lipid biosynthesis n.
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  1. LIPID BIOSYNTHESIS • Fatty acid biosynthesis-basic fundamentals • Fatty acid biosynthesis-elongation and desaturation • Triacylglycerols • Phospholipids • Cholesterol • Cholesterol metabolism

  2. Cytosol Requires NADPH Acyl carrier protein D-isomer CO2 activation Keto  saturated Mitochondria NADH, FADH2 CoA L-isomer No CO2 Saturated  keto Fatty Acid Biosynthesis Synthesis Beta Oxidation

  3. Rule: Fatty acid biosynthesis is a stepwise assembly of acetyl-CoA units (mostly as malonyl-CoA) ending with palmitate (C16 saturated) 3 Phases Activation Elongation Termination

  4. Cofactor CH3C~SCoA O O ATP HCO3- ADP + Pi CO2 -OOC-CH2C~SCoA active carbon Biocytin ACTIVATION Biotin Acetyl-CoA carboxylase Carboxybiocytin

  5. Acetyl-CoA CarboxylaseThe rate-controlling enzyme of FA synthesis • In Bacteria -3 proteins (1) Carrier protein with Biotin (2) Biotin carboxylase (3) Transcarboxylase • In Eukaryotes - 1 protein (1) Single protein, 2 identical polypeptide chains • (2) Each chain Mwt = 230,000 (230 kDa) (3) Dimer inactive (4) Activated by citrate which forms filamentous form of protein that can be seen in the electron microscope

  6. Yeast Fatty Acid Synthase Complex 2,500 kDa Multienzyme Complex 6 molecules of 2 peptide chains called A and B (66) A: (185,000) Acyl Carrier protein -ketoacyl-ACP synthase (condensing enzyme) -ketoacyl-ACP reductase B: (175,000) -hydroxy-ACP dehydrase enoyl-ACP reductase palmitoyl thioesterase Fatty Acid Synthase Complex

  7. H CH3 H HO O ACP HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser- O O O H H H CH3 H HO O O HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2 Adenine O O O O O H H H O OH O-P-O OH Acyl Carrier Protein Phosphopantetheine Cysteamine Acyl carrier protein 10 kDa Coenzyme A

  8. Initiation CH3C~SCoA CH3C- ACP ACP + HS-CoA O O O O -OOC-CH2C~S- CH2C~S- Overall Reaction Malonyl-CoA + ACP Acyl Carrier Protein CO2 HS-CoA NOTE: Malonyl-CoA carbons become new COOH end Nascent chain remains tethered to ACP CO2, HS-CoA are released at each condensation

  9. -Carbon CH3C- ACP ACP ACP O O O O O H D isomer CH3C- HO H CH2C~S- = C- C~S- CH2C~S- CH3C- H CH3CH2CH2C~S- ACP Elongation Reduction NADPH -Ketoacyl-ACP reductase Dehydration -H2O  -Hydroxyacyl-ACP dehydrase NADPH Reduction Enoyl-ACP reductase

  10. O Free to bind Malonyl-CoA -CH2CH2CH2C~S- ACP TERMINATION Ketoacyl ACP Synthase -KS Transfer to Malonyl-CoA Transfer to KS -S-ACP Split out CO2 CO2 When C16 stage is reached, instead of transferring to KS, the transfer is to H2O and the fatty acid is released

  11. O O O CH3-CH -CH2-C-S CH3-CH2-CH2-C-S S-C-CH2-CH2-CH3 Acetyl-CoA -SH -SH S HS CoA-SH C=O KS KS KS KS KS CH2 NADP+ O C=O NADPH H+ CH3-CH=CH-C-S CH3 O O OH -C-CH3 SH Malonyl-CoA S-C-CH3 ACP O CoA-SH -C-CH2-COO- S NADP+ NADPH H+ S Fatty Acid Synthase -Ketoacyl -ACP synthase Acetyl-CoA- ACP transacylase Initiation or priming Enoyl-ACP reductase -Hydroxyacyl-ACP dehydrase H2O Malonyl-CoA- ACP transacylase -Keto-ACP synthase (condensing enzyme) CO2 -Ketoacyl -ACP reductase Elongation

  12. Reduction Thioesterase palmitate release Substrate Entry AT MT DH KR ACP ER CE TE CH2 SH Translocation SH HS HS Translocation CH2 CE TE ER DH ACP KR MT AT Thioesterase palmitate release Reduction Substrate Entry

  13. Acetyl-CoA + 7 malonyl-CoA + 14NADPH + 14H+ Palmitate + 7CO2 + 14NADP+ + 8 HSCoA + 6H2O 7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA +7ADP + 7Pi + 7H+ 8 Acetyl-CoA + 14NADPH + 7H+ + 7ATP Palmitate + 14NADP+ + 8 HSCoA + 6H2O + 7ADP + 7Pi Overall Reactions 7H+

  14. acetyl-CoA PROBLEM: Fatty acid biosynthesis takes place in the cytosol. Acetyl-CoA is mainly in the Mitochondria How is acetyl-CoA made available to the cytosolic fatty acyl synthase? SOLUTION: Acetyl-CoA is delivered to cytosol from the mitochondria as CITRATE

  15. HS-CoA COO COO CH2 CH2 HO-C-COO HO-C-COO COO C=O CH2 CH2 COO COO CH2 COO Acetyl-CoA COO CO2 HO-C-H CH2 CO2 COO COO C=O NADP+ CH3 NADPH + H+ Acetyl-CoA mitochondria Citrate lyase OAA Malate dehydrogenase NADH L-malate L-malate Malic enzyme OAA Cytosol Pyr Pyruvate

  16. Post-Synthesis Modifications • C16 satd fatty acid (Palmitate) is the product • Elongation • Unsaturation • Incorporation into triacylglycerols • Incorporation into acylglycerol phosphates

  17. HS-CoA R-CH2CH2CH2C~SCoA OOC-CH2C~SCoA O O CO2 CH3C~SCoA O 3 2 1 R-CH2CH2CH2CCH2C~SCoA O O NADPH NADH - H2O NADPH R-CH2CH2CH2CH2CH2C~SCoA O Elongation of Chain (two systems) Malonyl-CoA* (cytosol) Acetyl-CoA (mitochondria) Elongation systems are found in smooth ER and mitochondria

  18. Desaturation Rules: The fatty acid desaturation system is in the smooth membranes of the endoplasmic reticulum There are 4 fatty acyl desaturase enzymes in mammals designated 9 , 6, 5, and 4 fatty acyl-CoA desaturase Mammals cannot incorporate a double bond beyond 9; plants can. Mammals can synthesize long chain unsaturated fatty acids using desaturation and elongation

  19. Rule: 2 2 3 1 The Desaturase System requires O2 and resembles an electron transport system Cyt b5 reductase NADH Cyt b5 O2 (FAD) Saturated FA-CoA NOTE: 1. System is in ER membrane 2. Both NADH and the fatty acid contribute electrons 3. Fatty acyl desaturase is considered a mixed function oxidase

  20. Fatty acid desaturation system C18-stearoly-CoA + O2 + 2H+ C189-oleyl-CoA + 2H2O Desaturase Desaturase 2 cyt b5 Fe2+ 2 cyt b5 Fe2+ Cyt b5 2H+ + cyt b5 reductase FAD cyt b5 reductase FADH2 Cyt b5 reductase NADH + H+ NAD+

  21. Palmitate Desaturase 16:0 Elongase Palmitoleate Stearate 16:1(9) 18:0 Permitted transitions in mammals Desaturase Oleate 18:1(9) Essential fatty acid Desaturase Linoleate Desaturase 18:2(9,12) -Linolenate Desaturase -Linolenate 18:3(6,9,12) 18:3(9,12,15) Elongase Eicosatrienoate 20:3(8,11,14) Desaturase Other lipids Arachidonate 20:4(5,8,11,14)