Fatty acid synthesis 2018

fatty acid synthesis

1. By DR KHALED SALEH ALGARIRI JANUARY 2018 FATTY ACIDS SYNTHSIS

2. INTRODUCTION 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

3. There are three systems for the synthesis of fatty acids De novo synthesis of FAs in cytoplasm Chain elongation in mitochondria Chain elongation in microsomes

4. SYNTHESIS OF FATTY ACIDS De Novo synthesis of fatty acids Elongation of fatty acids Desaturation of fatty acids • Saturated fatty acids are synthesized from acetyl CoA derived from glucose • Occur in cytoplasm • Acetyl fragments are added to the existing fatty acids • Occur in both cytoplasm and mitochondria • Double bonds are introduced into the fatty acids •Occur in microsomes

5. In mammals fatty acid synthesis occurs primarily in the cytosol of the liver and adipose tissues . It also occurs in mammary glands during lactation. Acetyl-CoA is the starting material for FA synthesis. However, most acetyl-CoA in mitochondria(from the breakdown of sugars, some amino acids and other fatty acids).  So, acetyl-CoA must be transferred from the mitochondria to the cytosol BUT Mitochondria not permeable to acetyl CoA De novo synthesis of FA

6. TRANSPORTATION OF ACETYL CoA  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.

7. TRANSPORTATION OF ACETYL CoA

8. De novo synthesis of fatty acid is the synthesis of saturated fatty acids from acetyl CoA that is primarily derived from glucose Definition DE NOVO SYNTHESIS OF FATTY ACIDS

9. carbohydrate intake - acetyl CoA - fatty acids synthesis » Occurred in cytosol » Need - acetyl CoA - NADPH ( from HMP shunt )

10. Enzymes and Cofactors involved in fatty acids synthesis Two main enzymes- Acetyl co A carboxylase Fatty acid Synthase Both the enzymes are multi enzyme complexes Coenzymes and cofactors are- Biotin NADPH Mn ++ Mg ++

11. Fatty acid synthase complex Is a polypeptide containing seven enzyme activities and acyl carrier protein (ACP) segment Acetyl transacylase AT Malonyl transacylase MT 3-ketoacyl synthase KS 3-ketoacyl reductase KR Enoyl reductase ER Thioesterase ACP contains the vitamin pantothenic acid in the form of 4'-phosphopantetheine (Pant). ACP is the part that carry the acyl groups during fatty acid synthesis

12. Fatty acid synthase complex Synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers

13. The first a round in fatty acids synthesis To initiate FA biosynthesis, malonyl and acetyl groups are activated on to the enzym e fatty acid synthase . Initially , a priming molecule of acetyl-CoA combines with a cysteine —SH group catalysed by acetyl transacylase . Malonyl -CoA combines with the adjacent — SH on the 4'-phosphopantetheine of ACP of the other monomer, catalyzed by malonyl transacylase (to form acetyl (acyl)- malonylenzyme .

14. The activation of molnyl group The acetyl group from acetyl-CoA is transferred to the Cys -SH group of the- ketoacyl ACP synthase This reaction is catalyzed by acetyl- CoA transacetylase .

15. 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 carbon atoms is synthesized

16. Step 1- Condensation Condensation of the activated acetyl and malonyl groups takes place to form Acetoacetyl -ACP . The reaction is catalyzed by β- ketoacyl -ACP synthase .

17. Step 2 - Reduction The Acetoacetyl - ACP is reduced to β-hydroxybutyryl- ACP, catalyzed by β- ketoacyl -ACP reductase . NADPH + H+ are required

18. Step 3- Dehydration  Dehydration yields a double bond in the product, trans- Δ 2 - butenoyl -ACP ,  Reaction is catalyzed by β- hydroxybutyryl -ACP dehydratase .

19. Step 4- Reduction Reduction of the double bond takesplace to form butyryl -ACP , Reaction is catalysed by enoyl-reductase . Another NADPH dependent reaction.

20. The growing chain is transferred from the acyl carrier protein  This reaction makes way for the next incoming malonyl group.  The enzyme involved is acetyl- CoAtransacetylase

21. Beginning of the second round of the fatty acids synthesis The butyryl group is on the Cys -SH group. The incoming malonyl group is first attached to ACP . In the condensation step , the entire butyryl group is exchanged for the carboxyl group on the malonyl residue

22. Repetition of these four steps leads to fatty acids synthesis

23. The result of fatty acyl synthase activity Seven cycles of condensation and reduction produce the 16-carbon saturated palmitoyl group , still bound toACP . Chain elongation usually stops at this point, and free palmitate is released from the ACP molecule by hydrolytic activity in the synthase complex. Smaller amounts of longer fatty acids such as stearate ( 18:0) are also formed In mammary gland, there is a separate Thioesterase specific for acyl r esidues of C 8 , C 10 or C12, which are subsequently found in milk lipids.

24. The overall reactions for the synthesis of palmitate from acety -CoA can divided in two parts First , the formation of seven malonyl -CoA molecules: 7Acetyl-CoA + 7CO 2 + 7ATP 7malonyl CoA + 7ADP + 7P i Then the seven cycles of condensation and reduction Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H + palmitate + 7CO 2 + 8CoA + 14NADP + + 6H 2 O The biosynthesis of FAs requires acetyl-CoA and the input of energy in the form of ATP and reducing power of NADPH. 8Acetyl-CoA + 7ATP + 14NADPH + 14H+ palmitate + 7CO2 + 8CoA + 14NADP+ + 7ADP + 7Pi + 6H2O The overall reactions

25. RGULATION OF FATTY ACIDS SYNTHESIS Enzymes Metabolites End products Hormones Diet

26. RGULATION OF FATTY ACIDS SYNTHESIS Allosteric control  Palmitoyl -CoA acts as a feedback inhibitor of the enzyme , and citrate is an activator .  When there is an increase in mitochondrial acetyl-CoA and ATP , citrate is transported out of mitochondria ,  Citrate becomes both the precursor of cytosolic acetyl-CoA and a signal for the activation of acetyl-CoA carboxylase

27. RGULATION OF FATTY ACIDS SYNTHESIS Phosphorylation Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via changes in its phosphorylation state

28. RGULATION OF FATTY ACIDS SYNTHESIS

29. FATTY ACID ELANGATION  Palmitate in animal cells is the precursor of other long-chained FAs.  By further additions of acetyl groups, fatty acid chain length is elongated through the action of FA elongation systems present in the smooth endoplasmic reticulum and the mitochondria .

30. THE DESATURATION OF FATTY ACIDS Palmitate and stearate serve as precursors of the two most common monounsaturated fatty acids of animal cells: palmitoleate ( 16:1 9 ), and Oleate (18:1 9 ). The double bond is introduced by fatty acyl-CoA desaturase in the smooth endoplasmic reticulum

31. THE FATE OF FATTY ACIDS Most of the FAs synthesized or ingested by an organism have one of two fates:  Incorporated into triacylglycerols for the storage of metabolic energy  Incorporated into the phospholipid components of membranes

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