hydroxyacyl-ACP (uses NADPH)
• Step 4: Dehydration – Elimination of H2O to
form Enoyl-ACP
• Step 5: Reduction – Reduce double bond to
form 4 carbon fully saturated acyl-ACP
Step 1: Loading Reactions
O
H3C C S CoA
acetyl-CoA
acetyl-CoA:ACP
transacylase
O
O
C
HS-ACP
H
O
C
C S CoA
H
malonyl-CoA
HS-ACP
malonyl-CoA:ACP
transacylase
HS-CoA
HS-CoA
O
H3C
C S ACP
acetyl-ACP
O
O
C
H
O
C
C S ACP
H
malonyl-ACP
Step 2: Condensation Rxn
O
H3C
C S ACP
acetyl-ACP
HS-Ketoacyl-ACP Synthase
HS-ACP
O
O
C
O
H
O
C
C S ACP
H
+
H3C C S
ketoacyl-ACP Synthase
malonyl-ACP
keto-ACP synthase
CO2
H3C
O
H
O
C
C
C S ACP
H
acetoacetyl-ACP
Step 3: Reduction
H3C
O
H
O
C
C
C S ACP
H
acetoacetyl-ACP
NADPH + H+
Ketoacyl-ACP Reductase
NADP+
OH H
H3C
C
C
H
H
O
C S ACP
β-hydroxybutyryl-ACP
Step 4: Dehydration
OH H
H3C
C
C
H
H
O
C S ACP
β-hydroxyacyl-ACP
β-hydroxyacyl-ACP
dehydrase
H20
H3C C
H
H
O
C
C S ACP
trans-enoyl-ACP
Step 5: Reduction
H3C C
H
O
C
C S ACP
trans-enoyl-ACP
H
NADPH + H+
enoyl-ACP reductase
NADP+
H
H
O
H3C C
C
C S ACP
H
H
trans-enoyl-ACP
Step 6: next condensation
H H O
H3C
C C C S ACP
H H
butyryl-ACP
HS-Ketoacyl-ACP Synthase
HS-ACP
O
O
C
H H O
H
O
C
C S ACP
H
+
H3C
C C C S KAS
H H
malonyl-ACP
keto-ACP synthase
CO2
H H O
H
O
H3C C C C
C
C S ACP
H H
H
ketoacyl-ACP
Termination
of Fatty
Acid
Synthesis
H O
H3C C C S ACP
H
Palmitoyl-ACP
14
Thioesterase
HS-ACP
H O
H3C C C O
H
Palmitic Acid
14
ATP + HS-CoA
Acyl-CoA
synthetase
AMP + PPi
H O
H3C
C C S CoA
H
14
Palmitoyl-CoA
Organization of Fatty Acid
Synthesis Enzymes
• In bacteria and plants, the fatty acid
synthesis reactions are catalyzed
individual soluble enzymes.
• In animals, the fatty acid synthesis
reactions are all present on
multifunctional polypeptide.
• The animal fatty acid synthase is a
homodimer of two identical 250 kD
polypeptides.
Animal Fatty Acid Synthase
Further Processing
of Fatty acids:
Desaturation and
Elongation
Regulation of FA Synthesis
• Allosteric modifiers, phosphorylation and
hormones
• Malonyl-CoA blocks the carnitine
acyltransferase and thus inhibits betaoxidation
• Citrate activates acetyl-CoA carboxylase
• Fatty acyl-CoAs inhibit acetyl-CoA
carboxylase
• Hormones regulate ACC
• Glucagon activates lipases/inhibits ACC
• Insulin inhibits lipases/activates ACC
Allosteric regulation
of fatty acid
synthesis occurs at
ACCase and the
carnitine
acyltransferase
Glucagon inhibits
fatty acid
synthesis while
increasing lipid
breakdown and
fatty acid βoxidation
Insulin prevents
action of glucagon