Fatty acid synthesis:- Everything you need to know

Fatty acid synthesis is a very important topic of biotechnology and biochemistry.
The following presentation includes everything from an introduction to fatty acids and de novo synthesis.
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1. FATTY ACID SYNTHESIS BY GUNVEEN, NIKITA, PRAKRITI, SHERYA AND RIYA This Photo by Unknown Author is licensed under CC BY-SA

2. Fatty acids are compounds containing a long hydrophobic hydrocarbon chain and a terminal carboxylate group. They are structural components of membrane lipids such as phospholipids and glycolipids. They are obtained from our diet, adipolysis and de novo synthesis. Carbohydrates, proteins and other molecules obtained from diet in excess of the body’s need can be converted to fatty acids, which are stored as triglycerides. This Photo by Unknown Author is licensed under CC BY-NC-ND This Photo by Unknown Author is licensed under CC BY-SA-NC

3. De novo Fatty Acid Synthesis Fatty acids are synthesized by an extra mitochondrial system. This system is present in many tissues, including liver, kidney ,brain,lungs mammary gland and adipose tissue. Acetyl-CoA is the immediate substrate, and free palmitate is the end product Its cofactor requirements include NADPH, ATP, Mn+2, biotin and HCO3- HCO3 is used as a source of co2. This Photo by Unknown Author is licensed under CC BY-SA

4. LOCATION OF FATTY ACID SYNTHESIS FA synthase complex is found exclusively in the cytosol

5. Acetyl CoA- The Main Component Of Fatty Acid Synthesis Acetyl CoA, which is 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 precursor for fatty acids, ketone bodies and sterols. This Photo by Unknown Author is licensed under CC BY-SA

6. Enzymes and cofactors involved in the process of Fatty Acid Synthesis STAGES OF FATTY ACID SYNTHESIS : Transport of acetyl CoA and NADPH into cytoplasm Conversion of acetyl CoA to malonyl CoA Reactions of fatty acid synthase complex Two main enzymes are involved in fatty acid synthesis :- Acetyl CoA carboxylase Fatty acid synthase Both these enzymes are multienzyme complexes Coenzymes and cofactors are :- Biotin NADPH Mn++ Mg++ This Photo by Unknown Author is licensed under CC BY-SA

7. Fatty acid synthase complex The Fatty Acid Synthase Complex is a polypeptide containing seven enzyme activities In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP) In yeast mammals and birds the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. This Photo by Unknown Author is licensed under CC BY-SA This Photo by Unknown Author is licensed under CC BY-SA-NC

8. The enzyme forms a dimer with two identical subunits. each subunit consists of 3 domain having in total 7 enzymes. These functionally active subunits lie in antiparallel orientation. The three domains are:- 1st domain - CONDENSING UNIT Beta-keto acyl synthase (KS) ; Acetyl transacylase (AT) and Malonyl transacylase (MT) 2nd domain - REDUCTION UNIT Dehydratase (DT) ; Enoyl reductase (ER) and Beta-ketoacyl reductase (R). This domain also contains Acyl carrier protein (ACP). 3rd domain - RELEASING UNIT Thio-esterase (TE). The first domain acts as an initial binding site. the 3rd domain releases the fatty acid synthesised. The two subunits independently operate and both can synthesize fatty acid simultaneously.

9. IMPORTANCE OF MULTIENZYME COMPLEX Multienzyme complex helps form compartmentalization of the process within the cell. this removes the consideration for permeability barriers. Synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. So all the enzymes are in equimolar concentration which helps increase the efficiency of the process in which these are involved.

10. Steps of fatty acid synthesis Step 1 is the input to fatty acid synthesis in acetyl-CoA, which is carboxylated to malonyl CoA. The reaction is catalyzed by Acetyl CoA carboxylase. ATP dependent carboxylation provides energy input. The CO2 is lost later during condensation with the growing fatty acid. The spontaneous decarboxylation drives the condensation reaction. As with other carboxylation reactions, the enzyme prosthetic group is biotin The reaction takes place in two steps : The biotin carboxylase domain catalyzes the ATP dependent carboxylation of biotin ( which is attached to a carrier protein ) using bicarbonate as a CO2 donor. In the second reaction, the carboxyl group is transferred from biotin to acetyl CoA to form malonyl CoA.

11. Overall reaction

12. The carboxylation reaction is driven to completion by the hydrolysis of ATP The Acetyl CoA carboxylase is the rate limiting enzyme of the pathway and is under tight short term control. Regulation of Acetyl CoA carboxylase: Positively regulated by: Citrate (allosterically) and dephosphorylation of the enzyme Negatively regulated by: Palmitoyl CoA ( endproduct regulation) and phosphorylation of the enzyme (through glucagon-cAMP cascade) the further steps are catalyzed by enzyme collectively known as fatty acid synthase complex.

13. Assembly of long chain fatty acids Once malonyl-CoA is synthesized, long carbon fatty acid chains may be assembled in a repeating four step sequence With each passage through the cycle the fatty acyl chain is extended by two carbons. When the chain reaches 16 carbons, the product palmitate leaves the cycle.

14. Function of the prosthetic group of the ACP It serves as a flexible arm, tethering the growing fatty acyl chain to the surface of the synthase complex. Carrying the reaction intermediates from one enzyme active site to the next

15. Activation of the acetyl group The acetyl group from acetyl-CoA is transferred to the Cys-SH group of the beta-ketoacyl ACP synthase This reaction is catalyzed by acetyl-CoA transacetylase

16. Activation of malonyl group Transfer of the malonyl group to the SH group of the ACP is catalyzed by malonyl CoA ACP transferase The charged acetyl and malonyl groups are now in close proximity to each other

17. Series of Reactions After activation, the processes involved are :- CONDENSATION REDUCTION DEHYDRATION REDUCTION These steps are repeated till a fatty acid with 16 carbon atoms is synthesized.

18. STEP 1 : CONDENSATION Activated acetyl and malonyl groups condense to form Acetoacetyl-ACP . The reaction is catalyzed by β- ketoacyl-ACP synthase .

19. STEP 2 : REDUCTION Acetoacetyl- ACP is reduced to β -hydroxy butyryl- ACP. The reaction is catalyzed by β -ketoacyl- ACP reductase. NADPH + H+ are required

20. STEP 3 : DEHYDRATION Dehydration yields a double bond in the product, trans- Δ2- butenoyl-ACP Reaction is catalysed by β- hydroxybutyryl-ACP dehydratase

21. STEP4 : REDUCTION Trans- Δ2- butenoyl-ACP is reduced to form Butyryl ACP. The reaction is catalysed by enzyme Enoyl Reductase.

22. Th e g r o win g chai n is t r an s f er r e d f r om the acyl carrier protein This reaction makes way for the next incoming malonyl group. The enzyme involved is acetyl-CoAtransacetylase

23. 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.

24. The result of fatty acyl synthase activity Seven cycles of condensation and reduction produce the 16-carbon saturated palmitoyl group, still bound to ACP. 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 residues of C8, C10 or C12, which are subsequently found in milk lipids.

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