Transcript Lecture 9 Fatty Acid Synthesis

Synthesis of Fatty acid
Dr Vivek Joshi,MD
Biosynthesis of Saturated Fatty Acids
 Main
pathway - cytosol
 Occurs
primarily in the liver and lactating
mammary gland, less so in adipose tissue
 Also present in the kidney, brain, lung
 Fatty acid synthesis require:
 Dietary carbohydrates
 Acetyl CoA
 NADPH
 ATP
HIGH INSULIN/WELL FED STATE
Biosynthesis of Saturated Fatty Acids
Source of NADPH
# Pentose phosphate pathway
Chief source
Also occurs in the
cytosol
Active in tissues active
in lipogenesis
# Malic enzyme
Malic Enzyme
BIOSYNTHESIS OF SATURATED FATTY ACIDS

Production of Cytosolic Acetyl CoA

Carboxylation of Acetyl CoA to Malonyl CoA

Fatty acid synthase complex
Production of Cytosolic Acetyl CoA
Acetyl CoA
Main building block of
fatty acids
Synthesized from
carbohydrates via
oxidation of pyruvate
within mitochondria
Doesn’t diffuse easily from
mitochondria to cytosol
Utilization of glucose for
lipogenesis is through
citrate
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PRODUCTION OF
CYTOSOLIC ACETYL
COA
High levels of ATP and NADH
InhibitsTCA Cycle
(Isocitrate Dehydrogenase)
Accumulation of Citrate
Fatty Acid synthesis
Production of Cytosolic
Acetyl CoA
Malic enzyme produces ~50%
NADPH needed for FA synthesis
Carboxylation of Acetyl CoA to Malonyl CoA
 Malonyl
CoA is synthesized
from acetyl CoA using ATP and
CO2
 The
reaction is catalyzed by
Acetyl CoA carboxylase
Carboxylation of Acetyl CoA to Malonyl CoA


Biotin-Dependent Carboxylation of Acetyl-CoA to
Malonyl-CoA by Acetyl-CoA Carboxylase (ACC)
Biotin: water soluble vitamin – functions as a CO2 carrier for
several important reactions including:
 Acetyl-CoA carboxylase
 Pyruvate carboxylase
 Propionyl CoA carboxylase
Biotin cofactor
Fatty Acid Synthase Complex
A dimer with identical polypeptide monomers that lie head to
tail
Each polypeptide monomer contains all 7 enzyme activities
and an ACP
Only the dimer is active because fatty acid synthesis requires:
# Thiol of the ACP in one monomer
# Thiol of the 3-ketoacyl synthase (condensing
enzyme) of the other monomer.
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Fatty Acid Synthase Complex
Enoyl Reductase
Dehydratase
Ketoacyl
Reductase
Acyl Carrier
Protein
Thio
estrase
D
E
R
K
R
Malonyl
transacylase
M
T
Acetyl transacylase
A
T
Ketoacyl
Synthase
ACP
K
S
4’ Phosphopantethein
Cyst
SH
SH
SH
SH
Cyst
4’ Phosphopantethein
K
S
ACP
A
T
M
T
D
E
R
K
R
Thio
estrase
FATTY ACID SYNTHASE COMPLEX CARRIES
OUT 7 ENZYME REACTIONS
The whole point of a multi-enzyme
complex:
1.
Coordinated activity
2.
Intermediates stably bound to
enzyme complex
3.
Efficiency
FLEXIBLE PHOSPHOPANTETHEINYL GROUP OF ACP CARRIES
SUBSTRATE FROM ONE ACTIVE SITE TO ANOTHER


Acetate (from acetyl CoA) is loaded onto ACP, immediately
moved to Cys-SH on condensing enzyme (CE) in Domain 1 of
polypeptide 1
Malonyl (malonyl Co-A) is loaded onto ACP on Domain 2 of
polypeptide 2
FATTY ACID SYNTHESIS
FATTY ACID SYNTHESIS
FATTY ACID SYNTHESIS
Fatty Acid
Synthesis
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Synthesis of Palmitic acid (16C)
Sequence repeated (7 cycles) until
Saturated 16-carbon acyl radical (palmitoyl) is formed
Liberated from the enzyme complex by the 7th enzyme,
thioesterase (deacylase)
Palmitate
Equation for overall synthesis of palmitate:
1 acetyl CoA + 7 malonyl CoA + 14NADPH + 14H+
1 palmitic acid + 7CO2 + 6H2O + 8CoA + 14NADP+
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Palmitic Acid – activated to palmityl CoA before can
proceed to any other pathway
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Elongation of Fatty Acid
 Occurs in the endoplasmic reticulum &mitochondria
Uses NADPH as reductant
Lengthens a fatty acid by using malonyl CoA as acetyl donor
Fatty acid lengthens by 2 carbons
Brain-Elongation capibilities-Very long chain fatty acids(24 C) –
Synthesis of Brain lipids
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FATTY ACID ELONGATION
mtsPinlacSUSOM
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FATTY ACID DESATURATION
 The fatty acid desaturase system-Electron transport system in the
ER that involves:
# Cytochrome b5
# Desaturase
# NADH-cytochrome b5 reductase
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Synthesis of Polyunsaturated Fatty Acids
Involves the desaturase and the elongase enzyme
systems
Additional double bonds into existing
monounsaturated
FA are always separated from each
other by a methylene group
Additional double bonds are all introduced between
the existing double bond and the carboxyl group.
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Palmitate, 16:0
Synthesis of
polyunsaturated Fatty acids
elongation
desaturation
Stearate, 18:0
desaturation
Palmitoleate, 16:1(9)
elongation
Oleate, 18:1(9)
longer saturated fatty acids
desaturation
in plants only
Linoleate, 18:2(9,12)
.
desaturation
in plants only
- Linolenate, 18:3(9,12,15)
desaturation
-Linolenate, 18:3(6,9,12)
elongation
Eicosatrienoate, 20:3(8,12,14)
desaturation
Other polyunsaturated
fatty acids
Arachidonate
20:4(5,8,11,14)
Synthesis of Unsaturated Fatty Acids
Human have 9,6,5 and 4 Desaturase-Can introduce double bonds
at Δ4 , Δ5 , Δ6 and Δ9, but never beyond Δ9 (Carbon 10 till the end)
Linoleic and Linolenic acid-Essential Fatty acids
First- double bond introduced into a saturated FA - nearly always in
the Δ9 position by the Δ9 desaturase in the endoplasmic
reticulum
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Essential Fatty Acids
Cannot be synthesized in the body
Supplied
in the diet-Vegetable oils
Can be synthesized by plants – can introduce double bonds in the
12 and 15 position
Found in structural lipids-Concerned with structural integrity of
membranes
.
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Regulation of Fatty Acid Synthesis
-Fatty acid Metabolism-Stringently controlled
-Synthesis &degradation are highly responsive to
physiological needs
-Acetyl CoA Carboxylase
# Catalyses the rate-limiting step in the Biosynthesis
of Fatty Acids
# Short Term Regulation
-Allosteric regulation
-Covalent modification
# Long Term Regulation: Induction and Repression
Allosteric Regulation of
Acetyl CoA Carboxylase
a) Citrate
b) Palmitoyl CoA
- Increases polymerization
- A feedback inhibitor
- Promotes depolymerization
Covalent Modification of Acetyl CoA Carboxylase
Phosphorylation of the key Enzyme – Increases depolymerization
LONG TERM REGULATION OF ACETYL COA CARBOXYLASE


High Calorie/High Carbohydrate diet and fat free diet-Increased
synthesis of Acetyl CoA Carboxylase/ High Insulin -Enhanced
Fatty acid synthesis
Low Calorie diet /Fasting/High Glucagon -Decreased synthesis
of Acetyl CoA Carboxylase-Decreased Fatty acid synthesis
Thank you