Fatty acid biosynthesis
By
Dr.Dahlia Badran
objectives
• Conversion of Acetyl CoA to Malonyl CoA by
acetyl Co A carboxylase (ACC)
• Regulation of acetyl Co A carboxylase (ACC)
activity
• Synthesis of Palmitate from Acetyl CoA and
Malonyl CoA by Fatty acid synthase
• Fatty Acid Synthase – Regulation
• Post-Synthesis Modifications
Overall View
Glucose
Cytosol
Pyruvate
KETONE BODIES
Acetyl CoA
Mito.
Fatty acids
Cytosol
Triacylglycerols
Synthesis of long-chain fatty acids from
acetyl CoA
• Primary site of FA synthesis is liver and
adipose tissue
• Suppressed by high fat diet (our diets!)
• De novo lipogenesis may not contribute much
to triacylglycerol biosynthesis except in the
fetal and newborn infant and in the lactating
mammary gland
Key Points
Acetyl CoA cannot penetrate mito. membrane
Excess Acetyl CoA results in citrate accumulation (FED
STATE)
Citrate lyase cleaves citrate to OAA and acetyl CoA
(1st step in fatty acid synthesis)
NADPH is formed and used for FA synthesis
Conversion of Acetyl CoA to Malonyl CoA
• ACC – Acetyl CoA carboxylase
• First committed step in FA synthesis
• Highly regulated – Phosphorylation and
allosteric control via local metabolites
Acetyl CoA Carboxylase
O
Acetyl CoA
H3C C SCoA
CO2
biotin
ACC
O
Malonyl CoA
-OOC H2C C SCoA
ACC-biotin
HCO3- + ATP
1
ADP + Pi
ACC-biotin-CO2
O
H3C C SCoA
2
ACC-biotin
O
-OOC
H2C C SCoA
Enzyme-biotin
HCO3 + ATP
1
ADP + Pi
Enzyme-biotin-CO2
O
ll
CH3-C-SCoA
acetyl-CoA
2
Enzyme-biotin
O
-
ll
O2C-CH2-C-SCoA
malonyl-CoA
The overall reaction, which is spontaneous, may be
summarized as:
HCO3- + ATP + acetyl-CoA  ADP + Pi + malonyl-CoA
ACC Regulation
• Covalent (phosphorylation)
• Allosteric
• Transcriptional
ACC regulation
Acetyl CoA
Malonyl CoA
• With a high carbohydrate diet, would you expect
high or low ACC activity?
• In the fasted state, would you expect high or low ACC
activity?
• Exercise?
• High Fat Diet?
ACC Regulation
Insulin
Glucagon
(-)
Phosphatase
(+)
ACC
(high activity)
(+)
Citrate
OH
?
ACC
(low activity)
P
(+)
Palmitoyl-CoA
(product)
ACC regulation - Phosphorylation
ACC
(high activity)
OH
ACC
(low activity)
P
AMP-Activated
Protein Kinase (high activity)
phosphatase
kinase
(+)
(+)
insulin
AMP-Activated
Protein Kinase
(low activity)
increase cAMP
Glucagon/epi
ACC regulation : Exercise
ACC
(high activity)
OH
ACC
(low activity)
AMP-Activated
Protein Kinase (high activity)
(+)
Exercise
P
ACC- gene transcription
• Fed state = Increase # of ACC molecules
– Insulin and glucose
• Starved state = decrease # of ACC molecules
– Glucagon = increase cAMP
Summary ACC regulation
Key Points – 1. ACC is high in fed state and
2. unphosphorylated form of ACC is active
A. Allosteric
* Citrate and palmitoyl CoA
B. Covalent – phosphorylation
* Protein phosphatase
* AMP-activated kinase
C. Transcription – long term
* insulin glucose
* glucagon cAMP
Synthesis of Palmitate from Acetyl CoA and
Malonyl CoA
• The second and final committed step in FAS is
catalyzed by fatty acid synthase
• Multifunctional polypeptide
• The reaction is complex (in 2 ways!!!!)
– Serial addition of 2-carbon fragments
– Many steps !
Fatty acid synthesis from acetyl-CoA & malonyl-CoA
occurs by a series of reactions that are:
 in bacteria catalyzed by 6 different enzymes plus a
separate acyl carrier protein (ACP)
 in mammals catalyzed by individual domains of a very
large polypeptide that includes an ACP domain.
Evolution of the mammalian Fatty Acid Synthase
apparently has involved gene fusion.
NADPH serves as electron donor in the two reactions
involving substrate reduction.
The NADPH is produced mainly by the Pentose Phosphate
Pathway.
steps
1.Condensation
2.Reduction
3.Dehydration
4.Reduction
Condensing Malonyl/acetyl-CoA Dehydratase Enoyl -Ketoacyl ACP Thioesterase
-C
nzyme (Cys) Transacylase (Ser)
Reductase Reductase (Pant)
Order of domains in primary structure of mammalian Fatty Acid Synthase
Palmitate, a 16-C saturated fatty acid, is the final product of the Fatty
Acid Synthase reactions.
1. a. How many acetyl-CoA used for initial priming of enzyme? _____
1
b. How many acetyl-CoA used for synthesis of each malonate? ____
1
c. How many malonate used (how many reaction cycles) per
synthesis of one 16-C palminate? ________
7
d. Total acetyl-CoA used for priming & for syntheisis of malonate,
a + b(c): ________
8
2. a. How many ~P bonds of ATP used for synthesis of each
malonate? ________
1
b. Total ~P bonds of
ATP used for synthesis of one 16-C palmitate,
2a(1c): ________
7
3. a. How many NADPH
used per reaction cycle? __________
2
b. Total NADPH used per synthesis of one 16-C palmitate, 3a(1c):
_________
14
O
-OOC H2C C SCoA
Fatty acid synthase
Fatty Acid Synthase - Regulation
No covalent or allosteric modification !
Very sensitive to hormonal and nutritional
factors (Your reading)
Fatty Acid Synthase is transcriptionally regulated.
In liver:
 Insulin, a hormone produced when blood glucose is
high, stimulates Fatty Acid Synthase expression.
Thus excess glucose is stored as fat.
Transcription factors that that mediate the
stimulatory effect of insulin include USFs (upstream
stimulatory factors) and SREBP-1.
SREBPs (sterol response element binding proteins)
were first identified for their regulation of cholesterol
synthesis.
 Polyunsaturated fatty acids diminish transcription of
the Fatty Acid Synthase gene in liver cells, by
suppressing production of SREBPs.
In fat cells:
Expression of SREBP-1 and of Fatty Acid Synthase is
inhibited by leptin, a hormone that has a role in
regulating food intake and fat metabolism.
Leptin is produced by fat cells in response to excess fat
storage.
Leptin regulates body weight by decreasing food intake,
increasing energy expenditure, and inhibiting fatty acid
synthesis.
Post-Synthesis Modifications
• C16 satd fatty acid (Palmitate) is the product
•
•
•
•
Elongation
desaturation
Incorporation into triacylglycerols
Incorporation into acylglycerol phosphates
Elongation and Desaturation
• Palmitate (16:0) is elongated and desaturated to
produce a variety of Fas Converted to
triacylglycerides and exported by liver as VLDL
• Elongated in 2 carbon steps: 2 systems for
elongation
– Mitochondria
– Endoplasmic reticulum
• Major elongation product is stearoyl CoA (C18)
Desaturation
(18:0: Stearic)
H3C
(CH 2)7
H
H
C
C
H
H
O
(CH 2)7
C
SCoA
D9
Stearoyl CoA desaturase
H3C
(CH 2)7
H
H
C
C
O
(CH 2)7
(18:1w9 or 18:1D9) Oleic Acid
C
SCoA
Rules:
Desaturation
The fatty acid desaturation system is
in the smooth membranes of the endoplasmic
Reticulum.
There are 4 fatty acyl desaturase enzymes in
mammals designated D9 , D6, D5, and D4 fatty
acyl-CoA desaturase.
Mammals cannot incorporate a double bond
beyond D9; plants can.
Mammals can synthesize long chain unsaturated
fatty acids using desaturation and elongation.
THANK YOU