Fatty Acid Synthesis Lecture Notes PDF

Fatty Acid Synthesis lipogenesis  It is the synthesis of TAGs mainly from carbohydrates , from fatty acid “ acyl COA” and glycerol “glycerol-3-P”.  Steps : 1) Biosynthesis of fatty acid 2) Activation of fatty acid 3) Biothynthesis of glycerol-3-P 4) Compination of 2) & 3) to form TAGs  B...

Fatty Acid Synthesis lipogenesis  It is the synthesis of TAGs mainly from carbohydrates , from fatty acid “ acyl COA” and glycerol “glycerol-3-P”.  Steps : 1) Biosynthesis of fatty acid 2) Activation of fatty acid 3) Biothynthesis of glycerol-3-P 4) Compination of 2) & 3) to form TAGs  Biosynthesis of fatty acid: There are three systems for the synthesis of fatty acids 1. De novo synthesis of FAs in cytoplasm 2. Chain elongation in mitochondria 3. Chain elongation in microsomes  De novo synthesis of FA  Opposite of beta oxidation in the sense that 2-carbon acetate units are linked to form even-chain, saturated fatty acids  Differs from Fatty acid degradation  In cytoplasm.  Acyl carrier protein rather than CoA  Enzymes linked in a complex  Utilizes NADPH  Unique pathways (unlike glycolysis/ gluconeogenesis) De novo synthesis of FAs  In mammals fatty acid synthesis occurs primarily in the cytosol of the liver and adipose tissues.It also occurs in mammary glands during lactation.  Uses acetyl-CoA, NADPH as starting material  Produces a pool of palmitic acid (16c) that can be further modified  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).  ACETYL CoA sources carbohydrates glucose fats glycogen glycolysis proteins pyruvate fatty acids amino acids oxidation fatty acid oxidation acetyl-CoA fatty acid synthesis citric acid cycle CO2 + energy Glucose in excess of metabolic needs results in fat deposition  SOURCES OF ACETYL CoA  Three metabolic reactions of food components produce acetyl CoA Glycolysis of glucose Oxidation of fatty acids Amino acid deamination  Each can act as a source of Acetyl-CoA  Acetyl-CoA is oxidised in the citric acid (Krebs) cycle producing energy  1-Acetyl coA from charbohydrates Excess carbs are transported to cytosol as citrate  2-Acetyl coA from protein Amino acid degradation leads to acetyl-CoA or citrate Citrate is transported to cytosol Net result is acetyl-CoA in cytosol  3- Acetyl coA from lipids The end product of oxidation of fatty acids is acetyl coA  Continue.. acetyl-CoA must be transferred from the mitochondria to the cytosol BUT Mitochondria not permeable to acetyl CoA  - Thus acetyl CoA condenses with oxaloacetate to form citrate which can pass out the mitochondrial membrane.  - In the cytoplasm, citrate is splitted again by ATP-citrate lyase enzyme into acetyl CoA and oxaloacetate. -Oxaloacetate which cannot cross the mitochondrial inner membrane is converted to malate. -Malate then may be: * exchanged for citrate to enhance fatty acid synthesis *or it is converted to pyruvate by a reaction which is catalyzed by malic enzyme. This enzyme acts on malic acid producing NADPH + H+ which is essential for fatty acid synthesis.  Sources of NADPH.H Pentose shunt ( HMP) Malic enzyme UDP-glucose dehydrogenase Cytoplasmic isocitrate dehydrogenase NAD/NADP transhydrogenase Glutamate dehydrogenase  Enzymes required for FA synthesis 1-acetyl-coA carboxylase  Is the committed step in fatty acid synthesis (Rate Limiting Reaction) 2-Fatty acid synthase  It is a multi-enzyme complex consist of 7 enzymes linked covalently in a single polypeptide chain.  It is a dimer, and each monomer is identical, consisting of one chain containing all seven enzyme activities of fatty acid synthase and an acyl carrier protein (ACP)  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 Steps of Extramitochondrial Pathway: De novo synthesis of FAs  4 Steps repeating cycle, extension 2C:  Condensation  Reduction  Dehydration  Additional reduction The rate limiting step is formation of malonyl CoA  Regulation of FA Synthesis  Allosteric regulation Acetyl CoA carboxylase, which catalyzes the first step in fatty acid synthesis, is a key control site. Activated by citrate, which increases in well-fed state and is an indicator of a plentiful supply of acetyl-CoA Inhibited by long-chain acyl- CoA  Hormonal Regulation of FA Synthesis  Acetyl CoA cayboxylase is activated by dephosphorylation and inactivated by phosphorylation (covalent modification)  Glucagon inhibits fatty acid synthesis while increasing lipid breakdown and fatty acid β-oxidation.  Insulin obosite action of glucagon  Inhibits lipases/activates acetyl Co A cayboxylase as insulin leads to dephosphorylation of acetyl CoA carboxylase enzyme and hence its activation. Fate of palmitate  Estrefication Elongation Desaturation Additional Elongation In mammalian systems FA elongation can occur either in : Microsomes Mitochondria Chain Elongation in Microsomes  The reactions are similar to that which occurs in the cytosolic FA synthase in that: a) The source of the 2 carbon units is malonyl CoA. b) NADPH is used as reducing power.  It is the main site for elongation of existing long chain FAs molecules.  Function: This system becomes active during myelination of the nerve in order to provide C22 and C24 fatty acids that are present in sphingolipids. Chain Elongation in Microsomes  Chain Elongation in Mitochondria  It differs from the microsomal system in that acetyl CoA is the source of the added 2C atoms (instead of malonyl CoA)  NADH and NADPH are sources of reducing agents  This system operate by simple reversal of the pathway of FA oxidation with the exception that, Condensation of acetyl CoA with acyl CoA replaces thiolase & NADPH-linked α,β-unsaturated acyl CoA reductase replaces FAD linked acyl CoA dehydrogenase.  Function: - This system utilizes NADH+H+ it will act only when there is high NADH+H+/NAD+ ratio that occurs under anaerobic conditions. - Thus the cells can get rid off excess NADH+H+. Chain Elongation in Mitochondria Biosynthesis of Unsaturated Fatty Acids  Desaturases introduce double bonds at specific positions in a fatty acid chain.  Mammalian cells are unable to produce double bonds at certain locations, e.g., ∆ 12.  Thus some polyunsaturated fatty acids are dietary essentials, e.g., linoleic acid, 18:2 cis ∆ 9,12 (18 C atoms long, with cis double bonds at carbons 9-10 & 12-13)  Biosynthesis of triacylglycerols  Both glycerol and Fatty acids must be activated by ATP before they can be incorporated into Acylglycerols.  It occurs mainly in microsomes of tissues as liver, kidney, intestine, adipose tissues and lactating mammary gland.  Activation of glycerol: In muscle or adipose tissue; Glycerol kinase enzyme is absent or low in activity so most of the glycerol 3- phosphate must be derived from an intermediate of the glycolytic system, (dihydroxy acetone phosphate), which forms glycerol-3-phosphate by reduction with NADH catalyzed by glycerol-3-phosphate dehydrogenase. Activation of Fatty Acids: Synthesis of triacylglycerols: