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Fatty Acid SynthesisDR MUHAMMAD MUSTANSAR
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Fatty acids
Fatty acids are a class of compounds containing a longhydrophobic hydrocarbon chain and a terminalcarboxylate group
They exist free in the body as well as fatty acyl esters inmore complex molecules such as triglycerides or
phospholipids. Fatty acids can be oxidized in all tissues, particularly
liver and muscle to provide energy
They are also structural components of membranelipids such as phospholipids and glycolipids.
Esterified fatty acids, in the form of triglycerides arestored in adipose cells
Fatty acids are also precursors of Eicosanoids
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Sources of Fatty acids
Diet
Adipolysis
De novo synthesis(from precursors)-
Carbohydrates, protein, and other
molecules obtained from diet in
excess of the bodys need can be
converted to fatty acids, which arestored as triglycerides
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Biosynthesis of Fatty acids
The excess dietary Carbohydrates & Proteinscan be converted to fatty acids and are stored asTri acyl Glycerol.
Denovo synthesis of Fatty acids takes place in
Liver, K idney, adipo se tissueandLactat ingMammary glands.
Site: Cytoplasm of the cell
Requirements:
Acetyl CoA source of Carbon atoms
NADPH provides reducing equivalents
ATP energy
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Fatty acid synthesis in 3 stages
(i) Production ofAcetyl CoA & NADPH
(ii) Conversion ofacetyl CoA to Malonyl CoA
(iii) Reactions ofFattyacid synthase complex.
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De novo fatty Acid Synthesis- IntroductionFatty acids are synthesized by an extra
mitochondrial systemThis system is present in many tissues, including
liver, kidney, brain, lung, mammary gland, and
adipose tissue.
Acetyl-CoAis the immediate substrate, and freepalmitateis the end product.
Its cofactor requirements include NADPH, ATP,
Mn2+, biotin, and HCO3 (as a source of CO2).
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Location of fatty acid synthesis
FA synthasecomplex is found
exclusively in
the cytosol.
The location
segregatessynthetic
processes from
degradative
reactions.
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Sources of NADPH
NADPH is involved as donor of reducingequivalents
The oxidative reactions of the pentose phosphate
pathway are the chief source of the hydrogen
required for the reductive synthesis of fatty acids.
Tissues specializing in active lipogenesisie, liver,
adipose tissue, and the lactating mammary gland
possess an active pentose phosphate pathway.
Other sources of NADPH include the reaction that
converts malate to pyruvate catalyzed by the "Malic
enzyme"(NADP malate dehydrogenase) and the extra
mitochondrial isocitrate dehydrogenase reaction
(probably not a substantial source, except in
ruminants).
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Acetyl co A- Sources and FateAcetyl co A, the
precursor for fatty
acid synthesis isproduced from
pyruvate,
ketogenic amino
acids, fatty acid
oxidation and by
alcoholmetabolism
It is a substrate
for TCA cycle and a
precursor for fatty
acids, ketone
bodies and sterols.
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Transportation of Acetyl co A
Fatty acid synthesis requires considerable
amounts of acetyl-CoA
Nearly all acetyl-CoA used in fatty acid
synthesis is formed in mitochondria
Acetyl co A has to move out from themitochondria to the cytosol
Cytosol site of acetate utilization
Mitochondria site of acetate synthesis
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Transportation of Acetyl co A
Acetate is shuttled out of mitochondria as citrate
The mitochondrial inner membrane is
impermeable to acetyl-CoA
Intra-mitochondrial acetyl-CoA first reacts with
oxaloacetate to form citrate, in the TCA cyclecatalyzed by citrate synthase
Citrate then passes into the cytosol through
the mitochondrial inner membrane on the
citrate transporter.
In the cytosol, citrate is cleaved by citrate
lyase regenerating acetyl-CoA.
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Transportation of Acetyl co A
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Enzymes and cofactors involved in the
process of Fatty acid synthesis
Two main enzymes-
Acetyl co A carboxylase
Fatty acid Synthase
Both the enzymes are multienzyme complexes
Coenzymes and cofactors are-
Biotin
NADPHMn++
Mg++
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Steps in Fatty acid synthase complex
1) Acetyl CoA is transferred to ACP by
Acetyl CoA ACP transacy lase(CoA is
removed). The two carbon unit acetate
which is attached to ACP is shifted to
cyste ineresidue ofketo acyl synthase
enzyme.
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2) Now Malonyl CoA is transferred to ACP by
Malonyl CoA ACP transacy lasewhere Co A
is removed
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3) The acetyl unit (2) which is attached to
cysteine combines with malonyl unit(3 C)
where Co2 is released to form keto acyl ,
ACP, Enzyme is keto acyl synthase.
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4) Ketoacyl ACPundergoes reduction to
form -hydroxy acyl ACP, enzyme is keto
Acyl reductase NADPH provides
Hydrogens.
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5)-hydroxy acyl ACPundergoes
dehydration where one water molecule is
removed to form Enoyl ACP(double bond
between 2 & 3 Carbons) enzyme is
dehydratase.
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6) Enoyl ACP undergoes reduction to form
acy l ACP or bu try l ACP, enzyme is enoyl
ACP reductase, NADPH provides
Hydrogens.
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7) The 4 carbon butryl acid attached to ACP is
shifted to cysteine residue and reactions 2
6 are repeated
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For 1 cycle carbon chain length increase by
2 carbons
(2) Acetyl acid
1 cycle
(4) Butyric acid
2 cycle
(6) Caproic acid
3 cycle
(8) Caprylic acid
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Series of Reactions
After activation, the processes involved are-
1. Condensation
2. Reduction
3. Dehydration
4. Reduction
These steps are repeated till a fatty acid with 16 carbonatoms is synthesized
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Repetition of these four steps leads
to fatty acid synthesis
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The overall reaction for the
synthesis of palmitate fromacetyl-CoA can be considered
in two parts.
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Part 1
First, the formation of seven malonyl-CoA molecules:
7Acetyl-CoA + 7CO2 + 7ATP
7malonyl CoA + 7ADP + 7Pi
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Part 2
Then the seven cycles of condensation andreduction
Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+
palmitate + 7CO2 + 8CoA +14NADP+ + 6H
2
O
The biosynthesis of FAs requires acetyl-CoA andthe input of energy in the form ofATP and reducingpower ofNADPH.
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But malonate is made from acetyl CoA
7 acetyl-CoA + 7 CO2 + 7 ATP 7 malonyl-CoA+ 7 ADP + 7 Pi + 7 H
+
So overall:
8 acetyl-CoA + 7 ATP + 14 NADPH palmitate+14 NADP+ + 8 CoASH + 6 H2O + 7 ADP + 7 Pi
The NADPH comes from the pentose phosphate
shunt. The source of acetyl-CoA is more complex.
Rxn for palmitate synthesis is:
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 7 H+
palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6H2O
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Comparison of -Oxidation & Fatty Acid
Synthesiseta Oxidationpathway
Fatty acid Synthesis
Location Mitochondrial Cytoplasmic
Acyl Carriers(Thiols) Coenzyme A 4 Phosphopantetheine
and Cysteine
Electron acceptors and
donors
FAD/NAD NADPH
OH Intermediates L D
2 Carbon
product/donor
Acetyl co A Acetyl co A/ Malonyl co
A