DR MUHAMMAD MUSTANSAR

Fatty Acid Synthesis

Fatty acids

Fatty acids are a class of compounds containing a long hydrophobic hydrocarbon chain and a terminal carboxylate group They exist free in the body as well as fatty acyl esters in more 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 membrane lipids such as phospholipids and glycolipids. Esterified fatty acids, in the form of triglycerides are stored in adipose cells Fatty acids are also precursors of Eicosanoids

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 are stored as triglycerides

Biosynthesis of Fatty acids

The excess dietary Carbohydrates & Proteins can be converted to fatty acids and are stored as Tri acyl Glycerol. Denovo synthesis of Fatty acids takes place in Liver, Kidney, adipose tissue and Lactating Mammary glands. Site: Cytoplasm of the cell Requirements: Acetyl CoA source of Carbon atoms NADPH provides reducing equivalents ATP energy

 Fatty acid synthesis in 3 stages

(i)

Production of Acetyl CoA & NADPH

Conversion of acetyl CoA to Malonyl CoA Reactions of Fattyacid synthase complex.

(ii) (iii)

De novo fatty SynthesisIntroduction Fatty acids are Acid synthesized by an extra

mitochondrial system This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue. Acetyl-CoA is the immediate substrate, and free palmitate is the end product. Its cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3 (as a source of CO2).

Location of fatty acid synthesis

FA synthase complex is found exclusively in the cytosol. The location segregates synthetic processes from degradative reactions.

Sources of NADPH
NADPH

is involved as donor of reducing equivalents 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).

Acetyl co A- Sources and Fate

Acetyl

co A, the precursor for fatty acid synthesis is produced from pyruvate, ketogenic amino acids, fatty acid oxidation and by alcohol metabolism
It

is a substrate for TCA cycle and a precursor for fatty acids, ketone bodies and sterols.

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 the mitochondria to the cytosol

Cytosol site of acetate utilization Mitochondria site of acetate synthesis

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 cycle catalyzed 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.

Transportation of Acetyl co A

Enzymes and cofactors involved in the process of Fatty acid synthesis

Two main enzymesAcetyl co A carboxylase Fatty acid Synthase Both the enzymes are multienzyme complexes Coenzymes and cofactors areBiotin NADPH Mn++ Mg++

Steps in Fatty acid synthase complex

1)

Acetyl CoA is transferred to ACP by

Acetyl CoA ACP transacylase (CoA is

removed). The two carbon unit acetate which is attached to ACP is shifted to cysteine residue of keto acyl synthase enzyme.

2) Now Malonyl CoA is transferred to ACP by Malonyl CoA ACP transacylase where Co A is removed

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.

4) Ketoacyl ACP undergoes reduction to

form -hydroxy acyl ACP, enzyme is keto

Acyl reductase NADPH provides

Hydrogens.

5) -hydroxy acyl ACP undergoes

dehydration where one water molecule is

removed to form Enoyl ACP (double bond

between 2 & 3 Carbons) enzyme is

dehydratase.

6) Enoyl ACP undergoes reduction to form acyl ACP or butryl ACP, enzyme is enoyl ACP reductase, NADPH provides

Hydrogens.

7) The 4 carbon butryl acid attached to ACP is shifted to cysteine residue and reactions 2

6 are repeated

 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

Series of Reactions
After activation, the processes involved are1. Condensation 2. Reduction 3. Dehydration 4. Reduction These steps are repeated till a fatty acid with 16 carbon atoms is synthesized

Repetition of these four steps leads to fatty acid synthesis

The overall reaction for the synthesis of palmitate from acetyl-CoA can be considered in two parts.

Part 1
First, the formation of seven malonyl-CoA molecules: 7Acetyl-CoA + 7CO2 + 7ATP

7malonyl CoA + 7ADP + 7Pi

Part 2
Then the seven cycles of condensation and reduction

Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+ palmitate + 7CO2 + 8CoA + 14NADP+ + 6H2O The biosynthesis of FAs requires acetyl-CoA and the input of energy in the form of ATP and reducing power of NADPH.

Rxn for palmitate synthesis is:

Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 7 H+ palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6H2O

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.

Comparison of -Oxidation & Fatty Acid Synthesis

eta Oxidation pathway Fatty acid Synthesis

Location
Acyl Carriers(Thiols) Electron acceptors and donors OH Intermediates 2 Carbon product/donor

Mitochondrial
Coenzyme A FAD/NAD L Acetyl co A

Cytoplasmic
4 Phosphopantetheine and Cysteine NADPH D Acetyl co A/ Malonyl co A