Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Lipid anabolism

2,028 views

Published on

The process of lipid synthesis is described in the slides

Published in: Science
  • Too busy to workout? NO PROBLEM! ONE MINUTE WEIGHT LOSS, CLICK HERE ♣♣♣ http://ishbv.com/1minweight/pdf
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Lipid anabolism

  1. 1. www.utm.my innovative ● entrepreneurial ● global 49 Celullar Biochemistry and Metabolism Metabolic Pathways for Lipids: Fatty Acid Synthesis Dr. Syazwani Itri Amran FBME
  2. 2. www.utm.my innovative ● entrepreneurial ● global 50 FA metabolism Breakdown Synthesis
  3. 3. www.utm.my innovative ● entrepreneurial ● global 51
  4. 4. www.utm.my innovative ● entrepreneurial ● global 52 Revisit fatty acids degradation Category of biochemical reaction Catabolism Anabolism Pathway location Cytosol Mitochondria Type of redox reaction Oxidation Reduction Shuttle mechanism Carnitine shuttle Citrate shuttle Electron carriers NADPH NAD+ / FAD
  5. 5. www.utm.my innovative ● entrepreneurial ● global 53 Excess Prots Excess Carbs Diet LIVER Mammary gland Adipose cells
  6. 6. www.utm.my innovative ● entrepreneurial ● global 54 Fatty acids synthesis ● Reduction process that builds up the hydrocarbon chain of fatty acids utilizing activated acyl unit and malonyl unit ● Occurs in the cytoplasm ● Catalyzed by fatty acid synthase containing 7 catalytic sites ● Incorporates carbon atoms from acetyl CoA into the growing fatty acid chain ●
  7. 7. www.utm.my innovative ● entrepreneurial ● global 55 Fatty acids synthesis ● Reverse process of FA degradation ● Driven by the release of CO2 in a decarboxylation step ● Energetically unfavourable process ● Reduction process involves NADPH ● Extension of fatty acid chain stops at 16C (saturated palmitate) Condensation Reduction Dehydration Reduction
  8. 8. www.utm.my innovative ● entrepreneurial ● global 56 Structure of Fatty acid synthase Acetyl CoA Acetyl CoA Acetyl CoA Acetyl CoA Elongation process occurs by attaching acetyl Co-A on the sulfhydryl group Fatty acid synthase Acyl carrier protein (ACP) -S-H phosphopentethiene -S-HCys
  9. 9. www.utm.my innovative ● entrepreneurial ● global 57 Localization of acetyl CoA into cytosol Activation of acetyl CoA to malonyl CoA Synthesis of fatty acid chain via addition of activated acetyl CoA
  10. 10. www.utm.my innovative ● entrepreneurial ● global 58 Fatty acid synthase Acyl carrier protein (ACP) -S-H phosphopentethiene Acetyl CoA Acetyl CoA Acetyl CoA Acetyl CoA Elongation process occurs by attaching acetyl Co-A on the sulfhydryl group Acetyl CoA Acetyl CoA Mitochondria Cytoplasm Acetyl CoA is synthesized in the matrix of the mitochondria but fatty acids are synthesized in the cytosol. How acetyl CoA is made available in the cytoplasm? -S-HCys Localization of acetyl CoA into cytosol β-oxidation Pyruvate Decarboxylation Ketogenesis Amino acids catabolism
  11. 11. www.utm.my innovative ● entrepreneurial ● global 59 Citrate shuttle : acetyl CoA transporter ● Acetyl CoA (water soluble)  citrate (1st reaction of the TCA cycle) ● In the cytosol, citrate undergo the reverse reaction producing oxaloacetate and acetyl CoA ● If the conditions favor, FA synthesis begins ● [ATP] allosterically inhibits isocitrate dehydrogenase (isocitrate is not converted to α-ketoglutarate & TCA stops) Builds up isocitrate, convert to citrate in the matrix
  12. 12. www.utm.my innovative ● entrepreneurial ● global 60 ● FAs are synthesised in the cytoplasm from acetyl-CoA. ● Acetyl-CoA generated from pyruvate by the action of PDH and β-oxidation of FAs, is in the mitochondria. ● So, acetyl-CoA has to be transported from the mitochondria to the cytoplasm. This is done via a shuttle system called the Citrate shuttle. ● Acetyl-CoA reacts with oxaloacetate to give citrate. A tricarboxylate translocase transports citrate from mitochondria to cytosol. ● In the cytosol, citrate is cleaved back to oxaloacetate and acetyl-CoA. This reaction is catalysed by ATP-citrate lyase and requires the hydrolysis of one molecule of ATP. FA Synthesis Regenerate acetyl CoA in the cytoplasm
  13. 13. www.utm.my innovative ● entrepreneurial ● global 61 For every 1 Acetyl-CoA transported into the cytosol, 1 NADPH results Q: Is that enough NADPH? We’re going to be making Palmitate (16C). So, we need ______ Acetyl-CoA (2C each) 8 Transported Acetyl-CoA ____ NADPH Q: Will that be enough? 2C + 2C + 2C + 2C + 2C + 2C + 2C + 2C A: Yes? No? 8 8 1 2 83 764 5 2 22 2222 = 14 NADPH Covered NOT covered A: The Pentose Phosphate Pathway Q. Where do the other 6 required NADPH molecules comes from?
  14. 14. www.utm.my innovative ● entrepreneurial ● global 62 Pentose Phosphate Pathway ● Another metabolic fate for glucose (other than glycolysis) ● Function of this alternative pathway 1. Synthesis of the coenzyme NADPH needed in lipid biosynthesis 2. Production of ribose 5-phosphate, a pentose derivative needed for the synthesis of nucleic acids and many coenzymes Pentose Phosphate Pathway is the metabolic pathway by which glucose is used to produce NADPH, ribose 5-phosphate (a pentose phosphate), and numerous other sugar phosphates. NADPH  used in anabolic reactions requiring electrons
  15. 15. www.utm.my innovative ● entrepreneurial ● global 63 ● FAs are synthesised in the cytoplasm from acetyl-CoA. ● Acetyl-CoA generated from pyruvate by the action of PDH and β-oxidation of FAs, is in the mitochondria. ● So, acetyl-CoA has to be transported from the mitochondria to the cytoplasm. This is done via a shuttle system called the Citrate shuttle. ● Acetyl-CoA reacts with oxaloacetate to give citrate. A tricarboxylate translocase transports citrate from mitochondria to cytosol. ● In the cytosol, citrate is cleaved back to oxaloacetate and acetyl-CoA. This reaction is catalysed by ATP-citrate lyase and requires the hydrolysis of one molecule of ATP. FA Synthesis Glu NADP+ NADPH Ri-5-P(Pentose Phosphate Pathway)
  16. 16. www.utm.my innovative ● entrepreneurial ● global 64 Localization of acetyl CoA into cytosol Activation of acetyl CoA Synthesis of fatty acid chain via addition of acetyl CoA
  17. 17. www.utm.my innovative ● entrepreneurial ● global 65 Activation of acetyl CoA ● Initiation of fatty acid synthesis ● Formation of malonyl CoA through irreversible carboxylation of acetyl CoA ● A CO2 is attached to acetyl CoA producing a 3C molecule ● Hydrolysis of ATP supply the energy needed to attach the CO2 Mn2+, Biotin
  18. 18. www.utm.my innovative ● entrepreneurial ● global 66 The intermediate: Malonyl-CoA ● Malonyl-CoA is an “activated” form of acetyl-CoA used for fatty acid biosynthesis.
  19. 19. www.utm.my innovative ● entrepreneurial ● global 67 ● Malonyl CoA inhibits CAT1 to prevent the entry of fatty acid into mitochondria carnitine acyltransferase I
  20. 20. www.utm.my innovative ● entrepreneurial ● global 68 Localization of acetyl CoA into cytosol Activation of acetyl CoA Synthesis of fatty acid chain via addition of acetyl CoA
  21. 21. www.utm.my innovative ● entrepreneurial ● global 69 * also bind to propionyl CoA in odd chain FA
  22. 22. www.utm.my innovative ● entrepreneurial ● global 70 Initiation of fatty acid synthesis • Attachment of acetyl group of acetyl CoA onto the sulfhydryl group on phosphopentediene (ACP domain) • Catalyzed by Acetyl transacylase •Release CoA Acetyl Acetyl CoA Acetyl CoA Elongation process occurs by attaching acetyl Co-A on the sulfhydryl group Fatty acid synthase Acyl carrier protein (ACP) -S-H phosphopentethiene -S-HCys CoA-SH Acetyl CoA
  23. 23. www.utm.my innovative ● entrepreneurial ● global 71 Acetyl Initiation of fatty acid synthesis Acetyl CoA Malonyl Acetyl CoA Fatty acid synthase Acyl carrier protein (ACP) -S-H phosphopentethiene -S-HCys CoA-SH •Transfering the acetyl group from phosphopentetiene to Cysteine residue (temporary) •Formation of linkage between malonate group of malonyl CoA and phosphopentediene sulfhydryl group (ACP domain) • Catalyzed by Malonyl transacylase (substrate specific) • Prepares for the elongation of fatty acid chain
  24. 24. www.utm.my innovative ● entrepreneurial ● global 72 Fatty acid synthesis Condensation Reduction Dehydration Reduction
  25. 25. www.utm.my innovative ● entrepreneurial ● global 73 Condensation • Decarboxylation reaction involves cleavage of high energy thioester bond * which supply enough energy to drives the whole reaction forward • The acetyl group moves from cystein residue onto malonate group on ACP • Product : acetoacetyl attached to ACP, CO2 released * Acyl-malonyl ACP condensing enzyme *Nucleophilic attack breaks the thioester bond
  26. 26. www.utm.my innovative ● entrepreneurial ● global 74 Reduction by NADPH • Acetoacetyl is transformed to D-3- hydroxybutyryl by converting the the carbonyl group into alcohol group • Reducing agent : NADPH + H+  NADP+ • Catalyzing enzyme : β-ketoacyl ACP reductase
  27. 27. www.utm.my innovative ● entrepreneurial ● global 75 Dehydration • Removal of hydroxyl group as H2O and formation of C=C • Catalyzed by 3-hydroxyacyl ACP dehydratase D-3-hydroxybutyryl-ACP crotonyl-ACP (Trans-∆2-enoyl )
  28. 28. www.utm.my innovative ● entrepreneurial ● global 76 Reduction by NADPH • Butyryl group is generated on ACP • NADPH reduced the C=C because the ultimate fatty acid chain produced is a saturated fatty acid • This completes the first elongation process containing 4C atoms Enoyl ACP reductase ● This whole cycle takes place 7 times in total to generate a 16C palmitate Butyryl-ACP crotonyl-ACP (Trans-∆2-enoyl )
  29. 29. www.utm.my innovative ● entrepreneurial ● global 77 Restarting the cycle Malonyl Fatty acid synthase Acyl carrier protein (ACP) -S-H phosphopentethiene -S-HCys CoA-SH Butyryl
  30. 30. www.utm.my innovative ● entrepreneurial ● global 78 Cleavage of 16C palmitate from ACP
  31. 31. www.utm.my innovative ● entrepreneurial ● global 79 From the 16C in palmitate, ____ C are from Malonyl-CoA the other ____ C are from __________. 14 2 Acetyl-CoA
  32. 32. www.utm.my innovative ● entrepreneurial ● global 80 THE END

×