1. Chapter 16 (Part 3)
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. 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
Citrate synthase
Citrate Lyase
Malate
dehydrogenase
Malate Enzyme
Pyruvate
carboxylase

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-CoA Carboxylase

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