Fatty acid synthesis ( Lipogenesis & Lipolysis )

1. Fatty acid synthesis(Lipogenesis &Lipolysis)

2. Lipogenesis • It can be divided into 3 processes: • Biosynthesis of glycerol. • Biosynthesis of fatty acids. • Biosynthesis of the triacylglycerol. • It occurs in most tissues especially adipose tissue, liver, lactating mammary gland and brain.

3. Biosynthesis of glycerol • Glucose is oxidized via glycolysis to dihydroxy acetone phosphate reduced to glycerol-3 phosphate by the enzyme glycerol-3 phosphate dehydrogenase.

4. Biosynthesis of fatty acids • Glucose is oxidized via glycolysis to pyruvic which undergoes oxidative decarboxylation, forming acetyl-CoA (building block of fatty acid synthesis).

5. Intracellular site of FA synthesis • Fatty acids synthesis may occur in the following: • Cytoplasmic (Extramitochondrial) FA synthesis. • Microsomal FA synthesis. • Mitochondrial FA synthesis.

6. Cytoplasmic (Extramitochondrial) FA synthesis. • This is the only system responsible for de novo synthesis of FA from active acetate. • Free palmitate is the main product.

7. Site: Many tissues, especially liver, kidney, brain, lung, lactating mammary gland and adipose tissue. • Source of acetyl-CoA Acetyl-CoA, the main building block for FA synthesis is formed from carbohydrate via oxidation of pyruvate within mitochondria.

10. Translocation of acetyl-CoA from mitochondria to cytoplasm • Step 1:Acetyl-CoA, formed from pyruvate within mitochondria, does not diffuse readily to cytoplasm (principle site for FA synthesis). • Step 2 :Translocation of acetyl CoAfrom mitochondria to the cytoplasm involves condensation with oxalacetate to form citrate which can pass out mitochondrial membrane.

12. Step 3: In cytoplasm :citrate splits again by ATP citrate lyaseenzyme into acetyl-CoAandoxalacetate.

13. Step 4: Acetyl CoAis converted to malonylCoA, an important intermediate in fatty acid synthesis, by acetyl CoAcarboxylasethat consumes ATP and requires biotin as a cofactor.

14. Step 5: malonylCoAis converted to fatty acid By Fatty acid synthase Palmitate, a 16-carbon saturated fatty acid, is the final product of fatty acid synthesis.

16. Step 6: OAA is converted to malate. Step 7: Malate is converted to pyruvateby malic enzyme, producing 1 NADPH. • NADPH is required for synthesis of palmitate and elongation of fatty acids. • NADPH is produced in the cytosol by both malic enzyme and the pentose phosphate pathway, which is the primary source.

18. Fatty acid synthase complex Fatty acid synthase, a large multifunctional enzyme complex, initiates and elongates the fatty acid chain in a cyclical reaction sequence. • This complex is a dimer i.e. formed of 2 polypeptide chains (2 subunits). • Each monomer contains all 7 enzymes of FA synthetase. • Acylradicle is found in combination with a protein called acyl carrier protein (ACP).

19. At the center is the ACP – acyl carrier protein - with its phosphopantetheine arm ending in –SH. • In close proximity is another SH group of B-ketoacylsynthase (condensing enzyme) of other monomer

20. synthesis of palmitate Palmitate, a 16-carbon saturated fatty acid, is the final product of fatty acid synthesis. • may be assembledin a repeating four-step sequence

21. The first round of FA biosynthesis • To initiate FA biosynthesis, malonyl and acetyl groups are activated on to the enzyme fatty acid synthase.

22. Step 1. • Condensation of an activated acyl group and two carbons derived from malonyl-CoA

23. Step 2. • The b-keto group is reduced to an alcohol by NADPH

24. Step 3. • The elimination of water creates a double bond.

25. Step 4. • The double bond is reduced to form the corresponding saturated fatty acyl group.

26. Repetition of these four steps leads to fatty acid synthesis • When reaches 16 carbons, the product leaves the cycle. • All the reactions in the synthetic process are catalyzed by a multi-enzyme complex, fatty acid synthase.

27. 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.

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

29. Part 1. • First, the formation of seven malonyl-CoA molecules: 7Acetyl-CoA + 7CO2 + 7ATP 7malonyl-CoA + 7ADP + 7Pi

30. 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.

31. The synthesis of long chain FA (Lipogenesis) is carried out by 2 enzyme system present in cytoplasm of the cell: • Acetyl CoAcarboxyalse. • FA synthase complex. • One glucose produces 2 acetyl CoA, and each acetyl CoA contains 2 carbons; therefore, four glucose molecules are required to produce the 16 carbons of palmitic acid.

32. LIPOLYSIS • Adipose cells are specialized for synthesis and storage of TG. • LIPOLYSIS complete hydorlysis of triglyceride yeild gelycerol and 3 fatty acids.

33. The hydrolysis of TGis done by 3 tissue lipases: • Hormone sensitive lipase initiates the process of lipolysis in the adipose tissue and is controlled by cAMP • Diacylglycerol lipase. • Monoacylglycerol lipase. • Diacylglycerol and monoacylglycerol lipases rapidly complete the hydrolysis of di and monoacylglycerols releasing free fatty acids and glycerol

34. The activity of hormone sensitive lipase in the adipose cells is regulated by different hormones. • Glucagon, Epinephrine, norepinepherineand aderenocorticotropic hormones stimulate lipolysis activate adenylatecyclase. increased production of cAMP

35. activates protein KinaseA subsequently activates lipases found in adipose tissue. • After lipolysis glycerol and free fatty acids diffuse through the plasma membrane and enters the blood stream.