fatty acids synthesis

7/30/2019 Fatty Acids Synthesis

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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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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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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

fatty acids synthesis

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