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Lipid metabolism 1.   2.   3. 4. 5. 6.

Lipogenesis Biosynthesis of fatty acids Formation of triglycerides Lipolysis Hydrolysis of triglycerides Fatty acid oxidation Synthesis of Ketone bodies Ketone bodies oxidation Biosynthesis of cholesterol Biosynthesis of phospholipids


Lipogenesis 1.   

 

Biosynthesis of saturated fatty acids It occurs in the cytosol Sources of acetyl CoA Acetyl CoA is derived from the oxidation of glucose via glycolysis and pyruvate dehydrogenase (in mitochondria). Sources of NADPH NADPH is generated by the action of the pentose phosphate pathway


Transport of acetyl CoA into the cytosol ď ľ

1.

2. 3.

Acetyl CoA is not able to cross the inner mitochondrial membrane and is transported into the cytosol via the acetyl CoA shuttle system Citrate synthetase catalyzes the reaction of acetyl CoA with oxaloacetate to form citrate in the mitochondria. Citrate is transported into the cytosol by a tricarboxylic acid transport system. Citrate reacts with CoA in the cytosol to form acetyl CoA and oxaloacetate. This reaction is catalyzed by citrate lyase and requires ATP


O O

C

C

CH2

OH

C

OH

H2O

O

CoASH

Citrate synthetase

CH2

C

OH

O

O

oxaloacetate

HO

+

citrate lyase

O CH3

C

ScoA

Acetyl CoA

H2O

CoASH

C CH2

C

C

OH

OH

O

Citrate


1. Formation of malonyl CoA ď ľ This

reaction is catalyzed by acetyl CoA carboxylase, which requires biotin as a cofactor to perform the carboxylation reaction. O

CH3

C

SCOA + HCO3

H2O Acetyl COA carboxylase

O O C CH2

O C

Malonyl CoA

Acetyl CoA ATP

ADP + Pi

SCOA


 Acetyl

CoA carboxylase is the key regulatory enzyme in fatty acid synthesis.  Activators. – Citrate. – Insulin.  Inhibitors.  Palmitoyl

CoA (free fatty acids).  Glucagons


2. Binding of acetyl CoA to acyl carrier protein (ACP) ď ľ

This reaction is catalyzed by the acetyl transacylase component of the fatty acid synthase enzyme complex.


3. Binding of malonyl CoA to acyl carrier protein (ACP) ď ľ

This reaction is catalyzed by the malonyl transacylase component of the fatty acid synthase enzyme complex.


4. Formation of acetoacetyl This reaction is catalyzed by the 3ketoacyl synthase component of the fatty acid synthase enzyme complex. CO2 O O O 3 Ketoacyl synthase O O CH SCOA + CH SCOA C 3 C C O 2 CH3 C CH2 C SCOA Malonyl CoA Acetyl CoA COASH 3 ketoacyl COA ď ľ


5. Formation of 3-hydroxyacyl COA ď ľ This

reaction is catalyzed by the 3ketoacyl reductase component of the fatty acid synthase enzyme complex. NADPH is required for this reaction

CH3

O

O

C CH2

C

OH

3-ketoacyl reductase SCOA

CH3

C CH2

O C

SCOA

H 3 ketoacyl COA NADPH + H+

NADP+

3 Hydroxyacyl COA


6. Formation of enoyl COA ď ľ

This reaction is catalyzed by the 3hydorxyacyl dehydratase component of the fatty acid synthase enzyme complex. OH

CH3

C CH2

O C

H 3 Hydroxyacyl COA

3 Hydroxyacyl COAdehydratase SCOA

CH3 H2O

O CH CH C

2 Enoyl COA

SCOA


7. Formation of acyl COA ď ľ This

reaction of catalyzed by the enoyl COA reductase component of the fatty acid synthase enzyme complex. NADPH is required for this O reaction Enoyl COA reductase O

CH3

CH CH C

CH3

SCOA

CH2

CH2 C

Acyl COA 2 Enoyl COA

NADPH + H+

NADP+

SCOA


ď ľ Acyl

COA then reacts with another malonyl COA and complete the cycle until reach to the target number. After several turns of the cycle, fatty acid- is released from the ACP fatty acid synthase complex by the enzyme thioesterase.


Biosynthesis of unsaturated fatty acids ď ľ The

double bonds are introduced between carbons 9 and 10 by fatty acid oxygenase in the endoplasmic reticulum. The enzyme is a mixedfunction oxygenase, which requires molecular oxygen and NADPH.


O R

CH2

CH2

(CH2 )7

C

O

Acyl transferase R

SCOA

CH2

CH2

(CH2 )7

C

Enz

COASH Acyl COA OH

Oxygenase

O R

O2 NADH +H

CH2

CH

Dehyderatase

Enz

H2O

NAD+ O

R

C

9 Hydroxy acyl

H2O +

CH (CH2 )7

CH (CH2 )7

C

Acyl transferase Enz

O R

COASH

CH

CH (CH2 )7

Enoyl COA

C

SCOA


Formation of triglycerides 1.

Activation of fatty acids (formation of acyl COA) O RCOH

AcylcoA synthetase

Fatty acid

COASH ATP

AMP+PPi

O RCO

SCOA

AcylCOA


2.

Activation of glycerol CH2OH CH2OH

CH2OH Glycerol kinase

CH2OH OH

CH2OH Glycerol

ATP

ADP

CHO

P

O

O Glycerol 3,phosphate


3.

Formation of triacylglycerols. CH2OH CH3OH

O

+

Glycerol 3 Phosphate CH2O Acyltransferase

R CSCOA

O

O 1 monoacyl glycerol CH2O CR CR Phosphate acyltransferase O

CHOH

CH2OP

COASH

CHO

CH2OP

O

COASH

CR2

CH2OP

R CSCOA 1 monoacyl glycerol Phosphate

Glycerol 3 Phosphate

O

1,2 Diacyl glycerol Phosphate phosphohydrolase

CH2O CHO

H2O

Pi

CR

1,2 Diacyl glycerol Phosphate

1,2 Diacyl glycerol acyltransferase

O

CR2

CH2OH

1,2 Diacyl glycerol

O CH2O CHO

O

R CSCOA

COASH

CR

O

CR2

O CH2O

CR3

Triglycerides

Lipogenesis 20080428 164232  
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