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Essential Insights on Fatty Acid Synthesis in Mammals

Learn about the key differences between fatty acid breakdown and biosynthesis, the role of enzymes, regulation mechanisms, and the steps involved in fatty acid synthesis. Explore how acetyl-CoA is converted into fatty acids in the cytosol and the crucial regulatory factors affecting this process.

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Essential Insights on Fatty Acid Synthesis in Mammals

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  1. Fatty acid Synthesis

  2. Fatty Acid Synthesis • In mammals fatty acid synthesis occurs primarily in the liver and adipose tissues • Also occurs in mammary glands during lactation. • Fatty acid synthesis and degradation go by different routes • There are four major differences between fatty acid breakdown and biosynthesis

  3. The differences between fatty acid biosynthesis and breakdown • Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA) • Synthesis in cytosol; breakdown in mitochondria • Enzymes of synthesis are one polypeptide • Biosynthesis uses NADPH/NADP+; breakdown uses NADH/NAD+

  4. ACP vs. Coenzyme A • Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)

  5. Citrate Lyase Citrate synthase Malate dehydrogenase Pyruvate carboxylase Malate Enzyme Fatty Acid Synthesis Occurs in the Cytosol • Must have source of acetyl-CoA • Most acetyl-CoA in mitochondria • Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis

  6. Fatty Acid Synthesis • Fatty acids are built from 2-C units derived from acetyl-CoA • Acetate units are activated for transfer to growing FA chain by conversion to malonyl-CoA • Decarboxylation of malonyl-CoA and reducing power of NADPH drive chain growth • Chain grows to 16-carbons (eight acetyl-CoAs) • Other enzymes add double bonds and more Cs

  7. Acetyl-CoA Carboxylase Acetyl-CoA + HCO3- + ATP  malonyl-CoA + ADP • The "ACC enzyme" commits acetate to fatty acid synthesis • Carboxylation of acetyl-CoA to form malonyl-CoA is the irreversible, committed step in fatty acid biosynthesis

  8. Acetyl-CoACarboxylase

  9. Regulation of Acetyl-CoA Carboxylase (ACCase) • ACCase forms long, active filamentous polymers from inactive protomers • Accumulation of palmitoyl-CoA (product) leads to the formation of inactive polymers • Accumulation of citrate leads to the formation of the active polymeric form • Phosphorylation modulates citrate activation and palmitoyl-CoA inhibition

  10. Regulation of Acetyl-CoA Carboxylase (ACCase) • Unphosphorylated ACCase has low Km for citrate and is active at low citrate • Unphosphorylated ACCase has high Ki for palmitoyl-CoA and needs high palmitoyl-CoA to inhibit • Phosphorylated E has high Km for citrate and needs high citrate to activate • Phosphorylated E has low Ki for palmitoyl-CoA and is inhibited at low palmitoyl-CoA

  11. Fatty Acid Synthesis • Step 1: Loading – transferring acetyl- and malonyl- groups from CoA to ACP • Step 2: Condensation – transferring 2 carbon unit from malonyl-ACP to acetyl-ACP to form 2 carbon keto-acyl-ACP • Step 3: Reduction – conversion of keto-acyl-ACP to hydroxyacyl-ACP (uses NADPH) • Step 4: Dehydration – Elimination of H2O to form Enoyl-ACP • Step 5: Reduction – Reduce double bond to form 4 carbon fully saturated acyl-ACP

  12. Step 1: Loading Reactions

  13. Step 2: Condensation Rxn

  14. Step 3: Reduction

  15. Step 4: Dehydration

  16. Step 5: Reduction

  17. Step 6: next condensation

  18. Termination of Fatty Acid Synthesis Acyl-CoA synthetase

  19. Organization of Fatty Acid Synthesis Enzymes • In bacteria and plants, the fatty acid synthesis reactions are catalyzed individual soluble enzymes. • In animals, the fatty acid synthesis reactions are all present on multifunctional polypeptide. • The animal fatty acid synthase is a homodimer of two identical 250 kD polypeptides.

  20. Animal Fatty Acid Synthase

  21. Further Processing of Fatty acids: Desaturation and Elongation

  22. Regulation of FA Synthesis • Allosteric modifiers, phosphorylation and hormones • Malonyl-CoA blocks the carnitine acyltransferase and thus inhibits beta-oxidation • Citrate activates acetyl-CoA carboxylase • Fatty acyl-CoAs inhibit acetyl-CoA carboxylase • Hormones regulate ACC • Glucagon activates lipases/inhibits ACC • Insulin inhibits lipases/activates ACC

  23. Allosteric regulation of fatty acid synthesis occurs at ACCase and the carnitine acyltransferase

  24. Glucagon inhibits fatty acid synthesis while increasing lipid breakdown and fatty acid b-oxidation Insulin prevents action of glucagon

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